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Controversies in cardiovascular care: silent myocardial ischemia
NASA Technical Reports Server (NTRS)
Hollenberg, N. K.
The objective evidence of silent myocardial ischemia--ischemia in the absence of classical chest pain--includes ST-segment shifts (usually depression), momentary left ventricular failure, and perfusion defects on scintigraphic studies. Assessment of angina patients with 24-hour ambulatory monitoring may uncover episodes of silent ischemia, the existence of which may give important information regarding prognosis and may help structure a more effective therapeutic regimen. The emerging recognition of silent ischemia as a significant clinical entity may eventually result in an expansion of current therapy--not only to ameliorate chest pain, but to minimize or eliminate ischemia in the absence of chest pain.
Myocardial perfusion imaging for detection of silent myocardial ischemia
Beller, G.A.
Despite the widespread use of the exercise stress test in diagnosing asymptomatic myocardial ischemia, exercise radionuclide imaging remains useful for detecting silent ischemia in numerous patient populations, including those who are totally asymptomatic, those who have chronic stable angina, those who have recovered from an episode of unstable angina or an uncomplicated myocardial infarction, and those who have undergone angioplasty or received thrombolytic therapy. Studies show that thallium scintigraphy is more sensitive than exercise electrocardiography in detecting ischemia, i.e., in part, because perfusion defects occur more frequently than ST depression and before angina in the ischemic cascade. Thallium-201 scintigraphy can be performed to differentiate a true- from a false-positive exercise electrocardiographic test in patients with exercise-induced ST depression and no angina. The development of technetium-labeled isonitriles may improve the accuracy of myocardial perfusion imaging. 11 references.
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Incidence of acute myocardial infarction in patients with exercise-induced silent myocardial ischemia
Assey, M.E.; Walters, G.L.; Hendrix, G.H.; Carabello, B.A.; Usher, B.W.; Spann, J.F. Jr.
Fifty-five patients with angiographically proved coronary artery disease (CAD) underwent Bruce protocol exercise stress testing with thallium-201 imaging. Twenty-seven patients (group I) showed myocardial hypoperfusion without angina pectoris during stress, which normalized at rest, and 28 patients (group II) had a similar pattern of reversible myocardial hypoperfusion but also had angina during stress. Patients were followed for at least 30 months. Six patients in group I had an acute myocardial infarction (AMI), 3 of whom died, and only 1 patient in group II had an AMI (p = 0.05), and did not die. Silent myocardial ischemia uncovered during exercise stress thallium testing may predispose to subsequent AMI. The presence of silent myocardial ischemia identified in this manner is of prognostic value, independent of angiographic variables such as extent of CAD and left ventricular ejection fraction.
Cardiovascular risk evaluation and prevalence of silent myocardial ischemia in subjects with asymptomatic carotid artery disease
Ciccone, Marco Matteo; Niccoli-Asabella, Artor; Scicchitano, Pietro; Gesualdo, Michele; Notaristefano, Antonio; Chieppa, Domenico; Carbonara, Santa; Ricci, Gabriella; Sassara, Marco; Altini, Corinna; Quistelli, Giovanni; Lepera, Mario Erminio; Favale, Stefano; Rubini, Giuseppe
Introduction: Silent ischemia is an asymptomatic form of myocardial ischemia, not associated with angina or anginal equivalent symptoms, which can be demonstrated by changes in ECG, left ventricular function, myocardial perfusion, and metabolism. The aim of this study was to evaluate the prevalence of silent myocardial ischemia in a group of patients with asymptomatic carotid stenosis. Methods: A total of 37 patients with asymptomatic carotid plaques, without chest pain or dyspnea, was investigated. These patients were studied for age, sex, hypertension, diabetes, dyslipidemia, smoking, and family history of cardiac disease, and underwent technetium-99 m sestamibi myocardial stress-rest scintigraphy and echo-color Doppler examination of carotid arteries. Results: A statistically significant relationship (P = 0.023) was shown between positive responders and negative responders to scintigraphy test when both were tested for degree of stenosis. This relationship is surprising in view of the small number of patients in our sample. Individuals who had a positive scintigraphy test had a mean stenosis degree of 35% ± 7% compared with a mean of 44% ± 13% for those with a negative test. Specificity of our detection was 81%, with positive and negative predictive values of 60% and 63%, respectively. Conclusion: The present study confirms that carotid atherosclerosis is associated with coronary atherosclerosis and highlights the importance of screening for ischemic heart disease in patients with asymptomatic carotid plaques, considering eventually plaque morphology (symmetry, composition, eccentricity or concentricity of the plaque, etc) for patient stratification. PMID:21468172
Prevalence of and variables associated with silent myocardial ischemia on exercise thallium-201 stress testing
Gasperetti, C.M.; Burwell, L.R.; Beller, G.A. )
The prevalence of silent myocardial ischemia was prospectively assessed in a group of 103 consecutive patients (mean age 59 +/- 10 years, 79% male) undergoing symptom-limited exercise thallium-201 scintigraphy. Variables that best correlated with the occurrence of painless ischemia by quantitative scintigraphic criteria were examined. Fifty-nine patients (57%) had no angina on exercise testing. A significantly greater percent of patients with silent ischemia than of patients with angina had a recent myocardial infarction (31% versus 7%, p less than 0.01), had no prior angina (91% versus 64%, p less than 0.01), had dyspnea as an exercise test end point (56% versus 35%, p less than 0.05) and exhibited redistribution defects in the supply regions of the right and circumflex coronary arteries (50% versus 35%, p less than 0.05). The group with exercise angina had more ST depression (64% versus 41%, p less than 0.05) and more patients with four or more redistribution defects. However, there was no difference between the two groups with respect to mean total thallium-201 perfusion score, number of redistribution defects per patient, multi-vessel thallium redistribution pattern or extent of angiographic coronary artery disease. There was also no difference between the silent ischemia and angina groups with respect to antianginal drug usage, prevalence of diabetes mellitus, exercise duration, peak exercise heart rate, peak work load, peak double (rate-pressure) product and percent of patients achieving greater than or equal to 85% of maximal predicted heart rate for age. Thus, in this study group, there was a rather high prevalence rate of silent ischemia (57%) by exercise thallium-201 criteria.
Silent myocardial ischemia and infarction in diabetics with peripheral vascular disease: Assessment by dipyridamole thallium-201 scintigraphy
Nesto, R.W.; Watson, F.S.; Kowalchuk, G.J.; Zarich, S.W.; Hill, T.; Lewis, S.M.; Lane, S.E. )
We investigated the incidence of silent myocardial ischemia and infarction as assessed by dipyridamole thallium scintigraphy in 30 diabetic patients with peripheral vascular disease and without clinical suspicion of coronary artery disease. Seventeen patients (57%) had thallium abnormalities, with reversible thallium defects compatible with ischemia in 14 patients (47%) and evidence of prior, clinically silent myocardial infarction in 11 patients (37%). Thallium abnormalities were most frequent in patients with concomitant hypertension and cigarette smoking (p = 0.001). These results suggest that unsuspected coronary artery disease is common in this particular group of patients with diabetes mellitus.
Prognostic importance of silent myocardial ischemia detected by intravenous dipyridamole thallium myocardial imaging in asymptomatic patients with coronary artery disease
Younis, L.T.; Byers, S.; Shaw, L.; Barth, G.; Goodgold, H.; Chaitman, B.R. )
One hundred seven asymptomatic patients who underwent intravenous dipyridamole thallium imaging were evaluated to determine prognostic indicators of subsequent cardiac events over an average follow-up period of 14 +/- 10 months. Univariate analysis of 18 clinical, scintigraphic and angiographic variables revealed that a reversible thallium defect, a combined fixed and reversible thallium defect, number of segmental thallium defects and extent of coronary artery disease were significant predictors of subsequent cardiac events. Of the 13 patients who died or had a nonfatal infarction, 12 had a reversible thallium defect. Stepwise logistic regression analysis selected a reversible thallium defect as the only significant predictor of cardiac events. When death or myocardial infarction was the outcome variable, a combined fixed and reversible thallium defect was the only predictor of outcome. In patients without previous myocardial infarction, the cardiac event rate was significantly greater in those with an abnormal versus normal thallium scan (55% versus 12%, p less than 0.001). Thus, intravenous dipyridamole thallium scintigraphy is a useful noninvasive test to risk stratify asymptomatic patients with coronary artery disease. A reversible thallium defect most likely indicates silent myocardial ischemia in a sizable fraction of patients in this clinical subset and is associated with an unfavorable prognosis.
The Frequency and Significance of Silent Myocardial Ischemia Due to Hyoscine Butylbromide Use in Peripheral Angiography
Maher, Richard; Phillips-Hughes, Jane; Banning, Adrian; Boardman, Philip
Purpose: Hyoscine-N-butylbromide (HB) is an anticholinergic drug used in digital subtraction angiography of the aortoiliac region because it decreases bowel gas movement artifact. HB also causes an increase in heart rate. We investigated whether this could cause silent myocardial ischemia (SMI) in susceptible patients during peripheral angiography. Methods: Thirty-six patients undergoing peripheral angiography were randomized into two groups, with 17 patients receiving 20 mg HB intraarterially during the angiogram and 19 patients receiving no drug. All patients were fitted with a Holter monitor that recorded the electrocardiogram before, during, and after the angiogram. Heart rate trends and ST segments were then analyzed. Results: Patients given HB had a statistically significant rise in heart rate compared with the control group. Although the difference was not statistically significant, two (12%) patients receiving HB had procedural ST depression compared with none in the control group. Pre- and postprocedural episodes of ST depression were common, occurring in 41% of patients receiving HB and 37% of patients receiving no drug, and were associated with an increase in heart rate. Conclusion: The infrequent episodes of procedural SMI, potentially caused by the positive chronotropic effects of HB, are probably insignificant when compared with the high frequency of SMI episodes occurring outside the procedure.
Clinical characteristics of silent myocardial ischemia diagnosed with adenosine stress 99mTc-tetrofosmin myocardial scintigraphy in Japanese patients with acute cerebral infarction.
Nomura, Tetsuya; Kusaba, Tetsuro; Kodama, Naotoshi; Terada, Kensuke; Urakabe, Yota; Nishikawa, Susumu; Keira, Natsuya; Matsubara, Hiroaki; Tatsumi, Tetsuya
It is well known that silent myocardial ischemia (SMI) often complicates patients with cerebral infarction and that stroke patients often die of ischemic heart disease. Therefore, it is considered important to treat myocardial ischemia in stroke patients. This study investigated SMI complicating Japanese patients with fresh stroke, using (99m)Tc-tetrofosmin myocardial scintigraphy with pharmacologic stress testing to elucidate their clinical manifestations. This study included 41 patients (26 men, mean age 76.0 ± 10.7 years) with acute cerebral infarction and no history of coronary artery disease. All patients underwent (99m)Tc-tetrofosmin myocardial scintigraphy with intravenous administration of adenosine to diagnose SMI. Of the 41 patients, myocardial ischemia was confirmed in 17 patients (41.5%). Atherosclerotic etiology was the major cause of stroke in the ischemia(+) group and embolic origin was the major cause in the ischemia(-) group. Patients with myocardial ischemia had a higher incidence of diabetes mellitus (52.9 vs 20.8%; P = 0.0323) and more than two conventional cardiovascular risk factors (64.7 vs 25.0%; P = 0.0110) compared with the nonischemic patients. Infarction subtype of atherosclerotic origin was an independent positive predictor of asymptomatic myocardial ischemia in patients with stroke. These findings indicate that the prevalence of asymptomatic myocardial ischemia is relatively high, especially in patients with stroke of atherosclerotic origin. Therefore, it is beneficial for us to narrow the target population who are at the highest risk when screening for SMI in Japanese patients with acute cerebral infarction. PMID:22124530
[Cross-country and downhill skiing in patients with myocardial infarct. Can silent ischemia be prevented by drug therapy?].
Völker, K; Hoppe, B; Krestin, M; Rost, R
The appearance of ST segment depression in the exercise ECG serves as a threshold criterion when it comes to determining the "loadability" of myocardial infarction patients carrying out sports activities. In 27 MI patients, the question was investigated as to the extent to which abnormalities taking the form of silent ischemic episodes could be found during cross-country skiing on plains or during downhill skiing at an altitude of 800 to 2,000 meters. Such silent ischemic attacks were found in 20 out of the 27 patients. Both the duration and incidence were higher during sports activities than during normal day-to-day activities. The heart rate at the time of the appearance of the ischemic episodes was lower in the 12-hour ECG than during ergometry. During sports activities, however, the heart rates were frequently higher than the given training pulse rates. Treatment with nitrates (Isoket retard 120 mg) reduced the incidence and duration of silent ischemias. On account of the spontaneous variability of the parameter, it needs to be interpreted with caution. The incidence of silent ischemic episodes during sports activities in patients with clinical anomalies should prompt a rigorous treatment with drugs, and careful supervision of training. PMID:2373455
Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1
Yu, Liming; Li, Qing; Yu, Bo; Yang, Yang; Jin, Zhenxiao; Duan, Weixun; Zhao, Guolong; Zhai, Mengen; Liu, Lijun; Yi, Dinghua; Chen, Min; Yu, Shiqiang
Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91phox expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process. PMID:26788242
Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers
Fleg, J.L.; Gerstenblith, G.; Zonderman, A.B.; Becker, L.C.; Weisfeldt, M.L.; Costa, P.T. Jr.; Lakatta, E.G. )
Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.
Three-year follow-up of patients with silent ischemia in the subacute phase of myocardial infarction after thrombolysis and early coronary intervention.
Lotze, U; Ozbek, C; Gerk, U; Kaufmann, H; Sen, S; Figulla, H R
In order to assess the prognostic value of silent myocardial ischemia in acute myocardial infarction after thrombolysis and early coronary angiography (14-48 h after start of thrombolysis) including percutaneous transluminal coronary angioplasty, if indicated, 126 patients underwent 24 h-Holter-monitoring in the early postinfarction period. The 24 h-Holter-recording was initiated directly after early coronary intervention (40+/-11 h after onset of symptoms). Of the 126 patients initially eligible for the study 29 had to be excluded from further analysis for clinical or methodical reasons. Of the remaining 97 patients, 10 (10%) had silent ischemia (group A) and 87/97 (90%) patients showed no significant ST-segment alterations. Both groups did not significantly differ from each other with regard to baseline clinical characteristics, severity of coronary artery disease and frequency of successful percutaneous transluminal coronary angioplasty. The left ventricular ejection fraction showed a trend towards lower values in patients with than in those without silent ischemia (47+/-15% vs. 55+/-13%, p=0.07). When both silent ischemia and left ventricular ejection fraction <40% were present, a subset of patients at high risk for cardiac death could be identified (specificity: 98%, positive predictive accuracy: 75%). By Kaplan-Meier analysis, significantly more cardiac deaths occurred in group A than in group B (30% vs. 6%, p<0.01) during the three-year follow-up (950+/-392 days) after acute myocardial infarction. Regarding the cardiac events during long-term follow-up (emergency percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, non-fatal reinfarction, and cardiac death) there was no significant difference between both groups (30% vs. 18%, NS). In conclusion, Holter monitor-detected silent ischemia in the subacute phase of myocardial infarction after thrombolysis followed by early delayed coronary intervention occurs in 10% of the patients
Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1.
Feng, Jianyu; Yang, Yang; Zhou, Yajun; Wang, Bodong; Xiong, Hongyan; Fan, Chongxi; Jiang, Shuai; Liu, Jun; Ma, Zhiqiang; Hu, Wei; Li, Tian; Feng, Xiao; Xu, Jianjun; Jin, Zhenxiao
Ischemia reperfusion (IR) injury (IRI) is associated with poor prognoses in the settings of both cardiac surgery and ischemic heart disease and causes mitochondrial oxidative stress and cell death. Silent information regulator 1 (SIRT1), a member of the histone deacetylase family, exerts anti-IRI effects. Bakuchiol (BAK), an analog of resveratrol and a monoterpene phenol isolated from the seeds of Psoralea corylifolia (Leguminosae), protects tissues from injury. This study was designed to investigate the protective effects of BAK treatment in the setting of myocardial IRI and to elucidate the potential mechanism of those effects. Prior to induction of IR, isolated rat hearts or cardiomyocytes were exposed to BAK in either the absence or presence of the SIRT1 inhibitors Sirtinol and SIRT1 siRNA. BAK exerted cardioprotective effects, as evidenced by the improvements noted in cardiac function following ischemia, attenuated myocardial apoptosis, and changes in several biochemical parameters (including increases in the level of the anti-apoptotic protein Bcl2, decreases in the level of the pro-apoptotic protein Bax, and decreases in the cleaved Caspase 3 level). However, Sirtinol and SIRT1 siRNA each blocked BAK-induced cardioprotection by inhibiting SIRT1 signaling. Additionally, BAK significantly increased the activities of mitochondrial succinate dehydrogenase, cytochrome c oxidase, and mitochondrial superoxide dismutase and decreased the production of malondialdehyde. These findings suggested that BAK significantly attenuated IR-induced mitochondrial oxidative damage. However, Sirtinol and SIRT1 siRNA abolished BAK-dependent mitochondrial function. In summary, our results demonstrate that BAK treatment attenuates IRI by attenuating IR-induced mitochondrial oxidative damage via the activation of SIRT1/PGC-1α signaling. PMID:27000151
Altered myocardial perfusion in patients with angina pectoris or silent ischemia during exercise as assessed by quantitative thallium-201 single-photon emission computed tomography
Mahmarian, J.J.; Pratt, C.M.; Cocanougher, M.K.; Verani, M.S. )
The extent of abnormally perfused myocardium was compared in patients with and without chest pain during treadmill exercise from a large, relatively low-risk consecutive patient population (n = 356) referred for quantitative thallium-201 single-photon emission computed tomography (SPECT). All patients had concurrent coronary angiography. Patients were excluded if they had prior coronary angioplasty or bypass surgery. Tomographic images were assessed visually and from computer-generated polar maps. Chest pain during exercise was as frequent in patients with normal coronary arteries (12%) as in those with significant (greater than 50% stenosis) coronary artery disease (CAD) (14%). In the 219 patients with significant CAD, silent ischemia was fivefold more common than symptomatic ischemia (83% versus 17%, p = 0.0001). However, there were no differences in the extent, severity, or distribution of coronary stenoses in patients with silent or symptomatic ischemia. Our major observation was that the extent of quantified SPECT perfusion defects was nearly identical in patients with (20.9 +/- 15.9%) and without (20.5 +/- 15.6%) exertional chest pain. The sensitivity for detecting the presence of CAD was significantly improved with quantitative SPECT compared with stress electrocardiography (87% versus 65%, p = 0.0001). Although scintigraphic and electrocardiographic evidence of exercise-induced ischemia were comparable in patients with chest pain (67% versus 73%, respectively; p = NS), SPECT was superior to stress electrocardiography for detecting silent myocardial ischemia. The majority of patients in this study with CAD who developed ischemia during exercise testing were asymptomatic, although they exhibited an angiographic profile and extent of abnormally perfused myocardium similar to those of patients with symptomatic ischemia.
[Silent myocardial ischemia and exercise-induced arrhythmia detected by the exercise test in the total health promotion plan (THP)].
Iwane, M; Shibe, Y; Itoh, K; Kinoshita, F; Kanagawa, Y; Kobayashi, M; Mugitani, K; Ohta, M; Ohata, H; Yoshikawa, A; Ikuta, Z; Nakamura, Y; Mohara, O
We investigated the prevalence and characteristics of ischemic heart disease especially silent myocardial ischemia (SMI) and arrhythmia in need of careful observation in the exercise stress tests in the Total Health Promotion Plan (THP), which was conducted between 1994-96 for the purpose of measuring cardiopulmonary function. All workers (n = 4,918, 4,426 males) aged 18-60 yr old in an occupational field were studied. Exercise tests with an ergometer were performed by the LOPS protocol, in which the maximal workload was set up as a presumed 70-80% maximal oxygen intake, or STEP (original multistage protocol). ECG changes were evaluated with a CC5 lead. Two hundred and fifteen people refused the study because of a common cold, lumbago and so on. Of 4,703 subjects, 17 with abnormal rest ECG and 19 with probable anginal pain were excluded from the exercise tests. Of 4,667 who underwent the exercise test, 37 (0.79%) had ischemic ECG change, and 155 (3.32%) had striking arrhythmia. These 228 subjects then did a treadmill exercise test with Bruce protocol. Twenty-two (0.47% of 4,703) showed positive ECG change, 9 (0.19%) of 22 had abnormal findings on a 201Tl scan. 8 (0.17%) were diagnosed as SMI (Cohn I), in which the prevalence of hypertension, hyperlipidemia, diabetes mellitus, smoker and positive familial history of ischemic heart disease was greater than that of all subjects. In a 15-30 month follow up, none has developed cardiac accidents. Exercise-induced arrhythmia was detected in 11 (0.23%) subjects. Four were non-sustained ventricular tachycardia without any organic disease, 4 were ventricular arrhythmia based on cardiomyopathy detected by echocardiography, 2 were atrial fibrillation and another was WPW syndrome. It is therefore likely that the ergometer exercise test in THP was effective in preventing sudden death caused by ischemic heart disease or striking arrhythmia. PMID:11329953
Silent myocardial ischemia: Assessment by exercise thallium-201 scintigraphy and coronary arteriography
Reisman, S.; Berman, D.S.; Maddahi, J.; Swan, H.J.C.
To determine the relationship between the presence or absence of exertional angina during treadmill testing (TT) and the extent and severity of exercise-induced ischemia (EII), the authors studied 96 consecutive patients (pts) with EII by Bruce protocol exercise (Ex) Tl-201 scintigraphy (greater than or equal to1 reversible segment (rev seg)). All pts underwent coronary angiography. Three-view Tl scintigrams were divided into 15 segs, and Tl uptake was graded visually in each seg using a 4 point score. Tl severity score (SS) was determined at Ex Tl imaging (ESS) and redistribution imaging (RSS). Severity of EII=ischemic severity score (ISS) derived as ESS-RSS. Extent of EII=number rev segs. Exertional angina was present in 48 pts (Gp I) and absent in 48 pts (Gp II).
Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening
Background Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. Methods DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. Results The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. Conclusions These results suggest that the
Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin.
Yu, Liming; Liang, Hongliang; Dong, Xiaochao; Zhao, Guolong; Jin, Zhenxiao; Zhai, Mengen; Yang, Yang; Chen, Wensheng; Liu, Jincheng; Yi, Wei; Yang, Jian; Yi, Dinghua; Duan, Weixun; Yu, Shiqiang
Diabetes mellitus (DM) increases myocardial oxidative stress and endoplasmic reticulum (ER) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia-reperfusion (MI/R) injury in type 2 diabetic state are still unknown. In this study, we developed high-fat diet-fed streptozotocin (HFD-STZ) rat, a well-known type 2 diabetic model, to evaluate the effect of melatonin on MI/R injury with a focus on silent information regulator 1 (SIRT1) signaling, oxidative stress, and PERK/eIF2α/ATF4-mediated ER stress. HFD-STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT1 inhibitor) and subjected to MI/R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI/R surgery. Melatonin markedly reduced MI/R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up-regulated SIRT1 expression, reduced oxidative damage, and suppressed PERK/eIF2α/ATF4 signaling. However, these effects were all attenuated by SIRT1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia-reperfusion injury-induced ER stress by activating SIRT1 signaling while SIRT1 siRNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT1 signaling in type 2 diabetic state aggravates MI/R injury. Melatonin ameliorates reperfusion-induced oxidative stress and ER stress via activation of SIRT1 signaling, thus reducing MI/R damage and improving cardiac function. PMID:26327197
[Myocardial responses to ischemia].
Borisenko, V G; Gubareva, E A; Kade, A Kh
The paper details the types of a myocardial response to impaired blood flow, such as myocardial stunning, hibernation, ischemic preconditioning, warm-up phenomenon, ischemic postconditioning, remodeling, and infarction. According to the pathogenesis, the authors identify several types of myocardial dysfunction in transient ischemic attack--uptake, delivery; and a mixed one. It is concluded the myocardial response to damage depends on a combination of influencing factors, a number of pathophysiological processes starting in the acute phase of ischemia achieve its peak in the late period. PMID:20564927
Transluminal coronary angioplasty in the treatment of silent ischemia
Bergin, P.; Myler, R.K.; Shaw, R.E.; Stertzer, S.H.; Clark, D.A.; Ryan, C.; Murphy, M.C.
Fifty-four asymptomatic patients with positive thallium exercise tests underwent coronary angiography followed by coronary angioplasty (PTCA), as the primary therapy for silent ischemia. The procedure was technically successful in 89% of these patients. Emergency bypass graft surgery was necessary in 2 (3.6%) and q-wave myocardial infarction occurred in 1 (1.8%) of these. All fifty-four patients have been followed for a mean of 35 months since angioplasty. Of the 48 patients with initially successful PTCA, 12 had either clinical restenosis (9/14 or 19%) or a new lesion (3/48 or 6%) during follow-up, which required a repeat PTCA. At the longest follow-up, 46 (85%) had been successfully treated with on or more PTCA procedures. Two patients (3.6%) had sustained late q-wave myocardial infarction and two additional patients reported angina pectoris. There were no deaths. Angioplasty as a primary therapy for silent ischemia appears efficacious, with success and restenosis rates comparable to those in the symptomatic population. Event-free survival is improved, compared with natural history data for patients with silent ischemia from other studies. Prudent risk/benefit analysis may help to define subgroups most likely to benefit from this intervention.
The TGF-B1 and IL-10 gene polymorphisms are associated with risk of developing silent myocardial ischemia in the diabetic patients.
Cruz, Miguel; Fragoso, José Manuel; Alvarez-León, Edith; Escobedo-de-la-Peña, Jorge; Valladares, Adan; Juárez-Cedillo, Teresa; Pérez-Méndez, Oscar; Vargas-Alarcón, Gilberto
Silent myocardial ischemia (SMI) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. Considering the prominent role of IL-10 and TGF-B1 as regulators of the inflammatory process and vascular physiology, the aim of the present study was to analyze whether IL-10 and TGF-B1 single nucleotide polymorphisms (SNPs) are associated with SMI. The IL-10-1082 A>G (rs1800896), IL-10-819 T>C (rs1800871), IL-10-592 A>C (rs1800872), TGF-β1-509 T>C (rs1800469), and TGF-β1 T29C (rs1800470) SNPs were analyzed by 5'exonuclease TaqMan genotyping assays in a group of 149 SMI patients and 248 healthy controls. The IL-10-1082 A>G (rs1800896) SNP was significantly associated with an increased risk of SMI as compared to controls under both dominant and heterozygous models (OR=1.77, Pdom=0.029 and OR=1.69, PHet=0.043). On the other hand, the TGF-β1 509 T>C (rs1800469) SNP was significantly associated with increased risk of SMI as compared to controls under a dominant and additive models (OR=1.82, Pdom=0.035, OR=1.50, Padd=0.026). Finally, the TGF-β1 T29C (rs1800470) SNP was significantly associated with increased risk of SMI as compared to controls under a co-dominant, dominant, recessive, and additive models (OR=3.63, PCod=0.004, OR=2.24, Pdom=0.002, OR=2.46, Prec=0.03 and OR=1.94, Padd=0.001). After adjusted for gender, age, and smoking, two haplotypes (CC and TT) were associated with decreased risk of SMI (OR=0.26, P<0.0001 and OR=0.15, P=0.017). In summary, our data suggest that the IL-10-1082 A>G (rs1800896), TGF-β1-509 T>C (rs1800469), and TGF-β1 T29C (rs1800470) SNPs play an important role in the risk of developing SMI. In our study, it was possible to distinguish two protective haplotypes in TGF-β1 for SMI development. PMID:24060592
Changes in endothelium-derived vascular regulatory factors during dobutamine-stress-induced silent myocardial ischemia in patients with Kawasaki disease.
Hino, Y; Ohkubo, T; Katsube, Y; Ogawa, S
The changes in endothelium-derived vascular regulatory factors during dobutamine (DOB)-induced myocardial ischemia (MI) were investigated in 21 patients with Kawasaki disease aged from 11 months to 18 years. They were classified into an ischemia group (8 patients) and a non-ischemia group (13 patients) based on the results of 99mTc myocardial scintigraphy and DOB stress 99mTc myocardial scintigraphy. In the ischemia group, MI was relatively mild, because there were ischemic changes on the electrocardiogram and no significant symptoms during DOB stress. Catheters were positioned near the orifice of the coronary artery (Ao) and at the coronary sinus (CS). Hemodynamics and the blood concentrations of lactic acid and endothelin-1, as well as NO3-, 6-keto-prostaglandin F1alpha, and thromboxane B2, (which are inactive metabolites of nitric oxide, prostaglandin I2 and thromboxane A2, respectively), were measured at rest and after DOB stress (maximum dose: 30 microg x kg(-1) x min(-1)). The CS/Ao ratio was determined for all parameters. The rate-pressure product, an index of work load, and the cardiac index were significantly increased by DOB stress in both groups. Coronary angiography showed no vasospasm of the epicardial coronary arteries before or after DOB stress in either group. The plasma concentrations of endothelin-1 and 6-keto-prostaglandin F1alpha were significantly increased after DOB stress in the ischemia group, but the serum concentration of NO did not increase. The lack of an increase in NO production during DOB stress may have contributed to the worsening of MI in patients with Kawasaki disease. PMID:10462014
Myocardial ischemia--association with perioperative cardiac morbidity.
Cunningham, A. J.
The development of ambulatory electrocardiographic recorders and analysers and the application of transesophageal echocardiography in the mid-1980's enabled investigators to quantify and describe the occurrence of silent as well as symptomatic ischemia in the perioperative period. Several technical advances which have recently occurred in ECG monitoring include the use of miniaturized digital computing equipment to store and analyze data. In addition, real time ST-segment analysis has become widely available on multicomponent monitors in both the operating room and intensive care units. The incidence of perioperative myocardial ischemia depends on the patient population, the surgical procedure, and the monitoring technique used. Several studies in the early 1990's have shown that cardiac morbidity in patients undergoing major, noncardiac surgery is best predicted by postoperative myocardial ischemia, rather than tradition preoperative clinical predictors. Long duration postoperative ischemia may be the factor most significantly associated with adverse cardiac outcome. Postoperative pain, physiological and emotional stress may all combine to cause tachycardia, hypertension, increase in cardiac output, and fluid shifts which, in high risk patients, might result in subendocardial ischemia and eventual myocardial infarction. If postoperative myocardial ischemia is the cause of late postoperative myocardial infarction in patients undergoing non-cardiac surgery, then treatment of postoperative myocardial ischemia should reduce morbidity. In addition, reducing pain and stress and avoiding postoperative hypoxemia might prevent postoperative myocardial ischemia and minimize the need for extensive preoperative cardiac evaluation. PMID:7825338
Long-term follow-up of patients with silent ischemia during exercise radionuclide angiography
Breitenbuecher, A.P.; Pfisterer, M.; Hoffmann, A.; Burckhardt, D. )
A retrospective 5 year follow-up study was performed in 140 patients with unequivocal ischemia during exercise radionuclide angiography (greater than or equal to 10% decrease in left ventricular ejection fraction or greater than or equal to 5% decrease in ejection fraction together with a distinct regional wall motion abnormality). In 84 patients (60%), ischemia during radionuclide angiography was silent (silent ischemia group), whereas 56 patients experienced angina during the test (symptomatic group). Work load and antianginal medication were similar in both groups. Critical cardiac events (unstable angina, myocardial infarction, cardiac death) occurred in 27% of patients in the silent ischemia group and 16% of those in the symptomatic group (p = NS); however, myocardial infarction or death was more frequent in patients with silent ischemia (22% versus 9%; p less than 0.05). If there was additional exercise-induced ST segment depression, the rate of critical events was further increased (p less than 0.05). The difference in critical cardiac events seemed to be influenced by the higher incidence of revascularization procedures in symptomatic patients, whereas medical therapy had no similar effect. Thus, these findings suggest that patients with documented severe ischemia should undergo left heart catheterization and revascularization irrespective of symptoms to improve their prognosis.
Perioperative myocardial ischemia reperfusion injury.
Shernan, Stanton K
Myocardial I-R injury contributes to adverse cardiovascular outcomes after cardiac surgery. The pathogenesis of I-R injury is complex and involves the activation, coordination, and amplification of several systemic and local proinflammatory pathways (Fig. 4). Treatment and prevention of perioperative morbidity associated with myocardial I-R will ultimately require a multifocal approach. Combining preoperative risk stratification (co-morbidity and surgical complexity), minimizing initiating factors predisposing to SIRS, limiting ischemia duration, and administering appropriate immunotherapy directed toward systemic and local proinflammatory mediators of I-R injury, should all be considered. In addition, the role of the genetic-environmental interactions in the pathogenesis of cardiovascular disease is also being examined. Thus, in the near future, preoperative screening for polymorphisms of certain inflammatory and coagulation genes should inevitably help reduce morbidity by permitting the identification of high-risk cardiac surgical patients and introducing the opportunity for gene therapy or pharmacogenetic intervention [42,64]. PMID:14562561
Association between Anger and Mental Stress-Induced Myocardial Ischemia
Pimple, Pratik; Shah, Amit; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon; Ibeanu, Ijeoma; Murrah, Nancy; Shallenberger, Lucy; Kelley, Mary; Raggi, Paolo; Vaccarino, Viola
Background Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. Methods [99mTc]sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task), and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielberger's State-Trait Anger Expression Inventory was used to assess different anger dimensions. Results The mean age was 50 years, 50% were female and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive and anxiety symptoms, each interquartile range increment in state-anger score was associated with 0.36 units adjusted increase in ischemia as measured by the summed difference score (95% CI: 0.14-0.59); the corresponding association for trait-anger was 0.95 (95% CI: 0.21-1.69). Anger expression scales were not associated ischemia. None of the anger dimensions were related to ischemia during exercise/pharmacological stress. Conclusion Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress, but not during exercise/pharmacological stress. Patients with this psychological profile may be at increased risk for silent ischemia induced by emotional stress and this may translate into worse prognosis. PMID:25497256
Echocardiographic assessment of myocardial ischemia
Dworrak, Birgit; Sanchis-Gomar, Fabian; Lucia, Alejandro; Buck, Thomas; Erbel, Raimund
Over the last 60 years, echocardiography has emerged as a dominant and indispensable technique for the detection and assessment of coronary heart disease (CHD). In this review, we will describe and discuss this powerful tool of cardiology, especially in the hands of an experienced user, with a focus on myocardial ischemia. Technical development is still on-going, and various new ultrasound techniques have been established in the field of echocardiography in the last several years, including tissue Doppler imaging (TDI), contrast echocardiography, three-dimensional echocardiography (3DE), and speckle tracking echocardiography (i.e., strain/strain rate-echocardiography). High-end equipment with harmonic imaging, high frame rates and the opportunity to adjust mechanical indices has improved imaging quality. Like all new techniques, these techniques must first be subjected to comprehensive scientific assessment, and appropriate training that accounts for physical and physiological limits should be provided. These limits will constantly be redefined as echocardiographic techniques continue to change, which will present new challenges for the further development of ultrasound technology. PMID:27500160
Echocardiographic assessment of myocardial ischemia.
Leischik, Roman; Dworrak, Birgit; Sanchis-Gomar, Fabian; Lucia, Alejandro; Buck, Thomas; Erbel, Raimund
Over the last 60 years, echocardiography has emerged as a dominant and indispensable technique for the detection and assessment of coronary heart disease (CHD). In this review, we will describe and discuss this powerful tool of cardiology, especially in the hands of an experienced user, with a focus on myocardial ischemia. Technical development is still on-going, and various new ultrasound techniques have been established in the field of echocardiography in the last several years, including tissue Doppler imaging (TDI), contrast echocardiography, three-dimensional echocardiography (3DE), and speckle tracking echocardiography (i.e., strain/strain rate-echocardiography). High-end equipment with harmonic imaging, high frame rates and the opportunity to adjust mechanical indices has improved imaging quality. Like all new techniques, these techniques must first be subjected to comprehensive scientific assessment, and appropriate training that accounts for physical and physiological limits should be provided. These limits will constantly be redefined as echocardiographic techniques continue to change, which will present new challenges for the further development of ultrasound technology. PMID:27500160
[Transition of myocardial ischemia to heart failure].
Ertl, G; Fraccarollo, D; Gaudron, P; Hu, K; Laser, A; Neubauer, S; Schorb, W
Myocardial ischemia results in myocardial dysfunction. Recovery may be delayed ("stunning"), or persistent if perfusion remains reduced ("hibernation") and ischemia may go on to necrosis, thus, contributing to chronic heart failure. In addition, myocardium not directly affected by ischemia may undergo adaptive processes like hypertrophy and dilatation, which may result in chronic left heart failure. This process is characterized by hemodynamic, neurohumoral, and progressive morphologic changes of the heart which are closely interrelated. Hemodynamic changes basically consist of an increase in left ventricular filling pressure and a decrease in global ejection fraction, and, in most cases years after myocardial infarction, in an increase in systemic vascular resistance and right atrial pressure. Neurohumoral changes consist of an increase in plasma catecholamines, atrial natriuretic factor and vasopressin, and in an activation of the renin-angiotensin-system. Plasma endothelin-1 was recently reported to be increased in patients with heart failure, and prognosis was related to endothelin levels. Diminished response of vessels to endothelium (EDRF/NO) dependent vasodilatation suggests impairment of vascular endothelium in heart failure. Local changes of cardiac neurohumoral systems could contribute to structural changes of the heart, e.g., systemic activation to hemodynamic changes. Structural changes of the heart are characterized by an increase in volume and thickness of surviving myocardium and an expansion of ischemic and necrotic myocardium. Molecular control of these processes which include various cell types, such as cardiomyocytes and cardiofibroblasts, are currently an issue of intense research and could result in specific therapeutic importance. PMID:9816648
[Myocardial ischemia-reperfusion injury and melatonin].
Sahna, Engin; Deniz, Esra; Aksulu, Hakki Engin
It is believed that myocardial ischemia-reperfusion injury is related to increased free radical generated and intracellular calcium overload especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger, antioxidant and can inhibit the intracellular calcium overload. In this review, we have summarized the fundamental of cardiac ischemia-reperfusion injury and the effects of melatonin on myocardial damage that related to cardiac ischemia-reperfusion injury. The total antioxidant capacity of human serum is related to melatonin levels. Incidence of sudden cardiac death is high in the morning hours. It has been shown that melatonin levels are significantly low at these times and patients with coronary heart disease have lower than normal individuals. These findings thought that melatonin would be valuable to test in clinical trials for prevention of possible ischemia-reperfusion-induced injury, especially life threatening arrhythmias and infarct size, effecting life quality, associated with thrombolysis, angioplasty, coronary artery spasm or coronary bypass surgery. PMID:16766282
Managing the asymptomatic diabetic patient with silent myocardial ischaemia.
Doubell, A F
Coronary artery disease is common in diabetic patients and remains the major cause of death in these patients. However myocardial ischaemia resulting from coronary lesions does not always give rise to symptoms. The managing physician must therefore consider the benefit of screening for silent myocardial ischaemia in diabetic patients. Screening all diabetic patients is not recommended. The challenge to the physician is to select the patient subgroups likely to benefit from screening. Patients with more than one cardiac risk factor (dyslipidaemia, hypertension, smoking, family history, micro-albuminuria) in addition to diabetes, as well as patients with established macrovascular disease, e.g. peripheral vascular disease, will benefit most from screening. A standard treadmill stress ECG is the recommended screening test. A number of additional tests have been proposed to select high-risk patients for screening. Of these, testing for microalbuminuria and elevated CRP levels are most likely to influence decision-making. Once silent ischaemia has been detected in a diabetic patient, the mainstay of treatment remains the aggressive control of risk factors, improvement of glycaemic control and aspirin therapy. The use of beta-blockers and ACE-inhibitors often need consideration. The attending physician must then consider referring the patient to a cardiologist for angiography and possible intervention. This decision is based on the presence of poor prognostic signs during the stress ECG and the number of risk factors present. Microalbuminuria and elevated CRP levels are helpful in assisting with the risk stratification process. PMID:12389062
Thallium-201 myocardial scintigraphy in acute myocardial infarction and ischemia
Wackers, F.J.
Thallium-201 scintigraphy provides a sensitive and reliable method of detecting acute myocardial infarction and ischemia when imaging is performed with understanding of the temporal characteristics and accuracy of the technique. The results of scintigraphy are related to the time interval between onset of symptoms and time of imaging. During the first 6 hr after chest pain almost all patients with acute myocardial infarction and approximately 50% of the patients with unstable angina will demonstrate /sup 201/TI pefusion defects. Delayed imaging at 2-4 hr will permit distinction between ischemia and infarction. In patients with acute myocardial infarction, the size of the perfusion defect accurately reflects the extent of the infarcted and/or jeopardized myocardium, which may be used for prognostic stratification. In view of the characteristics of /sup 201/TI scintigraphy, the most practical application of this technique is in patients in whom myocardial infarction has to be ruled out, and for early recognition of patients at high risk for complications.
Modulation of cardiac metabolism during myocardial ischemia.
Chagas, Antonio C P; Dourado, Paulo M M; Galvão, Tatiana de Fátima Gonçalves
Metabolic modulation during myocardial ischemia is possible by the use of specific drugs, which may induce a shift from free fatty acid towards predominantly glucose utilization by the myocardium to increase ATP generation per unit oxygen consumption. Three agents (trimetazidine, ranolazine, and perhexiline) have well-documented anti-ischaemic effects. However, perhexiline, the most potent agent currently available, requires plasma-level monitoring to avoid hepato-neuro-toxicity. Besides, the long-term safety of trimetazidine and ranolazine has yet to be established. In addition to their effect in ischemia, the potential use of these drugs in chronic heart failure is gaining recognition as clinical and experimental data are showing the improvement of myocardial function following treatment with several of them, even in the absence of ischemia. Future applications for this line of treatment is promising and deserves additional research. In particular, large, randomised, controlled trials investigating the effects of these agents on mortality and hospitalization rates due to coronary artery disease are needed. PMID:18991673
Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury
Singhal, Arun K.; Symons, J. David; Boudina, Sihem; Jaishy, Bharat; Shiu, Yan-Ting
Minimizing myocardial ischemia-reperfusion injury has broad clinical implications and is a critical mediator of cardiac surgical outcomes. "Ischemic injury" results from a restriction in blood supply leading to a mismatch between oxygen supply and demand of a sufficient intensity and/or duration that leads to cell necrosis, whereas ischemia-reperfusion injury occurs when blood supply is restored after a period of ischemia and is usually associated with apoptosis (i.e. programmed cell death). Compared to vascular endothelial cells, cardiac myocytes are more sensitive to ischemic injury and have received the most attention in preventing myocardial ischemia-reperfusion injury. Many comprehensive reviews exist on various aspects of myocardial ischemia-reperfusion injury. The purpose of this review is to examine the role of vascular endothelial cells in myocardial ischemia-reperfusion injury, and to stimulate further research in this exciting and clinically relevant area. Two specific areas that are addressed include: 1) data suggesting that coronary endothelial cells are critical mediators of myocardial dysfunction after ischemia-reperfusion injury; and 2) the involvement of the mitochondrial permeability transition pore in endothelial cell death as a result of an ischemia-reperfusion insult. Elucidating the cellular signaling pathway(s) that leads to endothelial cell injury and/or death in response to ischemia-reperfusion is a key component to developing clinically applicable strategies that might minimize myocardial ischemia-reperfusion injury. PMID:25558187
Caffeine reduces dipyridamole-induced myocardial ischemia
Smits, P.; Aengevaeren, W.R.; Corstens, F.H.; Thien, T. )
The mechanism of action of coronary vasodilation after dipyridamole may be based on inhibition of cellular uptake of circulating endogenous adenosine. Since caffeine has been reported to be a competitive antagonist of adenosine we studied the effect of caffeine on the outcome of dipiridamole-{sup 201}Tl cardiac imaging in one patient. During caffeine abstinence dipyridamole induced myocardial ischemia with down-slope ST depressions on the ECG, and reversible perfusion defects on the scintigrams. When the test was repeated 1 wk later on similar conditions, but now shortly after infusion of caffeine (4 mg/kg), the ECG showed nodepressions, and the scintigrams only slight signs of ischemia. We conclude that when caffeine abstinence is not sufficient, the widespread use of coffee and related products may be responsible for false-negative findings in dipyridamole-201Tl cardiac imaging.
Acute myocardial ischemia in adults secondary to missed Kawasaki disease in childhood.
Rizk, Sherif R Y; El Said, Galal; Daniels, Lori B; Burns, Jane C; El Said, Howaida; Sorour, Khaled A; Gharib, Soliman; Gordon, John B
Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients ≤40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged ≤40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood. PMID:25555655
Differences in autonomic nerve function in patients with silent and symptomatic myocardial ischaemia.
Shakespeare, C. F.; Katritsis, D.; Crowther, A.; Cooper, I. C.; Coltart, J. D.; Webb-Peploe, M. W.
BACKGROUND--Autonomic neuropathy provides a mechanism for the absence of symptoms in silent myocardial ischaemia, but characterisation of the type of neuropathy is lacking. AIM--To characterise and compare autonomic nerve function in patients with silent and symptomatic myocardial ischaemia. METHODS AND RESULTS--The Valsalva manoeuvre, heart rate variation (HRV) in response to deep breathing and standing, lower body negative pressure, isometric handgrip, and the cold pressor test were performed by patients with silent (n = 25) and symptomatic (n = 25) ambulatory ischaemia and by controls (n = 21). No difference in parasympathetic efferent function between patients with silent and symptomatic ischaemia was recorded, but both had significantly less HRV in response to standing than the controls (p < 0.005 for silent and p < 0.01 for symptomatic). Patients with silent ischaemia showed an increased propensity for peripheral vasodilatation compared with symptomatic patients (p < 0.02) and controls (p < 0.04). Impaired sympathetic function was found in patients with pure silent ischaemia (n = 4) compared with the remaining patients with silent ischaemia whose pain pathways were presumed to be intact. CONCLUSIONS--Patients with silent ischaemia and pain pathways presumed to be intact have an enhanced peripheral vasodilator response, and if this applied to the coronary vasculature it could provide a mechanism for limiting ischaemia to below the pain threshold. Patients with pure silent ischaemia have evidence of sympathetic autonomic dysfunction. Images PMID:8297687
Effects of carbon monoxide on myocardial ischemia
Allred, E.N.; Pagano, M. ); Bleecker, E.R.; Walden, S.M. ); Chaitman, B.R.; Dahms, T.E. ); Hackney, J.D.; Selvester, R.H. ); Warren, J. ); Gottlieb, S.O.
The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre-versus postexposure exercise test at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease.
Sphingolipid Therapy in Myocardial Ischemia-Reperfusion Injury
Gundewar, Susheel; Lefer, David J.
Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggests that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia reperfusion injury and their possible mechanisms of cardioprotection. PMID:17928150
Effects of carbon monoxide on myocardial ischemia.
Allred, E N; Bleecker, E R; Chaitman, B R; Dahms, T E; Gottlieb, S O; Hackney, J D; Pagano, M; Selvester, R H; Walden, S M; Warren, J
The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. The exposures resulted in postexercise carboxyhemoglobin (COHb) levels of 0.6% +/- 0.3%, 2.0% +/- 0.1%, and 3.9% +/- 0.1%. The results obtained on the 2%-COHb day and 3.9%-COHb day were compared to those on the room air day. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) decreases in the time to development of ischemic ST-segment changes after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. In addition, there were 4.2% (p = 0.027) and 7.1% (p = 0.002) decreases in time to the onset of angina after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre- versus postexposure exercise tests at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease. PMID:2040254
Panic attack triggering myocardial ischemia documented by myocardial perfusion imaging study. A case report
Background Chest pain, a key element in the investigation of coronary artery disease is often regarded as a benign prognosis when present in panic attacks. However, panic disorder has been suggested as an independent risk factor for long-term prognosis of cardiovascular diseases and a trigger of acute myocardial infarction. Objective Faced with the extreme importance in differentiate from ischemic to non-ischemic chest pain, we report a case of panic attack induced by inhalation of 35% carbon dioxide triggering myocardial ischemia, documented by myocardial perfusion imaging study. Discussion Panic attack is undoubtedly a strong component of mental stress. Patients with coronary artery disease may present myocardial ischemia in mental stress response by two ways: an increase in coronary vasomotor tone or a sympathetic hyperactivity leading to a rise in myocardial oxygen consumption. Coronary artery spasm was presumed to be present in cases of cardiac ischemia linked to panic disorder. Possibly the carbon dioxide challenge test could trigger myocardial ischemia by the same mechanisms. Conclusion The use of mental stress has been suggested as an alternative method for myocardial ischemia investigation. Based on translational medicine objectives the use of CO2 challenge followed by Sestamibi SPECT could be a useful method to allow improved application of research-based knowledge to the medical field, specifically at the interface of PD and cardiovascular disease. PMID:22999016
Assessment of Myocardial Ischemia with Cardiovascular Magnetic Resonance
Heydari, Bobak; Jerosch-Herold, Michael; Kwong, Raymond Y.
Assessment of myocardial ischemia in symptomatic patients remains a common and challenging clinical situation faced by physicians. Risk stratification by presence of ischemia provides important utility for both prognostic assessment and management. Unfortunately, current noninvasive modalities possess numerous limitations and have limited prognostic capacity. More recently, ischemia assessment by cardiovascular magnetic resonance (CMR) has been shown to be a safe, available, and potentially cost-effective alternative with both high diagnostic and prognostic accuracy. Cardiovascular magnetic resonance has numerous advantages over other noninvasive methods, including high temporal and spatial resolution, relatively few contraindications, and absence of ionizing radiation. Furthermore, studies assessing the clinical utility and cost effectiveness of CMR in the short-term setting for patients without evidence of an acute myocardial infarction have also demonstrated favorable results. This review will cover techniques of ischemia assessment with CMR by both stress-induced wall motion abnormalities as well as myocardial perfusion imaging. The diagnostic and prognostic performance studies will also be reviewed, and the use of CMR for ischemia assessment will be compared with other commonly used noninvasive modalities. PMID:22014487
Energy Drinks and Myocardial Ischemia: A Review of Case Reports.
Lippi, Giuseppe; Cervellin, Gianfranco; Sanchis-Gomar, Fabian
The use and abuse of energy drinks (EDs) is constantly increasing worldwide. We performed a systematic search in Medline, Scopus and Web of Science to identify evidence about the potential link between these beverages and myocardial ischemia. Overall, 8 case reports could be detected, all of which described a realistic association between large intake of EDs and episodes of myocardial ischemia. Interestingly, no additional triggers of myocardial ischemia other than energy drinks could be identified in the vast majority of cases. Some plausible explanations can be brought in support of this association. Most of the biological effects of EDs are seemingly mediated by a positive inotropic effect on cardiac function, which entails increase in heart rate, cardiac output and contractility, stroke volume and arterial blood pressure. Additional biological abnormalities reported after EDs intake include increased platelet aggregation, endothelial dysfunction, hyperglycemia as well as an increase in total cholesterol, triglycerides and low-density lipoprotein cholesterol. Although a causal relationship between large consumption of EDs and myocardial ischemia cannot be definitely established so far, concerns about the cardiovascular risk of excessive consumption of these beverages are seemingly justified. PMID:26320007
Verapamil prevents silent myocardial perfusion abnormalities during exercise in asymptomatic patients with hypertrophic cardiomyopathy
Udelson, J.E.; Bonow, R.O.; O'Gara, P.T.; Maron, B.J.; Van Lingen, A.; Bacharach, S.L.; Epstein, S.E.
Recent studies indicate that reversible 201Tl perfusion defects, compatible with silent myocardial ischemia, commonly develop during exercise in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy (HCM). To determine whether this represents a dynamic process that may be modified favorably by medical therapy, we studied 29 asymptomatic or minimally symptomatic patients with HCM, aged 12-55 years (mean, 28), with exercise 201Tl emission computed tomography under control conditions and again after 1 week of oral verapamil (mean dosage, 453 mg/day). Treadmill time increased slightly during verapamil (21.0 +/- 3.6 to 21.9 +/- 2.7 minutes, p less than 0.005), but peak heart rate-blood pressure product was unchanged (26.3 +/- 6.0 X 10(3)) compared with 25.0 +/- 6.4 X 10(3). Two midventricular short-axis images per study were divided into five regions each, and each of these 10 regions was then analyzed on a 0-2 scale by three observers blinded with regard to the patients' therapy. Average regional scores of 1.5 or less were considered to represent perfusion defects, and a change in regional score of 0.5 or more was considered to constitute a significant change. During control studies, 15 patients (52%) developed perfusion defects with exercise (average, 3.7 regions per patient). In 14 of these patients, all perfusion defects completely reversed after 3 hours of rest; one patient had fixed defects. After administration of verapamil, exercise perfusion scores improved in 10 of the 14 patients (71%) with reversible defects; there was overall improvement in 34 of 50 (68%) regions with initially reversible perfusion defects.
Angina and Mental Stress-Induced Myocardial Ischemia
Pimple, Pratik; Shah, Amit J.; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon; Ibeanu, Ijeoma; Raggi, Paolo; Vaccarino, Viola
Objective Mental stress-induced myocardial ischemia is a common phenomenon in patients with coronary artery disease (CAD) and an emerging prognostic factor. Mental stress ischemia is correlated with ambulatory ischemia. However, whether it is related to angina symptoms during daily life has not been examined. Methods We assessed angina-frequency (past month) in 98 post-myocardial infarction (MI) subjects (age 18-60 years) using the Seattle Angina Questionnaire. Patients underwent [99mTc]sestamibi SPECT perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score (SDS), the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. Results The mean age was 50 years, 50% were female and 60% were non-white. After adjustment for age, sex, smoking, CAD-severity, depressive, anger and anxiety symptoms, each 1-point increase in mental-stress SDS was associated with 1.73-unit increase in the angina-frequency score (95% CI: 0.09-3.37) and 17% higher odds of being in a higher angina-frequency category (OR: 1.17, 95% CI: 1.00-1.38). Depressive symptoms were associated with 12% higher odds of being in a higher angina-frequency category (OR: 1.12, 95% CI: 1.03-1.21). In contrast, exercise/pharmacological stress-induced SDS was not associated with angina-frequency. Conclusion Among young and middle-aged post-MI patients, myocardial ischemia induced by mental stress in the lab, but not by exercise/pharmacological stress, is associated with higher frequency of retrospectively reported angina during the day. Psychosocial stressors related to mental stress ischemia may be important contributory factor to daily angina. PMID:25727240
Early markers for myocardial ischemia and sudden cardiac death.
Sabatasso, Sara; Mangin, Patrice; Fracasso, Tony; Moretti, Milena; Docquier, Mylène; Djonov, Valentin
The post-mortem diagnosis of acute myocardial ischemia remains a challenge for both clinical and forensic pathologists. We performed an experimental study (ligation of left anterior descending coronary artery in rats) in order to identify early markers of myocardial ischemia, to further apply to forensic and clinical pathology in cases of sudden cardiac death. Using immunohistochemistry, Western blots, and gene expression analyses, we investigated a number of markers, selected among those which are currently used in emergency departments to diagnose myocardial infarction and those which are under investigation in basic research and autopsy pathology studies on cardiovascular diseases. The study was performed on 44 adult male Lewis rats, assigned to three experimental groups: control, sham-operated, and operated. The durations of ischemia ranged between 5 min and 24 h. The investigated markers were troponins I and T, myoglobin, fibronectin, C5b-9, connexin 43 (dephosphorylated), JunB, cytochrome c, and TUNEL staining. The earliest expressions (≤30 min) were observed for connexin 43, JunB, and cytochrome c, followed by fibronectin (≤1 h), myoglobin (≤1 h), troponins I and T (≤1 h), TUNEL (≤1 h), and C5b-9 (≤2 h). By this investigation, we identified a panel of true early markers of myocardial ischemia and delineated their temporal evolution in expression by employing new technologies for gene expression analysis, in addition to traditional and routine methods (such as histology and immunohistochemistry). Moreover, for the first time in the autopsy pathology field, we identified, by immunohistochemistry, two very early markers of myocardial ischemia: dephosphorylated connexin 43 and JunB. PMID:27392959
Spin label oximetry to assess extracellular oxygen during myocardial ischemia.
Baker, J E; Froncisz, W; Joseph, J; Kalyanaraman, B
We describe real-time measurement of myocardial oxygen consumption during ischemia in the intact heart. Measurement of extracellular oxygen concentration during myocardial ischemia by spin label oximetry has been limited by ischemia-induced reduction of the neutral, water-soluble nitroxide TEMPONE. We have overcome this problem by encapsulating the nitroxides. Isolated immature (7-10 d old) rabbit hearts (n = 8) were perfused aerobically within the cavity of a loop gap resonator with bicarbonate buffer containing an oxygen-sensitive, lipid-soluble nitroxide (14N-TEMPO laurate in FC-43 perfluorocarbon micelles) and a much less oxygen-sensitive and positively charged nitroxide (15N-TEMPO choline in multilamellar vesicles) as an internal standard. The ratio of the ESR signal amplitudes of these nitroxides was used as a sensitive index of oxygen concentration. Sequestration of the nitroxides decreased their reduction rate by ascorbate in comparison with nonsequestered nitroxides. Hearts were subjected to 60 min of global no-flow ischemia at 20 degrees C. Extracellular oxygen content (mean +/- SD) during aerobic perfusion was 1195 +/- 55 mumol/liter. The electron spin resonance signal from TEMPO laurate increased with the onset and progression of ischemia, consistent with a decrease in extracellular oxygen, while the signal for TEMPO choline was relatively unchanged. Extracellular oxygen content after 40 and 60 min of ischemia was reduced to 393 +/- 27 mumol/liter (p < .05) and 61 +/- 5 mumol/liter (p < .05), respectively. We conclude that spin-label oximetry can directly and precisely measure myocardial oxygen consumption at constant temperature during ischemia in the intact heart. PMID:8958135
Depressive Symptoms Are Associated with Mental Stress-Induced Myocardial Ischemia after Acute Myocardial Infarction
Wei, Jingkai; Pimple, Pratik; Shah, Amit J.; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon A.; Ibeanu, Ijeoma; Murrah, Nancy; Shallenberger, Lucy; Raggi, Paolo; Vaccarino, Viola
Objectives Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. Methods We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. Results There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress. PMID:25061993
Endogenous nitric oxide and myocardial adaptation to ischemia.
Heusch, G; Post, H; Michel, M C; Kelm, M; Schulz, R
Ischemic myocardium does not inevitably undergo necrosis but rather can survive through downregulation of contractile function, ie, "hibernate." To study the role of endogenous NO in this adaptation, 41 enflurane-anesthetized swine were subjected to 90 minutes of moderate left anterior descending coronary artery hypoperfusion and assigned to placebo (P), to 30 mg/kg N(G)-nitro-L-arginine (L-NNA) IV to inhibit NO synthase, or to aortic constriction (AO) to match the increased left ventricular pressure observed with L-NNA. During normoperfusion, a regional myocardial external work index (WI, mm Hg. mm, sonomicrometry and micromanometry) was reduced with L-NNA (from 326+/-27 [SEM] to 250+/-19, P<0.05) but increased with AO (from 321+/-16 to 363+/-19, P<0.05 versus L-NNA). At 10 minutes of ischemia, WI was lower with L-NNA (109+/-10, P<0.05) than P (180+/-22) and AO (170+/-11) and did not change further at 85 minutes of ischemia. Relationships between WI and transmural myocardial blood flow and oxygen consumption were shifted rightward by L-NNA versus P and AO at both 10 and 85 minutes of ischemia. The maximal increment in calcium-activated external work was not different during normoperfusion among groups but was decreased during ischemia with L-NNA. L-NNA transiently increased myocardial contractile calcium sensitivity along with systemic pressure but reduced it during ongoing ischemia. The free-energy change of ATP hydrolysis after an early ischemic decrease recovered toward baseline values in all groups, and necrosis was absent after 2 (triphenyltetrazolium chloride staining) or 8 (histology) hours of reperfusion. Thus, endogenous NO contributes to hibernation by reducing oxygen consumption and preserving calcium sensitivity and contractile function without an energy cost during ischemia. PMID:10903999
Role of cytokines in myocardial ischemia and reperfusion.
Sharma, H S; Das, D K
Mediators of myocardial inflammation, predominantly cytokines, have for many years been implicated in the healing processes after infarction. In recent years, however, more attention has been paid to the possibility that the inflammation may result in deleterious complications for myocardial infarction. The proinflammatory cytokines may mediate myocardial dysfunction associated with myocardial infarction, severe congestive heart failure, and sepsis. A growing body of literature suggests that inflammatory mediators could play a crucial role in ischemia-reperfusion injury. Furthermore, ischemia-reperfusion not only results in the local transcriptional and translational upregulation of cytokines but also leads to tissue infiltration by inflammatory cells. These inflammatory cells are a ready source of a variety of cytokines which could be lethal for the cardiomyocytes. At the cellular level it has been shown that hypoxia causes a series of well documented changes in cardiomyocytes that includes loss of contractility, changes in lipid metabolism and subsequent irreversible cell membrane damage leading to cell death. For instance, hypoxic cardiomyocytes produce interleukin-6 (IL-6) which could contribute to the myocardial dysfunction observed in ischemia reperfusion injury. Ischemia followed by reperfusion induces a number of other multi-potent cytokines, such as IL-1, IL-8, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1) as well as an angiogenic cytokine/ growth factor, vascular endothelial growth factor (VEGF), in the heart. Intrestingly, these multipotent cytokines (e.g. TNF-alpha) may induce an adaptive cytoprotective response in the reperfused myocardium. In this review, we have included a number of cytokines that may contribute to ventricular dysfunction and/or to the cytoprotective and adaptive changes in the reperfused heart. PMID:18472818
Oligophrenin1 protects mice against myocardial ischemia and reperfusion injury by modulating inflammation and myocardial apoptosis.
Niermann, Christina; Gorressen, Simone; Klier, Meike; Gowert, Nina S; Billuart, Pierre; Kelm, Malte; Merx, Marc W; Elvers, Margitta
The Rho family of small GTPases has been analyzed in cardiac physiology and pathophysiology including myocardial infarction (MI) in the last years. Contradictory results show either a protective or a declined effect of RhoA and the RhoA effector Rho-associated protein kinase (ROCK) in myocardial ischemia and reperfusion injury that is associated with cardiomyocyte survival and caspase-3 activation. Cardiac-specific deletion of Rac1 reduced ischemia reperfusion injury in diabetic hearts, whereas cardiomyocyte specific overexpression of active Rac1 predisposes the heart to increased myocardial injury with enhanced contractile dysfunction. GTPase-activating proteins (GAPs) control the activation of Rho proteins through stimulation of GTP hydrolysis. However, the impact of GAPs in myocardial ischemia and reperfusion injury remains elusive. Here we analyzed the role of oligophrenin1 (OPHN1), a RhoGAP with Bin/Amphiphysin/Rvs (BAR) domain known to regulate the activity of RhoA, Rac1 and Cdc42 in MI. The expression of Ophn1, RhoA and Rac1 is strongly upregulated 24h after myocardial ischemia. Loss of OPHN1 induced enhanced activity of Rho effector molecules leading to elevated cardiomyocyte apoptosis and increased migration of inflammatory cells into the infarct border zone of OPHN1 deficient mice. Consequently, echocardiography 24h after myocardial ischemia revealed declined left ventricle function in OPHN1 deficient mice. Our results indicate that OPHN1 mediated regulation of RhoA, Rac1 and Cdc42 is crucial for the preservation of cardiac function after myocardial injury. PMID:27117132
Lidocaine Enhances Contractile Function of Ischemic Myocardial Regions in Mouse Model of Sustained Myocardial Ischemia
Kania, Gabriela; Osto, Elena; Jakob, Philipp; Krasniqi, Nazmi; Beck-Schimmer, Beatrice; Blyszczuk, Przemyslaw; Eriksson, Urs
Rationale Perioperative myocardial ischemia is common in high-risk patients. The use of interventional revascularisation or even thrombolysis is limited in this patient subset due to exceedingly high bleeding risks. Blockade of voltage-gated sodium channels (VGSC) with lidocaine had been suggested to reduce infarct size and cardiomyocyte cell death in ischemia/reperfusion models. However, the impact of lidocaine on cardiac function during sustained ischemia still remains unclear. Methods Sustained myocardial ischemia was induced by ligation of the left anterior descending artery in 12–16 weeks old male BALB/c mice. Subcutaneous lidocaine (30 mg/kg) was used to block VGSC. Cardiac function was quantified at baseline and at 72h by conventional and speckle-tracking based echocardiography to allow high-sensitivity in vivo phenotyping. Infarct size and cardiomyocyte cell death were assessed post mortem histologically and indirectly using troponin measurements. Results Ischemia strongly impaired both, global systolic and diastolic function, which were partially rescued in lidocaine treated in mice. No differences regarding infarct size and cardiomyocyte cell death were observed. Mechanistically, and as shown with speckle-tracking analysis, lidocaine specifically improves residual contractility in the ischemic but not in the remote, non-ischemic myocardium. Conclusion VGSC blockade with lidocaine rescues function of ischemic myocardium as a potential bridging to revascularisation in the setting of perioperative myocardial ischemia. PMID:27140425
Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury.
Chong, Albert J; Pohlman, Timothy H; Hampton, Craig R; Shimamoto, Akira; Mackman, Nigel; Verrier, Edward D
Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury. PMID:12607707
Myocardial Ischemia: Lack of Coronary Blood Flow or Myocardial Oxygen Supply/Demand Imbalance?
Heusch, Gerd
Regional myocardial blood flow and contractile function in ischemic myocardium are well matched, and there is no evidence for an oxygen supply/demand imbalance. Thus, myocardial ischemia is lack of coronary blood flow with electric, functional, metabolic, and structural consequences for the myocardium. All therapeutic interventions must aim to improve blood flow to ischemic myocardium as much and as quickly as possible. PMID:27390331
In vivo study of myocardial elastography under graded ischemia conditions
NASA Astrophysics Data System (ADS)
Lee, Wei-Ning; Provost, Jean; Fujikura, Kana; Wang, Jie; Konofagou, Elisa E.
The capability of currently available echocardiography-based strain estimation techniques to fully map myocardial abnormality at early stages of myocardial ischemia is yet to be investigated. In this study, myocardial elastography (ME), a radio-frequency (RF)-based strain imaging technique that maps the full 2D transmural angle-independent strain tensor in standard echocardiographic views at both high spatial and temporal resolution is presented. The objectives were to (1) evaluate the performance of ME on mapping the onset, extent and progression of myocardial ischemia at graded coronary constriction levels (from partial to complete coronary flow reduction), and (2) validate the accuracy of the strain estimates against sonomicrometry (SM) measurements. A non-survival canine ischemic model (n = 5) was performed by gradually constricting the left anterior descending (LAD) coronary blood flow from 0% (baseline blood flow) to 100% (zero blood flow) at 20% increments. An open-architecture ultrasound system was used to acquire RF echocardiograms in a standard full short-axis view at the frame rate of 211 fps, at least twice higher than what is typically used in conventional echocardiographic systems, using a previously developed, fully automated composite technique. Myocardial deformation was estimated by ME and validated against sonomicrometry. ME estimates and maps transmural (1) 2D displacements using RF cross-correlation and recorrelation; and (2) 2D polar (radial and circumferential) strains, derived from 2D (i.e. both lateral and axial) displacement components, at high accuracy. Full-view strain images were shown and found to reliably depict decreased myocardial function in the region at risk at increased levels of coronary flow reduction. The ME radial strain was deemed to be a more sensitive, quantitative, regional measure of myocardial ischemia as a result of coronary flow reduction when compared to the conventional wall motion score index and ejection fraction
Asymptomatic myocardial ischemia following cold provocation
Shea, M.J.; Deanfield, J.E.; deLandsheere, C.M.; Wilson, R.A.; Kensett, M.; Selwyn, A.P.
Cold is thought to provoke angina in patients with coronary disease either by an increase in myocardial demand or an increase in coronary vascular resistance. We investigated and compared the effects of cold pressor stimulation and symptom-limited supine bicycle exercise on regional myocardial perfusion in 35 patients with stable angina and coronary disease and in 10 normal subjects. Regional myocardial perfusion was assessed with positron emission tomography and rubidium-82. Following cold pressor stimulation 24 of 35 patients demonstrated significant abnormalities of regional myocardial perfusion with reduced cation uptake in affected regions of myocardium: 52 +/- 9 to 43 +/- 9 (p less than 0.001 vs normal subjects). Among these 24 patients only nine developed ST depression and only seven had angina. In contrast, 29 of 35 patients underwent supine exercise, and abnormal regional myocardial perfusion occurred in all 29, with a reduction in cation intake from 48 +/- 10 to 43 +/- 14 (p less than 0.001 vs normal subjects). Angina was present in 27 of 29 and ST depression in 25 of 29. Although the absolute decrease in cation uptake was somewhat greater following cold as opposed to exercise, the peak heart rate after cold was significantly lower than that after exercise (82 +/- 12 vs 108 +/- 16 bpm, p less than 0.05). Peak systolic blood pressures after cold and exercise were similar (159 +/- 24 vs 158 +/- 28). Thus, cold produces much more frequent asymptomatic disturbances of regional myocardial perfusion in patients with stable angina and coronary disease than is suggested by pain or ECG changes.
[Transesophageal atrial stimulation--a test for myocardial ischemia].
Jović, A; Nekić-Borcilo, M; Troskot, R; Nekić, D; Knezević, A; Rados, G
The aim of the present study was to determine clinical value and the feasibility of transesophageal atrial pacing (TAP) in diagnosing myocardial ischemia in patients with coronary artery disease (CAD). Forty patients with CAD and with significant ST-segment depression in a standard 12-lead ECG during bicycle-stress testing underwent TAP. Rapid atrial stimulation was performed by using a very flexible six-polar polyurethane pacing lead introduced through the nares into the esophagus and connected to the stimulator allowing selection of rate, output voltage and pulse duration. The satisfactory atrial pacing was obtained by 28 +/- 6 V output and 7 +/- 1 ms pulse duration. Of 40 patients who underwent TAP, ischemic ECG changes were induced in 35 (u = 2,24 p < 0,05) and were very similar to those that occurred during bicycle-stress testing according to their intensity and distribution and affected ECG leads with comparable peak rate-pressure products. This suggests comparable sensitivity of TAP and bicycle-stress testing in discovering myocardial ischemia in CAD patients. Four patients had negative test for myocardial ischemia and in one TAP was discontinued because of intolerable chest discomfort. In conclusion, TAP is a reliable alternative technique for the assessment of coronary artery disease. In combination with some other noninvasive methods (echocardiography, scintigraphy, i.v. digital angiography), it has become a routine diagnostic procedure in cardiac patients. PMID:8028438
Cardiac cell survival and reversibility of myocardial ischemia.
Rashed, E; Depre, C
Because of a limited capacity for cell regeneration, the cardiac tissue, when submitted to ischemic stress, may activate endogenous mechanisms of cell survival resulting in physiological conditions of adaptation to ischemia, known as myocardial stunning, ischemic preconditioning and myocardial hibernation. These conditions result from a switch in gene and protein expression, which sustains cardiac cell survival in a context of oxygen deprivation and during the stress of reperfusion. Understanding how the molecular adaptation of the cardiac myocyte during stress sustains its survival in these conditions might help to define novel mechanisms of endogenous myocardial salvage, in order to expand the conditions of maintained cellular viability and functional salvage of the ischemic myocardium. This review summarizes recent progress made in the study of the molecular pathways controlling reversible ischemic dysfunction, and the unraveling of novel genomic paradigms. We also focus on the discovery and characterization of novel genes, which further increase our knowledge of myocardial ischemia and open novel therapeutic possibilities for ischemic heart disease. PMID:18942527
Protective Effect of Tetramethylpyrazine on Myocardial Ischemia-Reperfusion Injury
Qian, Weidong; Xiong, Xingjiang; Fang, Zhuyuan; Lu, Haiting; Wang, Zhensheng
Myocardial ischemia-reperfusion injury (MIRI) is a common pathological and physiological phenomenon. Tetramethylpyrazine is the extract of the traditional Chinese medicine Chuanxiong, which can exert protective effects on MIRI in multiple ways. This paper reviewed the current research progress and evidence about the cardiovascular effects of tetramethylpyrazine, which included protecting mitochondria and improving energy metabolism, scavenging oxygen free radicals (OFRs) to inhibit lipid peroxidation, attenuating calcium (Ca2+) overload and maintaining Ca2+ homeostasis in cells, inhibiting apoptosis and protecting myocardial cells, interfering with the inflammatory reaction and mitigating cell injury, interfering with cell signaling pathways, and improving function of endothelial cells and protecting myocardial cells. However, further rigorously designed randomized controlled trials are warranted. PMID:25152756
Protective metabolic effects of propranolol during total myocardial ischemia.
Veronee, C D; Lewis, W R; Takla, M W; Hull-Ryde, E A; Lowe, J E
Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37 degrees C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 +/- 1.4 minutes compared with 75.9 +/- 2.2 minutes in the propranolol-treated group (p less than 0.01). In addition to significantly delaying the onset of ischemic contracture, propranolol also decreased the rate of anaerobic glycolysis during ischemia. Ischemic contracture occurred in the control group with an average adenosine triphosphate level of 1.26 +/- 0.08 mumol compared to 0.91 +/- 0.08 mumol/gm wet weight for the beta blocked group (p less than 0.0025). These are the first data suggesting that the protective effects of beta blockade may be related to a beneficial effect on ischemic myocardial metabolism allowing myocardium to survive with lower levels of adenosine triphosphate. PMID:3018382
Design and fabrication of nanowire electrodes on a flexible substrate for detection of myocardial ischemia
NASA Astrophysics Data System (ADS)
Ramachandran, Vasuda; Yoon, Hargsoon; Varadan, Vijay K.
According to a report by the American Heart Association, there are approximately 3-4 million Americans that may experience silent Myocardial Ischemia (MI). Silent MI is a serious heart condition that can progress to a severe heart attack without any warning and the consequences of such an event can turn fatal quickly. Therefore, there is a strong need for a sensor that can continuously monitor the onset of the condition to prevent high risk individuals from deadly heart attacks. An increase in extracellular potassium levels is the first sign of MI and timely sensing with an implantable potassium sensing biosensor could play a critical role in detecting and expediting care. There are challenges in the development of an implantable potassium sensing electrode one of which includes signal drift. The incorporation of novel nanostructures and smarter materials hold the potential to combat these problems. This paper presents a unique design for an all-solid-state potassium sensing device which offers miniaturization along with enhanced signal transduction. These characteristics are important when it comes to implantable devices and signal drift. Sensor design details along with fabrication processes and sensing results are discussed.
Apperceptive signals demonstrating the dynamic disturbance of myocardial ischemia.
Moulder, P V; Flauto, B; Gallet, B; Galansky, S; Alexander, J A
Analog pressure signals (catheter-tip manometers) from the left atrium, left ventricle, and aorta and a flow signal from the arota were obtained in 25, open-chest, anesthetized dogs in which 115 episodes of ischemia were produced in an area of the left ventricle subtended by the distal left anterior descending coronary artery and its last major diagonal branch. The left ventricular pressure and its first derivative (dP/dt) were displayed as an X-Y loop. The character of this loop went through a unique series of dynamic changes in 110 of the 115 ischemic episodes, indicating that this is a useful tool for monitoring myocardial ischemia. Spectrum pairs of the above signals were analyzed with digital computational transfer functions in 14 ischemic episodes of three experiments and preliminary assessment reveals unique pole and zero changes in many pairs during each episode which also may prove to be a useful indicator of the hemodynamic disturbance incurred during myocardial ischemia. PMID:758716
Antithrombin is protective against myocardial ischemia and reperfusion injury
Wang, Jingying; Wang, Yanqing; Wang, Jinli; Gao, Junjie; Tong, Chao; Manithody, Chandrashekhara; Li, Ji; Rezaie, Alireza R.
Summary Background Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent antiinflammatory properties. Objectives The objective of this study is to investigate the antiinflammatory activity of wild-type AT (AT-WT) and a reactive center loop mutant of AT (AT-RCL) which is not capable of inhibiting thrombin. Methods Cardioprotective activities of AT-WT and AT-RCL were monitored in a mouse model of ischemia/reperfusion injury in which the left anterior descending coronary artery was occluded and then released. Results We demonstrate that AT markedly reduces myocardial infarct size by a mechanism that is independent of its anticoagulant activity. Thus, AT-RCL attenuated myocardial infarct size to the same extent as AT-WT in this acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide (fondaparinux) abrogating the cardioprotective activity of AT and a heparin-site mutant of AT exhibiting no cardioprotective property. We further demonstrate that AT up-regulates production of prostacyclin in myocardial tissues and inhibits expression of proinflammatory cytokines TNF-α and IL-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-κB signaling pathways. Conclusions Our results suggest that both AT and the non-anticoagulant AT-RCL, through their antiinflammatory signaling effects, elicit potent cardioprotective responses. Thus, AT may have therapeutic potential for treating cardiac ischemia/reperfusion injury. PMID:23582062
Lactation protects against myocardial ischemia-reperfusion injury in rats.
Shekarforoush, S; Safari, F
Some researchers have reported that lactation is effective in reducing cardiovascular disease risk factors. The purpose of this study was to investigate whether lactation may improve intrinsic tolerance against ischemia reperfusion (IR) injury. The rats were randomly divided into two groups (n = 8 in each group). In the lactation (Lact) group, the surgery was performed on postpartum day 21 (at the end of lactation period) and the results were compared with those of virgin female rats (control group). Cardiac IR injury was induced by means of left anterior descending coronary artery occlusion for 30 min followed by reperfusion for 120 min. Infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. At the end of the experiment, Mean arterial pressure in the control group was significantly lower than that in the Lact group. Myocardial infarct size was significantly reduced in the Lact group (23 ± 3% vs. 45 ± 8%, p < 0.05 in the control group). Lactation reduced the extent of myocardial injury induced by ischemia and reperfusion. So, lactation may increase cardiac tolerance to ischemic injury. PMID:26690029
Sickle cell anemia: does myocardial ischemia occur during crisis?
Norris, S.; Johnson, C. S.; Haywood, L. J.
The possibility that myocardial ischemia may be associated with chest pain during painful crises was evaluated prospectively in 20 patients (11 women and nine men) with sickle cell disease (19 SS, 1 S beta + thalassemia). Sixteen of 20 (80%) had abnormal ECGs, 7 (35%) had transient ST-T wave changes, and 3 (15%) had persistent ST-T wave changes, both consistent with ischemia; 6 (30%) had nonspecific ST-T changes, and 4 (20%) had normal tracings. Serum enzymes (CK, SGOT, LDH) were abnormal in 16 of 19 (84%); 1 had CK-MB detected, (5%) and 1 had LDH1 to LDH2 reversal. All 10 Tc-99m pyrophosphate scans performed were negative; 4 of 6 (66%) thallium-201 scans had focal defects, and 5 of 8 (63%) radionuclide angiograms (MUGAs) had focal wall motion abnormalities. Three of 8 (38%) MUGAs showed cardiac dilation, diffuse hypokinesis, and reduced ejection fractions. Thus, myocardial damage may be a potentially serious complication of patients with sickle cell anemia who present with chest pain during painful crises. Studies are indicated to define the significance and pathophysiology of these observations. PMID:2038080
Calpain system and its involvement in myocardial ischemia and reperfusion injury
Neuhof, Christiane; Neuhof, Heinz
Calpains are ubiquitous non-lysosomal Ca2+-dependent cysteine proteases also present in myocardial cytosol and mitochondria. Numerous experimental studies reveal an essential role of the calpain system in myocardial injury during ischemia, reperfusion and postischemic structural remodelling. The increasing Ca2+-content and Ca2+-overload in myocardial cytosol and mitochondria during ischemia and reperfusion causes an activation of calpains. Upon activation they are able to injure the contractile apparatus and impair the energy production by cleaving structural and functional proteins of myocytes and mitochondria. Besides their causal involvement in acute myocardial dysfunction they are also involved in structural remodelling after myocardial infarction by the generation and release of proapoptotic factors from mitochondria. Calpain inhibition can prevent or attenuate myocardial injury during ischemia, reperfusion, and in later stages of myocardial infarction. PMID:25068024
The prevalence of silent myocardial ischaemia in patients with white-coat hypertension.
Nalbantgil, I; Onder, R; Nalbantgil, S; Yilmaz, H; Boydak, B
The aim of this study was to estimate the incidence of silent myocardial ischaemia in patients with mild to moderate hypertension, white-coat hypertension (WCH) and those with normal blood pressure. Ambulatory electrocardiographic (ECG) monitoring was carried out in 272 cases with normal blood pressure, 164 cases with mild to moderate hypertension (diastolic blood pressure >95 and <114 mm Hg), and 106 cases with white-coat hypertension who were diagnosed with ambulatory blood pressure monitoring. The ages of the patients of all groups were between 42-61 years. There were no differences between the groups according to age, gender and other parameters. There were no anginal symptoms, and resting ECGs were in normal limits in all cases. The diagnosis of silent ischaemia was considered to be present if there was ST depression >2 mm/at least 120 sec in ambulatory ECG examination without angina or its equivalent cardiac symptoms. The incidence of silent ischaemia was 6.4%, 18.8%, and 26.2% in cases with normal blood pressure, WCH, and hypertension, respectively. The differences between groups were significant. It was concluded that WCH is not a benign condition, but shares some characteristics with essential hypertension. PMID:9655656
Usefulness of Neuron-Specific Enolase to Detect Silent Neuronal Ischemia After Percutaneous Coronary Intervention.
Goksuluk, Huseyin; Gulec, Sadi; Ozcan, Ozgur Ulas; Gerede, Menekse; Vurgun, Veysel Kutay; Ozyuncu, Nil; Erol, Cetin
Increased plasma levels of neuron-specific enolase (NSE) are related to damage of neurons and neuroendocrine cells. We aimed to investigate elevation of NSE after elective percutaneous coronary intervention (PCI) on the prediction of silent cerebral infarct (SCI). Study population consisted of 2 groups of patients. Group 1 included 92 consecutive patients with normal coronary angiograms, whereas group 2 consisted of 89 patients who underwent elective coronary stenting. NSE levels were studied before and 12 hours after the procedure. Elevation of >0.12 μg/L was considered as SCI. Forty-seven of 181 study patients (26%) had SCI after the procedure. NSE elevation was significantly more prevalent in patients with PCI than that of controls. Elevation of NSE was observed in 42% of patients who underwent elective PCI (n = 37) and 11% of the normal coronary artery group (n = 10) (p <0.001). The incidence of SCI was higher in active smokers and patients who had history of myocardial infarction (MI) (55% vs 10%, p <0.001 for active smokers and 40% vs 8%, p <0.001 for history of MI, respectively). Multivariate analysis demonstrated history of smoking (odds ratio [OR] 9.9; 95% confidence interval [CI] 3.7 to 26.9; p <0.001) and previous MI (OR 4.4; 95% CI 1.7 to 11.4; p = 0.01) as independent predictors of SCI. For patients who underwent elective PCI, NSE levels after procedure increases. Invasive coronary procedures have risk of SCIs, even in patients with normal coronary arteries. In conclusion, increased diagnosis of SCIs might improve understanding of their relation with invasive cardiac procedures, facilitate to prevent occurrence of silent microemboli and decrease the risk of adverse neurologic events. PMID:27134059
Sum of effects of myocardial ischemia followed by electrically induced tachycardia on myocardial function
Díez, José Luis; Hernándiz, Amparo; Cosín-Aguilar, Juan; Aguilar, Amparo; Portolés, Manuel
Background The alteration of contractile function after tachyarrhythmia ceases is influenced by the type of prior ischemia (acute coronary syndrome or ischemia inherent in a coronary revascularization procedure). We aimed to analyze cardiac dysfunction in an acute experimental model of supraphysiological heart rate preceded by different durations and types of ischemia. Material/Methods Twenty-four pigs were included in: (S1) series of ventricular pacing; (S2, A and B) series with 10 or 20 min, respectively, of coronary occlusion previous to ventricular pacing; S3 with 20 brief, repeated ischemia/reperfusion processes prior to ventricular pacing and; (S4) control series. Overall cardiac function parameters and regional myocardial contractility at the apex and base of the left ventricle were recorded, as were oxidative stress markers (glutathione and lipid peroxide serum levels). Left ventricular pacing at 60% over baseline heart rate was performed for 2 h followed by 1 h of recovery. Results High ventricular pacing rates preceded by short, repeated periods of coronary ischemia/reperfusion resulted in worse impairment of overall cardiac and regional function that continued to be altered 1 h after tachycardia ceased. There was significant reduction of stroke volume (26.9±5.3 basal vs. 16±6.2 ml; p<0.05), LVP; dP/dt and LAD flow (13.1±1.5 basal vs. 8.4±1.6 ml/min; p<0.05); the base contractility remained altered when recovering compared to baseline (base SF: 5.6±2.8 vs. 2.2±0.7%; p<0.05); and LPO levels were higher than less aggressive series at the end of recovery. Conclusions Ischemia and tachycardia accumulate their effects, with increased cardiac involvement depending on the type of ischemia. PMID:23722244
Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy
Nesto, R.W.; Phillips, R.T.; Kett, K.G.; Hill, T.; Perper, E.; Young, E.; Leland, O.S. Jr.
Patients with diabetes mellitus and coronary artery disease are thought to have painless myocardial ischemia more often than patients without diabetes. We studied 50 consecutive patients with diabetes and 50 consecutive patients without diabetes, all with ischemia, on exercise thallium scintigraphy to show the reliability of angina as a marker for exertional ischemia. The two groups had similar clinical characteristics, treadmill test results, and extent of infarction and ischemia, but only 7 patients with diabetes compared with 17 patients without diabetes had angina during exertional ischemia. In diabetic patients the extent of retinopathy, nephropathy, or peripheral neuropathy was similar in patients with and without angina. Angina is an unreliable index of myocardial ischemia in diabetic patients with coronary artery disease. Given the increased cardiac morbidity and mortality in such patients, periodic objective assessments of the extent of ischemia are warranted.
Silent left ventricular dysfunction during routine activity after thrombolytic therapy for acute myocardial infarction
Kayden, D.S.; Wackers, F.J.; Zaret, B.L. )
To investigate prospectively the occurrence and significance of postinfarction transient left ventricular dysfunction, 33 ambulatory patients who underwent thrombolytic therapy after myocardial infarction were monitored continuously for 187 +/- 56 min during normal activity with a radionuclide left ventricular function detector at the time of hospital discharge. Twelve patients demonstrated 19 episodes of transient left ventricular dysfunction (greater than 0.05 decrease in ejection fraction, lasting greater than or equal to 1 min), with no change in heart rate. Only two episodes in one patient were associated with chest pain and electrocardiographic changes. The baseline ejection fraction was 0.52 +/- 0.12 in patients with transient left ventricular dysfunction and 0.51 +/- 0.13 in patients without dysfunction (p = NS). At follow-up study (19.2 +/- 5.4 months), cardiac events (unstable angina, myocardial infarction or death) occurred in 8 of 12 patients with but in only 3 of 21 patients without transient left ventricular dysfunction (p less than 0.01). During submaximal supine bicycle exercise, only two patients demonstrated a decrease in ejection fraction greater than or equal to 0.05 at peak exercise; neither had a subsequent cardiac event. These data suggest that transient episodes of silent left ventricular dysfunction at hospital discharge in patients treated with thrombolysis after myocardial infarction are common and associated with a poor outcome. Continuous left ventricular function monitoring during normal activity may provide prognostic information not available from submaximal exercise test results.
Polyamine metabolism in rat myocardial ischemia-reperfusion injury.
Han, Liping; Xu, Changqing; Guo, Yimin; Li, Hongzhu; Jiang, Chunming; Zhao, Yajun
This study was focused on investigating the involvement of polyamine metabolism in the myocardial ischemia-reperfusion injury (MIRI) in an in vivo rat model. A branch of the descending left coronary artery was occluded for 30 min followed by 2 h, 6 h, 12 h, and 24 h reperfusion. Then the expression of spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) and the concentrations of polyamines were assessed. It was found that the expression of SSAT and ODC were upregulated after reperfusion and the concentrations of spermidine and spermine were significantly decreased, while putrescine concentration was significantly increased. The results suggest that MIRI may cause disturbance of polyamine metabolism, and it may play a critical role in MIRI. PMID:18077014
[Value of the exercise test in asymptomatic myocardial ischemia].
Iturralde, P; Hernández, D; de Micheli, A; Colín, L; Romero, L; Villarreal, A; Férez, S; Miguel Casanova, J; Barrera, M; González-Hermosillo, J A
To evaluate the predictive value of ischemic ST segment depression without associated chest pain during exercise testing, data were analyzed from 7305 studies. Two hundred thirty six patients were included in this study and were separated in 2 groups. Group A consisted of 169 patients without chest pain who, during exercise testing, showed a positive ST segment response (at least 1.5 mm of horizontal or downward ST segment depression for at least 0.08 second, compared with the resting baseline value), and Group B consisted of 67 patients who had both chest pain and a positive ST segment response. Selective coronary angiogram was performed on all patients. Each Group was separated into 3 sub-group according to the Cohn criteria: sub-group I (asymptomatic persons 8.3 vs 19.4%); sub-group II (patients with history of Myocardial Infarction 36.7% vs 19.4%); sub-group III (patients with chronic angina 55% vs 61.2%). The clinical characteristics, coronary risk factors, distribution of coronary artery disease, and exercise test response were similar in both groups. During treadmill exercise, the mean heart rate was 140.6 +/- 22 in group A versus 127.1 +/- 23 in the group B. The pressure-rate product was 2.4 +/- 0.8 versus 1.9 +/- 0.5, respectively (P less than or equal to 0.05). The predictive value for severe coronary artery disease of an exercise test in patients with asymptomatic ischemia was 77.5% as compared with 89.6% in the group with angina. This study confirms the high frequency of asymptomatic myocardial ischemia during exercise testing, compared with patients who had angina during exercise testing, with high percentage of prediction (77.5%) for coronary artery disease. PMID:2344225
Silent myocardial ischaemia in chronic stable angina: a study of its frequency and characteristics in 150 patients.
Mulcahy, D; Keegan, J; Crean, P; Quyyumi, A; Shapiro, L; Wright, C; Fox, K
One hundred and fifty unselected patients with documented coronary artery disease were studied to establish the frequency and characteristics of silent myocardial ischaemia. Patients underwent ambulatory ST segment monitoring off all routine antianginal treatment (total 6264 hours) and exercise testing (n = 146). Ninety one patients (61%) had a total of 598 episodes of significant ST segment change, of which 446 (75%) were asymptomatic. Twenty seven patients (18%) had only painless episodes; 14 (9%) patients only painful episodes; 50 patients (33%) had both painless and painful episodes. The mean number of ST segment changes per day was 2.58 (1.95 silent); however, 11 patients (7%) had 50% of all silent episodes, and 48 patients (32%) had 91% of all silent episodes. Fifty nine patients (39%) had no ST segment changes on ambulatory monitoring, and 73 patients (49%) had no evidence of silent ischaemia. Episodes of silent ischaemia occurred with a similar circadian distribution to that of painful ischaemia, predominantly between 0730 and 1930. There was a similar mean rise in heart rate at the onset of both silent and painful episodes of ischaemia. Silent ischaemia was significantly more frequent in patients with three vessel disease than in those with single vessel disease, and was also significantly related to both time to 1 mm ST depression and maximal exercise duration on exercise testing. There was a highly significant relation between the mean number and duration of episodes of silent ischaemia in patients with positive exercise tests when compared with those with negative tests. No episode of ventricular tachycardia was recorded in association with silent ischaemic change. PMID:3203036
In vivo determination of acute myocardial ischemia based on photoacoustic imaging with a focused transducer
NASA Astrophysics Data System (ADS)
Li, Zhifang; Li, Hui; Chen, Haiyu; Xie, Wengming
The location and ischemia extent are two important parameters for evaluating the acute myocardial ischemia (AMI). A focused-transducer-based photoacoustic imaging method was employed to assess time-dependent AMI. Our preliminary results show that the photoacoustic signal could identify the myocardium. The intensity and area of photoacoustic images of myocardium could be used for characterizing the ischemia extent and scope of myocardial ischemia. The results also imply that the intensity and area of photoacoustic images are the rapid fall of an exponential model with an increase of delaying time after the left anterior descending coronary artery (LAD) occlusion. These experimental results were consistent with the clinical characteristics. The findings suggest that the photoacoustic imaging be a potential tool for the real-time assessment of acute myocardial ischemia during surgical operation.
Imaging of cocaine-induced global and regional myocardial ischemia
Oster, Z.H.; Som, P.; Wang, G.J.; Weber, D.A. )
Severe and often fatal cardiac complications have been reported in cocaine users with narrowed coronary arteries caused by atherosclerosis as well as in young adults with normal coronaries. The authors have found that in normal dogs cocaine induces severe temporary hypoperfusion of the left ventricle as indicated by a significantly lower 201Tl concentration compared to the baseline state. The most significant decrease in uptake occurred 5 min after injection and was more pronounced in the septal and apical segments. Following intravenous administration of cocaine, instead of gradual disappearance of 201Tl from the left ventricle, there was continuous increase in 201Tl concentration in the left ventricle. These imaging experiments indicate that the deleterious effects of cocaine on the heart are probably due to spasm of the coronaries and decreased myocardial perfusion. Since spasm of the large subpericardial vessels does not seem to explain the magnitude of the increased coronary resistance and decreased coronary flow after cocaine as described in the literature, it is suggested that microvascular spasm of smaller vessels plays a major role in the temporary decrease in perfusion. The data may also suggest that severe temporary myocardial ischemia is probably the initiating factor for the cardiac complications induced by cocaine.
Silent ischemia after coronary angioplasty: Evaluation of restenosis and extent of ischemia in asymptomatic patients by tomographic thallium-201 exercise imaging and comparison with symptomatic patients
Hecht, H.S.; Shaw, R.E.; Chin, H.L.; Ryan, C.; Stertzer, S.H.; Myler, R.K. )
One hundred sixteen patients were evaluated to determine the ability of single photon emission computed tomographic (SPECT) thallium-201 exercise and redistribution imaging to detect silent ischemia secondary to restenosis in asymptomatic patients after single and multiple vessel percutaneous transluminal coronary angioplasty and the findings were compared with SPECT imaging detection of restenosis in symptomatic patients. The value of exercise electrocardiography (ECG) and the amount of ischemic myocardium in symptomatic and asymptomatic patients were determined. Forty-one patients were asymptomatic after angioplasty; 77% of these had chest pain before angioplasty. Seventy-five patients had chest pain after angioplasty; 99% of these had chest pain before angioplasty. Restenosis occurred in 61% of asymptomatic and 59% of symptomatic patients and in 46% of the vessels in both asymptomatic and symptomatic patients. Sensitivity, specificity and accuracy for detection of restenosis by SPECT in individual patients were 96%, 75% and 88% versus 91%, 77% and 85%, respectively, in the asymptomatic versus symptomatic groups (p = NS). Sensitivity, specificity and accuracy for restenosis detection in individual vessels were 90%, 89% and 89% versus 84%, 77% and 84%, respectively, in the asymptomatic and symptomatic groups (p = NS), with similar results for the three major arteries. Sensitivity and accuracy of exercise ECG were significantly less than those of SPECT imaging for the patients with silent (40% and 44%) and symptomatic (59% and 64%) ischemia (p less than 0.001). Restenosis of vessels in the patients with silent and symptomatic ischemia was associated with an equal amount and degree of severity of ischemic myocardium in the two groups.
Etanercept Attenuates Myocardial Ischemia/Reperfusion Injury by Decreasing Inflammation and Oxidative Stress
Yang, Mei; Chen, Jianchang; Zhao, Jing; Meng, Mei
The protective role of etanercept in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether etanercept modulates neutrophil accumulation, TNF-α induction and oxidative stress in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+ etanercept. The results demonstrated that compared to MI/R, etanercept reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels, and both serum and myocardial TNF-α production. Etanercept also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. In summary, our data suggested that etanercept has protective effects against MI/R injury in rats, which may be attributed to attenuating inflammation and oxidative stress. PMID:25260027
[Effect and mechanism of icariin on myocardial ischemia-reperfusion injury model in diabetes rats].
Hu, Yan-wu; Liu, Kai; Yan, Meng-tong
To study the therapeutic effect and possible mechanism of icariin on myocardial ischemia-reperfusion injury ( MIRI) model in diabetes rats. The model of diabetic rats were induced by Streptozotocin (STZ), then the model of MIRI was established by ligating the reversible left anterior descending coronary artery for 30 min, and then reperfusing for 120 min. totally 40 male SD were randomly divided into five groups: the control group (NS), the ischemia reperfusion group (NIR), the diabetes control group (MS), the diabetic ischemia reperfusion group (MIR) and the diabetic ischemia reperfusion with icariin group (MIRI). The changes in blood glucose, body weight and living status were observed; the enzyme activity of serum CK-MB, LDH, GSH-Px and myocardium SOD and the content MDA and NO in myocardium were detected; the myocardial pathological changes were observed by HE staining; the myocardial Caspase-3, the Bcl-2, Bax protein expressions were detected by Western blot. The result showed that the diabetes model was successfully replicated; myocardial ischemia-reperfusion injury was more serious in diabetes rats; icariin can increase NO, SOD, GSH-Px, Bcl-2 protein expression, decrease MDA formation, CK-MB and LDH activities and Caspase-3 and Bcl-2 protein expressions and myocardial damage. The result suggested that icariin may play a protective role against ischemia reperfusion myocardial injury in diabetes rats by resisting oxidative stress and inhibiting cell apoptosis. PMID:27071263
Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage
NASA Astrophysics Data System (ADS)
Webb, Andrew; Bond, Richard; McLean, Peter; Uppal, Rakesh; Benjamin, Nigel; Ahluwalia, Amrita
Nitric oxide (NO) is thought to protect against the damaging effects of myocardial ischemia-reperfusion injury, whereas xanthine oxidoreductase (XOR) normally causes damage through the generation of reactive oxygen species. In the heart, inorganic nitrite has the potential to act as an endogenous store of NO, liberated specifically during ischemia. Using a detection method that we developed, we report that under ischemic conditions both rat and human homogenized myocardium and the isolated perfused rat heart (Langendorff preparation) generate NO from in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 µM) reduced infarct size from 47.3 ± 2.8% (mean percent of control ± SEM) to 17.9 ± 4.2% and 17.4 ± 1.0%, respectively (P < 0.001), and was associated with comparable improvements in recovery of left ventricular function. This protective effect was completely blocked by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO). In summary, the generation of NO from •, rather than damaging.
[Protective effect of lornoxicam on development of myocardial infarction in rats under conditions of ischemia and ischemia-reperfusion].
Gavrilova, S A; Lipina, T V; Zagidullin, T R; Fominykh, E S; Golubeva, A V; Varenik, E N; Parnes, E Ia; Semenov, P A
Activation of inflammation and enzyme cyclooxygenase with formation of proinflammatory prostaglandins is a key element of development of myocardial infarction in patients with acute coronary syndrome. Basing on literature data and own experience we suggested that single intravenous injection of 230 mg/kg of nonselective inhibitor of type 1 and 2 cyclooxygenase lornaxicam in the phase of initialization of inflammation 20 min after onset of ischemia would lead to reduction of myocardial infarction volume in rats in irreversible ischemia and ischemia with subsequent reperfusion. The conducted study allowed to reveal that administration of lornoxicam in recommended for human use dose lowered mortality of animals and increased number of capillaries per one cardiomyocyte in case of irreversible coronary artery occlusion. In ischemia-reperfusion as in irreversible myocardial ischemia lornoxicam reduced volume of necrosis and degree of thinning of left ventricular wall in the region of infarction, and lowered volume of connective tissue in periinfarction zone of the myocardium in remote period. PMID:19076093
Investigation of ischemia modified albumin, oxidant and antioxidant markers in acute myocardial infarction
Hazini, Ahmet; Işıldak, İbrahim; Alpdağtaş, Saadet; Önül, Abdullah; Şenel, Ünal; Kocaman, Tuba; Dur, Ali; Iraz, Mustafa; Uyarel, Hüseyin
Introduction Acute myocardial infarction (AMI) is still one of the most common causes of death worldwide. In recent years, for diagnosis of myocardial ischemia, a new parameter, called ischemia modified albumin (IMA), which is thought to be more advantageous than common methods, has been researched. Aim In this study, systematic analysis of parameters considered to be related to myocardial ischemia has been performed, comparing between control and myocardial ischemia groups. Material and methods We selected 40 patients with AMI and 25 healthy controls for this study. Ischemia modified albumin levels, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) antioxidant enzyme activities and non-enzymatic antioxidants such as retinol, α-tocopherol, β-carotene and ascorbic acid levels were investigated in both groups. Glutathione (GSH) and malondialdehyde (MDA) levels, which are indicators of oxidative stress, were compared between patient and control groups. Results Ischemia modified albumin levels were found significantly higher in the AMI diagnosed group when compared with controls. The MDA level was elevated in the patient group, whereas the GSH level was decreased. SOD, GPx and CAT enzyme levels were decreased in the patient group, where it could be presumed that oxidative stress causes the cardiovascular diseases. Conclusions Due to the increased oxidative stress, non-enzymatic and enzymatic antioxidant capacity was affected. Systematic investigation of parameters related to myocardial infarction has been performed, and it is believed that such parameters can contribute to protection and early diagnosis of AMI and understanding the mechanism of development of the disease. PMID:26677379
Antiapoptotic Effect of Simvastatin Ameliorates Myocardial Ischemia/Reperfusion Injury
Hadi, Najah R.; Al-amran, Fadhil; Yousif, Maitham; Zamil, Suhaad T.
Background. Myocardial ischemial reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. Injury of myocardium due to ischemial reperfusion includes cardiac contractile dysfunction, arrhythmias, and irreversible myocytes damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. Objective. This study was undertaken to investigate the potential role of Simvastatin in the amelioration of myocardial I/R injury induced by ligation of coronary artery in a rat model. Materials and Methods. Adult male Swiss Albino rats were randomized into 4 equal groups. Group (1): sham group: rats underwent the same anesthetic and surgical procedures as those in the control group except ligation of LAD coronary artery, group (2): control group: rats were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (3): control vehicle group: rats received vehicle of Simvastatin (normal saline) via IP injection and were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (4): Simvastatin treated group: rats were pretreated with Simvastatin 1 mg/kg i.p. 1 hr before ligation of LAD coronary artery. At the end of experiment (2 hr of reperfusion), blood samples were collected from the heart for the measurement of plasma level of cardiac troponin I (cTnI). After that the heart was harvested and divided into 3 parts; one part was used for measurement of apoptosis, another part was homogenized for the measurement of tissue tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α, and the last part for histopathology study. Results. Compared with the sham group, levels of myocardial TNF-α and IL-1β, IL-6
Acute myocardial infarction and myocardial ischemia-reperfusion injury: a comparison
Hashmi, Satwat; Al-Salam, Suhail
Myocardial infarction (MI) denotes the death of cardiac myocytes due to extended ischemia. Myocardial reperfusion is the restoration of coronary blood flow after a period of coronary occlusion. Reperfusion has the potential to salvage ischemic myocardium but paradoxically can cause injury, a phenomenon called as 'reperfusion injury' (IR). Standard histologic, immunohistochemical and Elisa techniques were used to study the histopathologic, oxidative, apoptotic and inflammatory changes in MI and IR. The IL-6 levels in the LV of the MI group were significantly raised as compared to the IR group (P=0.0008). Plasma IL-6 was also significantly increased in the MI group as compared to the IR group (P=0.031). MI model was also associated with increase in the neutrophil polymorphs number in the infarction related myocardium as compared to the re-perfused myocardium. A significant increase in troponin I level in the MI group as compared to the IR group is also seen (P=0.0001). Our IR model showed enhanced pro-apoptotic mediators like cleaved caspase-3 (P=0.005) and cytochrome c in the myocardium as compared to the MI model. In conclusion, myocardial damage in MI is mainly due to ischemic necrosis and inflammatory mechanisms while apoptosis is the main mechanism of cell death in IR in addition to limited ischemic necrosis. PMID:26464621
The role of neutrophils in myocardial ischemia-reperfusion injury.
Jordan, J E; Zhao, Z Q; Vinten-Johansen, J
Reperfusion of ischemic myocardium is necessary to salvage tissue from eventual death. However, reperfusion after even brief periods of ischemia is associated with pathologic changes that represent either an acceleration of processes initiated during ischemia per se, or new pathophysiological changes that were initiated after reperfusion. This 'reperfusion injury' shares many characteristics with inflammatory responses in the myocardium. Neutrophils feature prominently in this inflammatory component of postischemic injury. Ischemia-reperfusion prompts a release of oxygen free radicals, cytokines and other proinflammatory mediators that activate both the neutrophils and the coronary vascular endothelium. Activation of these cell types promotes the expression of adhesion molecules on both the neutrophils and endothelium, which recruits neutrophils to the surface of the endothelium and initiate a specific cascade of cell-cell interactions, leading first to adherence of neutrophils to the vascular endothelium, followed later by transendothelial migration and direct interaction with myocytes. This specific series of events is a prerequisite to the phenotypic expression of reperfusion injury, including endothelial dysfunction, microvascular collapse and blood flow defects, myocardial infarction and apoptosis. Pharmacologic therapy can target the various components in this critical series of events. Effective targets for these pharmacologic agents include: (a) inhibiting the release or accumulation of proinflammatory mediators, (b) altering neutrophil or endothelial cell activation and (c) attenuating adhesion molecule expression on endothelium, neutrophils and myocytes. Monoclonal antibodies to adhesion molecules (P-selectin, L-selectin, CD11, CD18), complement fragments and receptors attenuate neutrophil-mediated injury (vascular injury, infarction), but clinical application may encounter limitations due to antigen-antibody reactions with the peptides. Humanized
Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients.
Kim, Bong-Sung; Jacobs, Denise; Emontzpohl, Christoph; Goetzenich, Andreas; Soppert, Josefin; Jarchow, Mareike; Schindler, Lisa; Averdunk, Luisa; Kraemer, Sandra; Marx, Gernot; Bernhagen, Jürgen; Pallua, Norbert; Schlemmer, Heinz-Peter; Simons, David; Stoppe, Christian
In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients. PMID:27055858
Protective effect of caffeine administration on myocardial ischemia/reperfusion injury in rats.
Li, Xu-Yong; Xu, Lin; Lin, Guo-Sheng; Li, Xiao-Yan; Jiang, Xue-Jun; Wang, Tao; Lü, Jing-Jun; Zeng, Bin
Many studies have examined the association between coffee consumption and risk of cardiovascular disease, but the results remain controversial. Caffeine is one of the main biologically active compounds of coffee. The aim of this study was to investigate the potential role of caffeine on myocardial ischemia/reperfusion (I/R) injury in the rats. We administered caffeine (25 mg/kg per day) or saline in rats for 4 weeks before myocardial ischemia/reperfusion operation. Compared with the sham group, caffeine treatment decreased ischemia-associated infarct size, serum creatine kinase, and lactate dehydrogenase 3-h reperfusion after 30-min ischemia. Myocardial neutrophil infiltration (assessed by myeloperoxidase activity) was significantly decreased compared with the control group. Meanwhile, caffeine reduced the myocardial apoptosis and suppressed the activation of caspase 3 during myocardial I/R. Importantly, we observed a strong poly(ADP-ribose) polymerase (PARP) activation during myocardial I/R, and caffeine administration inhibited PARP activation and attenuated the expression of PARP-related proinflammatory mediators such as inducible nitric oxide synthetase, IL-6, and TNF-α, all of which may be correlated with downregulated nuclear factor κB activity. We concluded that caffeine protected against myocardial I/R injury by inhibiting inflammation and apoptosis. PMID:21558980
New insights into symptomatic or silent atrial fibrillation complicating acute myocardial infarction.
Stamboul, Karim; Fauchier, Laurent; Gudjoncik, Aurelie; Buffet, Philippe; Garnier, Fabien; Lorgis, Luc; Beer, Jean Claude; Touzery, Claude; Cottin, Yves
Atrial fibrillation (AF) is the most frequent heart rhythm disorder in the general population and contributes not only to a major deterioration in quality of life but also to an increase in cardiovascular morbimortality. The onset of AF in the acute phase of myocardial infarction (MI) is a major event that can jeopardize the prognosis of patients in the short-, medium- and long-term, and is a powerful predictor of a poor prognosis after MI. The suspected mechanism underlying the excess mortality is the drop in coronary flow linked to the acceleration and arrhythmic nature of the left ventricular contractions, which reduce the left ventricular ejection fraction. The principal causes of AF-associated death after MI are linked to heart failure. Moreover, the excess risk of death in these heart failure patients has also been associated with the onset of sudden death. Whatever its form, AF has a major negative effect on patient prognosis. In recent studies, symptomatic AF was associated with inhospital mortality of 17.8%, to which can be added mortality at 1year of 18.8%. Surprisingly, silent AF also has a negative effect on the prognosis, as it is associated with an inhospital mortality rate of 10.4%, which remains high at 5.7% at 1year. Moreover, both forms of AF are independent predictors of mortality beyond traditional risk factors. The frequency and seriousness of silent AF in the short- and long-term, which were until recently rarely studied, raises the question of systematically screening for it in the acute phase of MI. Consequently, the use of continuous ECG monitoring could be a simple, effective and inexpensive solution to improve screening for AF, even though studies are still necessary to validate this strategy. Finally, complementary studies also effect of oxidative stress and endothelial dysfunction, which seem to play a major role in triggering this rhythm disorder. PMID:26525569
Qishen Yiqi Drop Pill improves cardiac function after myocardial ischemia
JianXin, Chen; Xue, Xu; ZhongFeng, Li; Kuo, Gao; FeiLong, Zhang; ZhiHong, Li; Xian, Wang; HongCai, Shang
Myocardial ischemia (MI) is one of the leading causes of death, while Qishen Yiqi Drop Pill (QYDP) is a representative traditional Chinese medicine to treat this disease. Unveiling the pharmacological mechanism of QYDP will provide a great opportunity to promote the development of novel drugs to treat MI. 64 male Sprague-Dawley (SD) rats were divided into four groups: MI model group, sham operation group, QYDP treatment group and Fosinopril treatment group. Echocardiography results showed that QYDP exhibited significantly larger LV end-diastolic dimension (LVEDd) and LV end-systolic dimension (LVEDs), compared with the MI model group, indicating the improved cardiac function by QYDP. 1H-NMR based metabonomics further identify 9 significantly changed metabolites in the QYDP treatment group, and the QYDP-related proteins based on the protein-metabolite interaction networks and the corresponding pathways were explored, involving the pyruvate metabolism pathway, the retinol metabolism pathway, the tyrosine metabolism pathway and the purine metabolism pathway, suggesting that QYDP was closely associated with blood circulation. ELISA tests were further employed to identify NO synthase (iNOS) and cathepsin K (CTSK) in the networks. For the first time, our work combined experimental and computational methods to study the mechanism of the formula of traditional Chinese medicine. PMID:27075394
Effect of a Transient Period of Ischemia on Myocardial Cells
Kloner, Robert A.; Ganote, Charles E.; Whalen, Daniel A.; Jennings, Robert B.
Changes produced in the posterior papillary muscle of the dog following 40 minutes of circumflex artery occlusion and 0 to 20 minutes of blood reflow were studied by electron miroscopy. With no reflow of blood, myocardial cells were modestly swollen, contained amorphous matrix densities in the mitochondria, had aggregation and margination of nuclear chromatin and relaxation of myofibrils. With as little as 2 minutes of blood reflow, cells developed contraction bands and were greatly swollen due to a generalized increase in sarcoplasmic space, formation of vacuoles and swelling of mitochondria. Frequently, cell membranes were lifted away from the myofibers, forming large subsarcolemmal blebs which appeared capable of compressing adjacent capillaries. The extracellular space did not appear to be enlarged, and the marked tissue edema found after reflow was due primarily to accumulation of intracellular fluid. In addition to explosive cell swelling, there was, over the 2- to 20-minute period of reflow, a progressive increase in size and number of granular mitochondrial dense bodies of the calcium accumulation type. No significant changes in lysosomes were observed. The speed with which the morphologic changes developed during very early reflow periods suggests that irreversible ischemic injury produces a defect in cell volume regulation during the phase of ischemia and that this defect becomes manifest if arterial flow is restored to the affected cells. ImagesFig 7Fig 8Fig 9Fig 10Fig 11Fig 12Fig 13Fig 14Fig 15Fig 1Fig 2Fig 3Fig 4Fig 5Fig 6 PMID:4814895
Humanized cobra venom factor decreases myocardial ischemia reperfusion injury
Gorsuch, W. Brian; Guikema, Benjamin J.; Fritzinger, David C.; Vogel, Carl-Wilhelm; Stahl, Gregory L.
Cobra venom factor (CVF) is a complement activating protein in cobra venom, which functionally resembles C3b, and has been used for decades for decomplementation of serum to investigate the role of complement in many model systems of disease. The use of CVF for clinical practice is considered impractical because of immunogenicity issues. Humanization of CVF was recently demonstrated to yield a potent CVF-like molecule. In the present study, we demonstrate that mice treated with recombinant humanized CVF (HC3-1496) are protected from myocardial ischemia-reperfusion (MI/R) injuries with resultant preservation of cardiac function. Also, C3 deposition in the myocardium following MI/R was not observed following treatment with HC3-1496. HC3-1496 led to complement activation and depletion of C3, but preserved C5 titers. These data suggest, unlike CVF, HC3-1496 does not form a C5 convertase in the mouse, similar to recent studies in human sera/plasma. These results suggest that humanized CVF (HC3-1496) protects the ischemic myocardium from reperfusion injuries induced by complement activation and represents a novel anti-complement therapy for potential clinical use. PMID:19747734
Myocardial ischemia analysis based on electrocardiogram QRS complex.
Song, Jinzhong; Yan, Hong; Xu, Zhi; Yu, Xinming; Zhu, Ruiyun
Electrocardiogram (ECG) is an economic, convenient, and non-invasive detecting tool in myocardial ischemia (MI), and its clinical appearance is mainly exhibited by the changes in ST-T complex. Recently, QRS complex characters were proposed to analyze MI by more and more researchers. In this paper, various QRS complex characters were extracted in ECG signals, and their relationship was analyzed systematically. As a result, these characters were divided into two groups, and there existed good relationship among them for each group, while the poor relationship between the groups. Then these QRS complex characters were applied for statistical analysis on MI, and five characters had significant differences after ECG recording verification, which were: QRS upward and downward slopes, transient heart rate, angle R and angle Q. On the other hand, these QRS complex characters were analyzed in frequency domain. Experimental results showed that the frequency features of RR interval series (Heart Rate Variability, HRV), and QRS barycenter sequence had significant differences between MI states and normal states. Moreover, QRS barycenter sequence performed better. PMID:21971843
Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study.
Uys, A S; Malan, L; van Rooyen, J M; Steyn, H S; Reimann, M; Ziemssen, T
Chronically elevated blood pressure has been associated with impaired NO-mediated vasodilation and structural vascular disease risk. This study aimed to determine whether significant associations exist regarding NO metabolite (NOx) responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. The study included 81 African and 94 Caucasian male teachers stratified via median splits into low and high NOx ethnic groups. Ambulatory blood pressure, electrocardiogram monitoring and ultrasound carotid intima-media thickness (CIMT) images were obtained. Cardiovascular measurements and fasting blood for NOx responses were measured during rest and on challenging the cardiovascular system with the Stroop colour-word conflict test. African men displayed significantly higher resting NOx as well as higher number of 24 h silent ischemic events than their Caucasian counterparts. Low NOx African men displayed enhanced α-adrenergic and ECG ST segment depression acute mental stress responses as well as 24 h silent ischemic events associated with CIMT (adjusted R(2) = 0.47; β = 0.25; confidence interval (CI) = 0.13, 0.41). African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed α-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. The association between myocardial ischemia and CIMT in this group emphasized their risk for future coronary artery disease and cerebrovascular events. PMID:24401953
Crocin-Elicited Autophagy Rescues Myocardial Ischemia/Reperfusion Injury via Paradoxical Mechanisms.
Zeng, Chao; Li, Hu; Fan, Zhiwen; Zhong, Lei; Guo, Zhen; Guo, Yaping; Xi, Yusheng
Crocin, the main effective component of saffron, exerts protective effects against ischemia/reperfusion injury during strokes. However, the effects of crocin in myocardial ischemia/reperfusion injury, and the mechanisms involved, remain unknown. Pretreated with crocin for 7 days, C57BL/6N mice were subjected to 30 min of myocardial ischemia followed by 12[Formula: see text]h of reperfusion (for cardiac function and infarct size, cell apoptosis and necrosis). Neonatal mouse cardiomyocytes were subjected to 2 h of hypoxia followed by 4 h of reoxygenation. NMCM's survival was assessed during hypoxia and reoxygenation in the presence or absence of the autophagy inhibitor 3-methyladenine or the inducer rapamycin. Western blotting was used to evaluate AMPK, Akt, and autophagy-related proteins. Autophagosome was observed using electron microscopy. In the in vivo experiment, crocin pretreatment significantly attenuated infarct size, myocardial apoptosis and necrosis, and improved left ventricular function following ischemia/reperfusion. In vitro data revealed that autophagy was induced during hypoxia, the levels of which were intensely elevated during reoxygenation. Crocin significantly promoted autophagy during ischemia, accompanied with the activation of AMPK. In contrast, crocin overtly inhibited autophagy during reperfusion, accompanied with Akt activation. Induction and inhibition of autophagy mitigated crocin induced protection against NMCMs injury during hypoxia and reoxygenation, respectively. Our data suggest that crocin demonstrated a myocardial protective effect via AMPK/mTOR and Akt/mTOR regulated autophagy against ischemia and reperfusion injury, respectively. PMID:27109157
Improvement of myocardial ischemic dysfunction with dichloroacetic acid: experimental study by repeated ischemia in dogs.
Okuda, K; Nohara, R; Fujita, M; Tamaki, N; Konishi, J; Sasayama, S
We investigated metabolic factors related to the recovery of myocardial function during ischemia and after reperfusion using dichloroacetic acid (DCA) in canine models with repeated 10-min regional ischemia and reperfusion. Administration of 100 mg/kg DCA, which activates pyruvate dehydrogenase, improved regional wall motion significantly as compared with the nontreated controls (p < 0.05). The mechanism was studied by determining changes in myocardial levels of pH, glucose, lactate, and nonesterified fatty acids (NEFA). Glucose extraction was increased significantly during ischemia and reperfusion by the pretreatment of DCA (p < 0.01). the calculated contribution of glucose to myocardial oxidative metabolism during ischemia and reperfusion was greater than that of NEFA and lactate in case of DCA treatment. The uptake of [99mTc]pyrophosphate (PYP), which reflects myocardial injury, was also significantly suppressed by DCA (p < 0.01). pH was not affected by an infusion of DCA. These findings suggest that the activation of glucose metabolism by DCA, which is impaired and reduced during ischemia and reperfusion, may be responsible for the improved myocardial function after reperfusion. PMID:8606539
Effect of hydrogen sulfide on inflammatory cytokines in acute myocardial ischemia injury in rats
Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors. PMID:25667680
Effect of regional myocardial ischemia on sympathetic nervous system as assessed by fluorine-18-metaraminol
Schwaiger, M.; Guibourg, H.; Rosenspire, K.; McClanahan, T.; Gallagher, K.; Hutchins, G.; Wieland, D.M. )
With the introduction of radiolabeled catecholamine analogues, the noninvasive evaluation of the cardiac sympathetic nervous system has become possible. This study evaluated the effect of regional ischemia on myocardial retention of the new norepinephrine analogue 6-({sup 18}F) fluorometaraminol (FMR) in the open chest dog model. Six dogs were injected intravenously with FMR following 30-min occlusion of the left anterior descending artery. Six sham animals served as control group. Regional myocardial blood flow as determined by microspheres decreased 87% during ischemia (p less than 0.01), but was not significantly different from control myocardium following reperfusion. Regional myocardial 18F activity as determined postmortem was significantly reduced in reperfused myocardium (-34%), which paralleled an 18% reduction of tissue norepinephrine concentration. Thus, short time periods of coronary occlusion affect neuronal function indicating the sensitivity of the sympathetic nerve terminals to ischemia. FMR provides a new tracer approach for the characterization of neuronal integrity in postischemic myocardium.
Molecular Characterization of Reactive Oxygen Species in Myocardial Ischemia-Reperfusion Injury
Zhou, Tingyang; Chuang, Chia-Chen; Zuo, Li
Myocardial ischemia-reperfusion (I/R) injury is experienced by individuals suffering from cardiovascular diseases such as coronary heart diseases and subsequently undergoing reperfusion treatments in order to manage the conditions. The occlusion of blood flow to the tissue, termed ischemia, can be especially detrimental to the heart due to its high energy demand. Several cellular alterations have been observed upon the onset of ischemia. The danger created by cardiac ischemia is somewhat paradoxical in that a return of blood to the tissue can result in further damage. Reactive oxygen species (ROS) have been studied intensively to reveal their role in myocardial I/R injury. Under normal conditions, ROS function as a mediator in many cell signaling pathways. However, stressful environments significantly induce the generation of ROS which causes the level to exceed body's antioxidant defense system. Such altered redox homeostasis is implicated in myocardial I/R injury. Despite the detrimental effects from ROS, low levels of ROS have been shown to exert a protective effect in the ischemic preconditioning. In this review, we will summarize the detrimental role of ROS in myocardial I/R injury, the protective mechanism induced by ROS, and potential treatments for ROS-related myocardial injury. PMID:26509170
Concentrated Ambient Particles Alter Myocardial Blood Flow during Acute Ischemia in Conscious Canines
Bartoli, Carlo R.; Wellenius, Gregory A.; Coull, Brent A.; Akiyama, Ichiro; Diaz, Edgar A.; Lawrence, Joy; Okabe, Kazunori; Verrier, Richard L.; Godleski, John J.
Background Experimental and observational studies have demonstrated that short-term exposure to ambient particulate matter (PM) exacerbates myocardial ischemia. Objectives We conducted this study to investigate the effects of concentrated ambient particles (CAPs) on myocardial blood flow during myocardial ischemia in chronically instrumented conscious canines. Methods Eleven canines were instrumented with a balloon occluder around the left anterior descending coronary artery and catheters for determination of myocardial blood flow using fluorescent microspheres. Telemetric electrocardiographic and blood pressure monitoring was available for four of these animals. After recovery, we exposed animals by inhalation to 5 hr of either filtered air or CAPs (mean concentration ± SD, 349.0 ± 282.6 μg/m3) in a crossover protocol. We determined myocardial blood flow during a 5-min coronary artery occlusion immediately after each exposure. Data were analyzed using mixed models for repeated measures. The primary analysis was based on four canines that completed the protocol. Results CAPs exposure decreased total myocardial blood flow during coronary artery occlusion by 0.12 mL/min/g (p < 0.001) and was accompanied by a 13% (p < 0.001) increase in coronary vascular resistance. Rate–pressure product, an index of myocardial oxygen demand, did not differ by exposure (p = 0.90). CAPs effects on myocardial blood flow were significantly more pronounced in myocardium within or near the ischemic zone versus more remote myocardium (p interaction < 0.001). Conclusions These results suggest that PM exacerbates myocardial ischemia by increased coronary vascular resistance and decreased myocardial perfusion. Further studies are needed to elucidate the mechanism of these effects. PMID:19337504
Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia
Robich, Michael P.; Osipov, Robert M.; Nezafat, Reza; Feng, Jun; Clements, Richard T.; Bianchi, Cesario; Boodhwani, Munir; Coady, Michael A.; Laham, Roger J.; Sellke, Frank W.
Introduction Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia. Methods and Results Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/day orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac magnetic resonance imaging and coronary angiography 7 weeks later, prior to sacrifice and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (p<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (p=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (p=0.32). Tissue blood flow during stress was 2.8 fold greater in HCRV swine when compared to HCC swine (p=0.04). Endothelial dependent microvascular relaxation response to Substance P was diminished in HCC swine which was rescued by resveratrol treatment (p=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine v. control swine (p=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV v. HCC swine of the following markers of angiogenesis: VEGF (p=0.002), peNOS(ser1177)(p=0.04), NFkB (p=0.004), and pAkt(thr308)(p=0.001). Conclusion Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelial dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway. PMID:20837905
Direct imaging of myocardial ischemia: a potential new paradigm in nuclear cardiovascular imaging.
Jain, Diwakar; He, Zuo-Xiang
Myocardial perfusion imaging has been in clinical use for over 30 years, serving as an effective, reliable, and relatively simple tool for diagnosis, risk stratification, and long-term follow-up of patients with suspected or known coronary artery disease. However, a unique strength of nuclear imaging is its ability to provide tools for imaging biochemical and metabolic processes and receptor and transporter functions at molecular and cellular levels in intact organisms under a wide variety of physiologic conditions. Despite their high resolution and technical sophistication, other imaging modalities currently do not have this capability. Metabolic imaging techniques using radiolabeled free fatty acid and glucose analogs provide a unique ability to image myocardial ischemia directly in patients with known or suspected coronary artery disease. These techniques can potentially overcome some of the limitations of currently used stress-rest perfusion imaging and also provide a unique opportunity to detect and image an episode of ischemia in the preceding hours even in the absence of other markers of ongoing myocardial ischemia. We describe recent studies using fluorine 18-labeled deoxyglucose and iodine 123 beta-methyl-p-iodophenyl-pentadecanoic acid for imaging myocardial ischemia. PMID:18761264
Three-Dimensional Visualization of Myocardial Ischemia Based on the Standard Twelve-Lead Electrocardiogram
Ruixia, Tian; Xun, Chen
A novel method was proposed for transforming the ischemic information in the 12-lead electrocardiogram (ECG) into the pseudo-color pattern displayed on a 3D heart model based on the projection of a ST injury vector in this study. The projection of the ST injury vector at a point on the heart surface was used for identifying the presence of myocardial ischemia by the difference between the projection value and the detection threshold. Supposing that myocardial ischemia was uniform and continuous, the location and range of myocardial ischemia could be accurately calculated and visually displayed in a color-encoding way. The diagnoses of the same patient were highly consistent (kappa coefficient k = 0.9030) between the proposed method used by ordinary people lacking medical knowledge and the standard 12-lead ECG used by experienced cardiologists. In addition, the diagnostic accuracy of the proposed method was further confirmed by the coronary angiography. The results of this study provide a new way to promote the development of the 3D visualization of the standard 12-lead ECG, which has a great help for inexperienced doctors or ordinary family members in their diagnosis of patients with myocardial ischemia. PMID:27433278
Inhibition of carnitine synthesis protects against left ventricular dysfunction in rats with myocardial ischemia.
Aoyagi, T; Sugiura, S; Eto, Y; Yonekura, K; Matsumoto, A; Yokoyama, I; Kobayakawa, N; Omata, M; Kirimoto, T; Hayashi, Y; Momomura, S
During myocardial ischemia, inhibition of the carnitine-mediated transportation of fatty acid may be beneficial because it facilitates glucose utilization and prevents an accumulation of fatty acid metabolites. We orally administered 3-(2,2,2-trimethyl hydrazinium) propionate (MET), an inhibitor of carnitine synthesis, for 20 days to rats. Then we evaluated left ventricular (LV) function during brief ischemia by using a buffer-perfused isovolumic heart model. After 15 min of reoxygenation after the transient ischemia, LV peak systolic pressure (PSP) almost completely returned to the baseline level in rats given MET (96 +/- 4%), whereas it was only partially (77 +/- 16%) recovered in the placebo-treated rats. We induced myocardial infarction in other rats by ligating the left anterior descending coronary artery. Then the animals were given MET for 20 days, and LV function was compared. In the placebo-treated rats (with myocardial infarction, but without drug treatment), LVPSP was lower than that in the sham group [108 +/- 19 (n = 10) vs. 136 +/- 15 mm Hg (n = 13); p < 0.05], and the time constant (T) of LV pressure decay was elongated (36 +/- 4 vs. 30 +/- 7 ms; p < 0.05). In MET-treated groups, however, neither PSP nor T differed from those in the sham group. In conclusion, inhibition of the carnitine-mediated transportation of fatty acid by MET protected against left ventricular dysfunction in acute and chronic myocardial ischemia. PMID:9335406
Induced coronary spasm without electrocardiographic signs or symptoms of myocardial ischemia
Cipriano, P.R.
Angiographic studies have shown that coronary artery spasm can be induced with ergonovine maleate. Coronary artery spasm induced by ergonovine maleate in these studies was nearly always accompanied by chest pain and electrocardiographic changes of myocardial ischemia. This report demonstrates that coronary artery spasm induced by ergonovine maleate may be diagnosed by angiography in the absence of these signs or symptoms.
Three-Dimensional Visualization of Myocardial Ischemia Based on the Standard Twelve-Lead Electrocardiogram.
Ma, Ying; Sheng, Yang; Ruixia, Tian; Xun, Chen
A novel method was proposed for transforming the ischemic information in the 12-lead electrocardiogram (ECG) into the pseudo-color pattern displayed on a 3D heart model based on the projection of a ST injury vector in this study. The projection of the ST injury vector at a point on the heart surface was used for identifying the presence of myocardial ischemia by the difference between the projection value and the detection threshold. Supposing that myocardial ischemia was uniform and continuous, the location and range of myocardial ischemia could be accurately calculated and visually displayed in a color-encoding way. The diagnoses of the same patient were highly consistent (kappa coefficient k = 0.9030) between the proposed method used by ordinary people lacking medical knowledge and the standard 12-lead ECG used by experienced cardiologists. In addition, the diagnostic accuracy of the proposed method was further confirmed by the coronary angiography. The results of this study provide a new way to promote the development of the 3D visualization of the standard 12-lead ECG, which has a great help for inexperienced doctors or ordinary family members in their diagnosis of patients with myocardial ischemia. PMID:27433278
ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice
Gandhi, Chintan; Motto, David G.; Jensen, Melissa; Lentz, Steven R.
Epidemiologic studies suggest that elevated VWF levels and reduced ADAMTS13 activity in the plasma are risk factors for myocardial infarction. However, it remains unknown whether the ADAMTS13-VWF axis plays a causal role in the pathophysiology of myocardial infarction. In the present study, we tested the hypothesis that ADAMTS13 reduces VWF-mediated acute myocardial ischemia/reperfusion (I/R) injury in mice. Infarct size, neutrophil infiltration, and myocyte apoptosis in the left ventricular area were quantified after 30 minutes of ischemia and 23.5 hours of reperfusion injury. Adamts13−/− mice exhibited significantly larger infarcts concordant with increased neutrophil infiltration and myocyte apoptosis compared with wild-type (WT) mice. In contrast, Vwf−/− mice exhibited significantly reduced infarct size, neutrophil infiltration, and myocyte apoptosis compared with WT mice, suggesting a detrimental role for VWF in myocardial I/R injury. Treating WT or Adamts13−/− mice with neutralizing Abs to VWF significantly reduced infarct size compared with control Ig–treated mice. Finally, myocardial I/R injury in Adamts13−/−/Vwf−/− mice was similar to that in Vwf−/− mice, suggesting that the exacerbated myocardial I/R injury observed in the setting of ADAMTS13 deficiency is VWF dependent. These findings reveal that ADAMTS13 and VWF are causally involved in myocardial I/R injury. PMID:22983446
Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in rats
Background Large body of evidences accumulated in clinical and epidemiological studies indicate that hearts of diabetic subjects are more sensitive to ischemia reperfusion injury (IRI), which results in a higher rate of mortality at post-operation than that of non-diabetes. However, experimental results are equivocal and point to either increased or decreased susceptibility of the diabetic hearts to IRI, especially at the early stage of the disease. The present study was designed to test the hypothesis that the duration/severity of the indexed ischemia is a major determinant of the vulnerability to myocardial IRI at early stage of diabetes. Methods Four weeks streptozotocin (STZ)-induced diabetic (D) and non-diabetic (C) Sprague–Dawley rats were randomly assigned to receive 30 or 45 min of left anterior descending artery ligation followed by 2 or 3 hours of reperfusion, respectively. Cardiac function was recorded by using Pressure-Volume (PV) conduction system. Myocardial infarct size was determined with triphenyltetrazolium chloride staining. Plasma Creatine kinase-MB (CK-MB), Lactate dehydrogenase (LDH) release, myocardial nitric oxide(NO) content and nitrotyrosine formation, 15-F2t-Isoprostane and plasma superoxide dismutase (SOD) were measured with colorimetric assays. Cardiomyocyte apoptosis was assessed by TUNEL staining. Myocardial TNFα, Caspase-3, STAT3, Akt, and GSK-3β were determined by Western blotting. Results Prolongation of ischemia but not reperfusion from 30 min to 45 min significantly increased infarct size in D compared to C rats (P < 0.05), accompanied with significantly increased plasma CK-MB (P < 0.05). Prolongation of the duration of either ischemia or reperfusion significantly increased plasma LDH release and myocardial 15-F2t-Isoprostane and reduced plasma SOD activity, with concomitant reduction of myocardial NO and increase of nitrotyrosine formation in D relative to C (P < 0.05). Prolongation of ischemia and
Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice
Oh, Young-Bin; Ahn, Min; Lee, Sang-Myeong; Koh, Hyoung-Won; Lee, Sun-Hwa; Kim, Suhn Hee; Park, Byung-Hyun
Recent studies have documented that Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury. PMID:23680658
Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia.
Goldstein, Richard S; Gallowitsch-Puerta, Margot; Yang, Lihong; Rosas-Ballina, Mauricio; Huston, Jared M; Czura, Christopher J; Lee, David C; Ward, Mae F; Bruchfeld, Annette N; Wang, Haichao; Lesser, Martin L; Church, Adam L; Litroff, Adam H; Sama, Andrew E; Tracey, Kevin J
Cerebral and myocardial ischemia, two of the leading causes of morbidity and mortality worldwide, are associated with inflammation that can lead to multiple organ failure and death. High-mobility group box 1(HMGB1), a recently described mediator of lethal systemic inflammation, has been detected in individuals with severe sepsis and hemorrhagic shock, but its role during ischemic injury in humans is unknown. To determine whether systemic HMGB1 levels are elevated after ischemic injury, a prospective observational study was performed in subjects with a diagnosis of either Acute Coronary Syndrome (ACS) or cerebral vascular ischemia (transient ischemic attack or cerebral vascular accident). Subjects (n, 16; age [mean], 67+/-16.3 years) were enrolled in the North Shore-LIJ emergency department within 24 h of symptom onset. Blood samples were collected, and HMGB1 levels analyzed by Western blot analysis using previously described methods (Wang et al. Science. 1999). Control samples were obtained from healthy age- and sex-matched volunteers (n, 16; age [mean], 68+/-15.8 years). Here, we report that serum HMGB1 levels were significantly elevated in both myocardial ischemia subjects (myocardial control serum HMGB1, 1.94+/-2.05 ng/mL, vs. myocardial ischemia serum HMGB1, 159+/-54.3 ng/mL; P<0.001); and in cerebral ischemia subjects (cerebral control serum HMGB1, 16.8+/-10.9 ng/mL, vs. cerebral ischemia serum HMGB1, 218+/-18.8 ng/mL; P<0.001). These results suggest that systemic HMGB1 levels are elevated in human ischemic disease. PMID:16721263
Ribose-enhanced myocardial recovery following ischemia in the isolated working rat heart.
Pasque, M K; Spray, T L; Pellom, G L; Van Trigt, P; Peyton, R B; Currie, W D; Wechsler, A S
Recovery for myocardial adenosine triphosphate (ATP) following moderate periods of ischemic is dependent upon the availability of adenosine monophosphate (AMP) and diphosphate (ADP) for rephosphorylation. Recovery of AMP and ADP levels following ischemia is, in turn, determined by the rates of salvage and de novo adenine nucleotide synthesis. Phosphoribosyl pyrophosphate (PRPP) availability is rate limiting in both salvage and de novo adenine nucleotide synthesis. Parenteral ribose infusions in rats have been documented to elevate myocardial PRPP levels with resultant enhancement of adenine nucleotide synthesis. In this study postischemic recovery of myocardial function and ATP levels in isolated, working rat hearts given ribose infusions before and after ischemia was compared with recovery in control hearts subjected to the same protocol without ribose administration. The mean percent of functional recovery in control hearts following 15 minutes of warm ischemia reached values of 56.7 +/- 4.1%, 63.5% +/- 4.3%, 65.9% +/- 4.6%, and 70.5% +/- 4.7% at 2, 5, 10, and 15 minutes of work following ischemia. Hearts perfused with ribose demonstrated improved mean percent return of function at similar intervals of postischemic work with values of 67.9% +/- 4.2%, 73.7% +/- 3.7%, 81.0% +/- 3.5% (* = p less than 0.02 versus control) *and 85.4% +/- 3.3%, *respectively. Determinations of myocardial ATP levels (mumoles/gm of dry weight) made at the end of 15 minutes of postischemic work were significantly higher (p less than 0.02) in the ribose-treated hearts (18.9 +/- 0.7) than in controls (16.3 +/- 0.6). Infusion of ribose before and after ischemia is a biochemically logical method of improving postischemic myocardial ATP and functional recovery by manipulation of adenine nucleotide synthetic pathways. PMID:6174831
Multiple coronary arterial loops as a cause of myocardial ischemia
NASA Technical Reports Server (NTRS)
Bashour, Tali T.; Mansour, Nagi N.; Lee, Damon
A case of long-standing angina with ischemia documented by exercise testing and thallium scintigraphy in a patient who had multiple proximal loops in all three major coronary arteries in the absence of luminal stenosis, is reported.
Caveolin-1/-3: therapeutic targets for myocardial ischemia/reperfusion injury.
Yang, Yang; Ma, Zhiqiang; Hu, Wei; Wang, Dongjin; Jiang, Shuai; Fan, Chongxi; Di, Shouyin; Liu, Dong; Sun, Yang; Yi, Wei
Myocardial ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. Caveolae, caveolin-1 (Cav-1), and caveolin-3 (Cav-3) are essential for the protective effects of conditioning against myocardial I/R injury. Caveolins are membrane-bound scaffolding proteins that compartmentalize and modulate signal transduction. In this review, we introduce caveolae and caveolins and briefly describe the interactions of caveolins in the cardiovascular diseases. We also review the roles of Cav-1/-3 in protection against myocardial ischemia and I/R injury, and in conditioning. Finally, we suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included, herein, is potentially useful for the design of future studies and should advance the investigation of caveolins as therapeutic targets. PMID:27282376
Echocardiographic analysis with a two-dimensional strain of chronic myocardial ischemia induced with ameroid constrictor in the pig.
Caillaud, Dominique; Calderon, Joachim; Réant, Patricia; Lafitte, Stéphane; Dos Santos, Pierre; Couffinhal, Thierry; Roques, Xavier; Barandon, Laurent
Despite much progress in the medical management of myocardial ischemia, several problems remain and experimental models help to improve our understanding of the pathophysiology involved in this domain. The ameroid constrictor model is the most widely used to create ischemia but evaluation of patent ischemia is still under debate. In the present study, we describe the potential of a two-dimensional (2D) strain for experimentally evaluating myocardial ischemia in the pig. An ameroid constrictor was placed around the circumflex artery in 30 pigs. Angiography showed 90% stenosis at one and two months. Left ventricular function was moderately altered and associated with mitral valve insufficiency in 30% of cases. Longitudinal and circumference strains were dramatically modified in the ischemic inferior-lateral zone compared to the healthy anterior zone (P<0.01) at one and two months. We correlated these results to myocardial ischemia by using contrast echocardiography, which showed a significant reduction in myocardial perfusion in the ischemic zone compared to the uninjured area, and by using histological analysis. We showed that evaluation of the 2D strain could be an interesting approach for assessing myocardial ischemia after ameroid constrictor implantation. The 2D strain represents a useful tool for the evaluation of experimental models of myocardial ischemia. PMID:20139196
Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview.
Zughaib, M E; Sun, J Z; Bolli, R
There are multiple mechanisms whereby ACE inhibitors could be beneficial during myocardial ischemia and reperfusion, including: i) reduced formation of angiotensin II, ii) decreased metabolism of bradykinin, iii) antioxidant activity, and iv) possibly other unknown mechanisms. Reduced formation of angiotensin II should be beneficial because this peptide exerts several actions that are potentially detrimental to the ischemic/reperfused myocardium, including vasoconstriction, increased release of norepinephrine, stimulation of phospholipase C and/or A2, and increased afterload with an attendant increase in oxygen demands. Reduced metabolism of bradykinin could be beneficial by increasing myocardial glucose uptake, by causing vasodilation, and by stimulating production of endothelium-derived relaxing factor and prostacyclin. Although earlier studies suggested that sulfhydryl-containing ACE inhibitors scavenge superoxide anions, recent data have shown that these drugs scavenge hydroxyl radical and hypochlorous acid with no effect on superoxide anion. Studies in isolated hearts have demonstrated that ACE inhibitors attenuate the metabolic, arrhythmic, and contractile dearrangements associated with ischemia and reperfusion, and have suggested that such beneficial effects are mediated by potentiation of bradykinin and/or increased synthesis of prostacyclin. Studies in models of myocardial stunning after brief (15-min) ischemia in vivo (anesthetized dogs) suggest that ACE inhibitors enhance the recovery of contractile function after a single brief ischemic episode. No data are available regarding the effect of these drugs on myocardial stunning after a prolonged, partly reversible episode, after multiple consecutive brief ischemic episodes, and after global ischemia. The mechanism for the salutary effects of ACE inhibitors on stunning remains a mystery. It may involve an antioxidant action (in the case of thiol-containing molecules) or potentiation of prostaglandins (in
Impact of myocardial ischemia on myocardial revascularization in stable ischemic heart disease. Lessons from the COURAGE and FAME 2 trials.
Torosoff, M T; Sidhu, M S; Boden, W E
In patients with stable ischemic heart disease (SIHD), myocardial revascularization should be performed to either improve survival or improve symptoms and functional status among patients who are not well controlled with optimal medical therapy (OMT). A general consensus exists on the core elements of OMT, which include both lifestyle intervention and intensive secondary prevention with proven pharmacotherapies. By contrast, however, there is less general agreement as to what constitutes the optimal approach to revascularization in SIHD patients. The COURAGE and FAME 2 randomized trials form the foundation of the current clinical evidence base and raise the important question: "What is the impact of myocardial ischemia on myocardial revascularization in stable ischemic heart disease?" PMID:23695652
Protective Effects of L-Malate against Myocardial Ischemia/Reperfusion Injury in Rats
Ding, Shiao; Yang, Yang; Mei, Ju
Objective. To investigate the protective effects of L-malate against myocardial ischemia/reperfusion (I/R) injury in rats. Methods. Male Sprague-Dawley rats were randomly assigned to the following groups: sham (sham), an ischemia/reperfusion (I/R) model group (model), an DMF pretreated group (DMF), and 5 L-malate pretreated groups (15, 60, 120, 240, or 480 mg/kg, gavage) before inducing myocardial ischemia. Plasma LDH, cTn-I, TNF-α, hs-CRP, SOD, and GSH-PX were measured 3 h later I/R. Areas of myocardial infarction were measured; hemodynamic parameters during I/R were recorded. Hearts were harvested and Western blot was used to quantify Nrf2, Keap1, HO-1, and NQO-1 expression in the myocardium. Results. L-malate significantly reduced LDH and cTn-I release, reduced myocardial infarct size, inhibited expression of inflammatory cytokines, and partially preserved heart function, as well as increasing antioxidant activity after myocardial I/R injury. Western blot confirmed that L-malate reduced Kelch-like ECH-associated protein 1 in ischemic myocardial tissue, upregulated expression of Nrf2 and Nrf2 nuclear translocation, and increased expression of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1, which are major targets of Nrf2. Conclusions. L-malate may protect against myocardial I/R injury in rats and this may be associated with activation of the Nrf2/Keap1 antioxidant pathway. PMID:26941825
Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion.
Buerke, M; Murohara, T; Skurk, C; Nuss, C; Tomaselli, K; Lefer, A M
In the present study, the cardioprotective effects of insulin-like growth factor I (IGF-I) were examined in a murine model of myocardial ischemia reperfusion (i.e., 20 min + 24 hr). IGF-I (1-10 micrograms per rat) administered 1 hr prior to ischemia significantly attenuated myocardial injury (i.e., creatine kinase loss) compared to vehicle (P < 0.001). In addition, cardiac myeloperoxidase activity, an index of neutrophil accumulation, in the ischemic area was significantly attenuated by IGF-I (P < 0.001). This protective effect of IGF-I was not observed with des-(1-3)-IGF-I. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated markedly increased DNA fragmentation due to programmed cell death (i.e., apoptosis) compared to nonischemic myocardium. Furthermore, IGF-I significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. Therefore, IGF-I appears to be an effective agent for preserving ischemic myocardium from reperfusion injury and protects via two different mechanisms--inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes. Images Fig. 5 PMID:7644533
Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury
Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping
Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID:27469291
Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury.
Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping
Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID:27469291
Molecular Mechanisms and Physiological Significance of Autophagy during Myocardial Ischemia and Reperfusion
Matsui, Yutaka; Kyoi, Shiori; Takagi, Hiromitsu; Hsu, Chiao-Po; Hariharan, Nirmala; Ago, Tetsuro; Vatner, Stephen F; Sadoshima, Junichi
Autophagy is an intracellular bulk degradation process whereby cytoplasmic proteins and organelles are degraded and recycled through lysosomes. In the heart, autophagy plays a homeostatic role at basal levels, and the absence of autophagy causes cardiac dysfunction and the development of cardiomyopathy. Autophagy is induced during myocardial ischemia and further enhanced by reperfusion. Although induction of autophagy during the ischemic phase is protective, further enhancement of autophagy during the reperfusion phase may induce cell death and appears to be detrimental. In this review we discuss the functional significance of autophagy and the underlying signaling mechanism in the heart during ischemia/reperfusion. PMID:18227645
Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion.
Wang, Meijing; Tsai, Ben M; Kher, Ajay; Baker, Lauren B; Wairiuko, G Mathenge; Meldrum, Daniel R
Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-alpha, IL-1beta, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-alpha, IL-1beta, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R. PMID:15374831
Dictionary-Driven Ischemia Detection From Cardiac Phase-Resolved Myocardial BOLD MRI at Rest.
Bevilacqua, Marco; Dharmakumar, Rohan; Tsaftaris, Sotirios A
Cardiac Phase-resolved Blood-Oxygen-Level Dependent (CP-BOLD) MRI provides a unique opportunity to image an ongoing ischemia at rest. However, it requires post-processing to evaluate the extent of ischemia. To address this, here we propose an unsupervised ischemia detection (UID) method which relies on the inherent spatio-temporal correlation between oxygenation and wall motion to formalize a joint learning and detection problem based on dictionary decomposition. Considering input data of a single subject, it treats ischemia as an anomaly and iteratively learns dictionaries to represent only normal observations (corresponding to myocardial territories remote to ischemia). Anomaly detection is based on a modified version of One-class Support Vector Machines (OCSVM) to regulate directly the margins by incorporating the dictionary-based representation errors. A measure of ischemic extent (IE) is estimated, reflecting the relative portion of the myocardium affected by ischemia. For visualization purposes an ischemia likelihood map is created by estimating posterior probabilities from the OCSVM outputs, thus obtaining how likely the classification is correct. UID is evaluated on synthetic data and in a 2D CP-BOLD data set from a canine experimental model emulating acute coronary syndromes. Comparing early ischemic territories identified with UID against infarct territories (after several hours of ischemia), we find that IE, as measured by UID, is highly correlated (Pearson's r=0.84) with respect to infarct size. When advances in automated registration and segmentation of CP-BOLD images and full coverage 3D acquisitions become available, we hope that this method can enable pixel-level assessment of ischemia with this truly non-invasive imaging technique. PMID:26292338
Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury
Doukas, John; Wrasidlo, Wolfgang; Noronha, Glenn; Dneprovskaia, Elena; Fine, Richard; Weis, Sara; Hood, John; DeMaria, Anthony; Soll, Richard; Cheresh, David
Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (γ and δ) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K γ/δ inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period. PMID:17172449
Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury.
Doukas, John; Wrasidlo, Wolfgang; Noronha, Glenn; Dneprovskaia, Elena; Fine, Richard; Weis, Sara; Hood, John; Demaria, Anthony; Soll, Richard; Cheresh, David
Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (gamma and delta) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K gamma/delta inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period. PMID:17172449
PET/CT Imaging in Mouse Models of Myocardial Ischemia
Gargiulo, Sara; Greco, Adelaide; Gramanzini, Matteo; Petretta, Maria Piera; Ferro, Adele; Larobina, Michele; Panico, Mariarosaria; Brunetti, Arturo; Cuocolo, Alberto
Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT), high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET) allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing. PMID:22505813
PET/CT imaging in mouse models of myocardial ischemia.
Gargiulo, Sara; Greco, Adelaide; Gramanzini, Matteo; Petretta, Maria Piera; Ferro, Adele; Larobina, Michele; Panico, Mariarosaria; Brunetti, Arturo; Cuocolo, Alberto
Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT), high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET) allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing. PMID:22505813
[Efficacy of various antioxidants in experimental ischemia and myocardial infarct in the rat].
Poliukhovich, G S; Vasil'eva, L P; Maslova, G T; Boboriko, T L; Speranskiĭ, S D
Complex of vitamins E and C showed the most effective antinecrotic action in rats with simulated myocardial infarction in series of antioxidants studied: ascorbate, alpha-tocopherol, quercetine, derivatives of o-benzoquinone OBQ2 and OBQ3. Stabilization of lipid peroxidation in cardiomyocytes, increase in biomembranes stability and absence of distinct alterations in the antioxidative enzymatic system were found in rats with ischemia and myocardial infarction after treatment with the complex. Protective effect of the vitamins E and C complex was realised via antiradical mechanism. PMID:1750212
Transient mitral regurgitation: An adjunctive sign of myocardial ischemia during dipyridamole-thallium imaging
Lette, J.; Gagnon, A.; Lapointe, J.; Cerino, M.
A patient developed transient exacerbation of a mitral insufficiency murmur and a reversible posterior wall perfusion defect during dipyridamole-thallium imaging. Coronary angiography showed significant stenoses of both the right and the circumflex coronary arteries that supply the posterior papillary muscle. Cardiac auscultation for transient mitral incompetence, a sign of reversible papillary muscle dysfunction, is a simple and practical adjunctive test for myocardial ischemia during dipyridamole-thallium imaging. It may confirm that an isolated reversible posterior wall myocardial perfusion defect is truly ischemic in nature as opposed to an artifact resulting from attenuation by the diaphragm.
Triterpenoid saponins with anti-myocardial ischemia activity from the whole plants of Clematis tangutica.
Zhang, Wei; Yao, Min-Na; Tang, Hai-Feng; Tian, Xiang-Rong; Wang, Min-Chang; Ji, Lan-Ju; Xi, Miao-Miao
Four new triterpenoid saponins named clematangosides A-D (1-4) along with six known saponins (5-10) were isolated from the whole plants of Clematis tangutica. Their structures were determined by extensive spectral analysis and chemical evidences. All saponins were evaluated for their protective effects in hypoxia-induced myocardial injury model. Compounds 2-4, 6, and 10 exhibited anti-myocardial ischemia activities with ED50 values in the range of 75.77-127.22 µM. PMID:23670628
Intravenous Sphingosylphosphorylcholine Protects Ischemic and Postischemic Myocardial Tissue in a Mouse Model of Myocardial Ischemia/Reperfusion Injury
Herzog, Christine; Schmitz, Martina; Levkau, Bodo; Herrgott, Ilka; Mersmann, Jan; Larmann, Jan; Johanning, Kai; Winterhalter, Michael; Chun, Jerold; Müller, Frank Ulrich; Echtermeyer, Frank; Hildebrand, Reinhard; Theilmeier, Gregor
HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL. In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3 was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injury in vivo via the S1P3 receptor. PMID:21274265
Intra-QRS Spectral Changes Accompany ST Segment Changes During Episodes of Myocardial Ischemia
Gramatikov, Boris; Iyer, Vivek
Background Coronary artery disease and myocardial ischemia cause substantial morbidity and mortality. While ischemia is traditionally diagnosed on the 12-lead electrocardiogram (ECG) by shifts in the ST segment, electrical changes are also produced within the QRS complex during depolarization of ischemic ventricular tissue, though these are often of small amplitude and can be missed in traditional ECG analysis. We explore the utility of an easily implemented spectral analysis method for detecting intra-QRS changes during episodes of myocardial ischemia, using Holter recordings from the European ST-T database. Methods Time-frequency distributions of QRS complexes from each recording were computed using the continuous wavelet transform. Indices corresponding to frequency content of four overlapping frequency bands were computed: F1 (24–35 Hz), F2 (30–45 Hz), F3 (40–60 Hz), and F4 (50–80 Hz). Values of these indices were compared during annotated episodes of ST change and during a baseline during the recording. Results Marked changes in intra-QRS frequency content were identified during ischemia, grouped by ECG lead analyzed. In lead III, a pronounced and statistically significant increase in the highest frequency sub-bands (F3 and F4) was consistently observed. Analysis of anterior precordial leads also showed significant increases in F4. Conclusions Intra-QRS time-frequency analysis using the continuous wavelet transform can identify a spectral signature corresponding to myocardial ischemia in the range 24–80 Hz. Intra-QRS spectral analysis has the potential for many clinical applications. PMID:25266140
A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Kim, Se-Chan; Boehm, Olaf; Meyer, Rainer; Hoeft, Andreas; Knüfermann, Pascal; Baumgarten, Georg
Surgical trauma by thoracotomy in open-chest models of coronary ligation induces an immune response which modifies different mechanisms involved in ischemia and reperfusion. Immune response includes cytokine expression and release or secretion of endogenous ligands of innate immune receptors. Activation of innate immunity can potentially modulate infarct size. We have modified an existing murine closed-chest model using hanging weights which could be useful for studying myocardial pre- and postconditioning and the role of innate immunity in myocardial ischemia and reperfusion. This model allows animals to recover from surgical trauma before onset of myocardial ischemia. Volatile anesthetics have been intensely studied and their preconditioning effect for the ischemic heart is well known. However, this protective effect precludes its use in open chest models of coronary artery ligation. Thus, another advantage could be the use of the well controllable volatile anesthetics for instrumentation in a chronic closed-chest model, since their preconditioning effect lasts up to 72 hours. Chronic heart diseases with intermittent ischemia and multiple hit models are other possible applications of this model. For the chronic closed-chest model, intubated and ventilated mice undergo a lateral blunt thoracotomy via the 4th intercostal space. Following identification of the left anterior descending a ligature is passed underneath the vessel and both suture ends are threaded through an occluder. Then, both suture ends are passed through the chest wall, knotted to form a loop and left in the subcutaneous tissue. After chest closure and recovery for 5 days, mice are anesthetized again, chest skin is reopened and hanging weights are hooked up to the loop under ECG control. At the end of the ischemia/reperfusion protocol, hearts can be stained with TTC for infarct size assessment or undergo perfusion fixation to allow morphometric studies in addition to histology and
Myocardial ischemia-reperfusion injury is enhanced in a model of systemic allergy and asthma.
Hazarika, Surovi; Van Scott, Michael R; Lust, Robert M
Despite epidemiological evidence of cardiovascular complications in asthmatics, the direct contribution of asthmatic pathophysiology to cardiovascular effects is unknown. Considering parallels in underlying pathophysiology, we tested the hypothesis that presence of systemic allergy and asthma worsens the outcome of myocardial ischemia-reperfusion injury. Systemic allergy and asthma were created in rabbits by repeated intraperitoneal injections of allergen with adjuvant, followed by an airway challenge in two groups. Nonsensitized animals served as controls. In situ myocardial ischemia-reperfusion was induced in anesthetized animals by a 30-min ligation of a coronary artery, followed by 3 h of reperfusion. Ischemia-reperfusion was done at 24 h after intraperitoneal boost (1 DB) and 7 days (7 DB) after the last intraperitoneal injection and at 24 h (1DAWCH) and 7 days (7DAWCH) after airway challenge. The infarct size (determined by 2,3,5-triphenyltetrazolium chloride staining, normalized to area at risk) was significantly higher in all sensitized groups compared with control (1DB, 31 +/- 4; 7DB, 28.9 +/- 2.6; 1DAWCH, 66.1 +/- 4.1; 7DAWCH, 28.9 +/- 9.2; control, 16.7 +/- 3.2; means +/- SE; P < 0.01 by ANOVA; n = 6). The 1DAWCH group showed significantly greater infarct than all other groups (P < 0.05). Myocardial neutrophil infiltration was significantly higher in the sensitized groups compared with control (P < 0.01). Tissue neutrophil counts showed a strong positive correlation to infarct sizes (r2 = 0.9). These observations indicate that the presence of systemic allergy and asthma is associated with increased myocardial neutrophil infiltration during acute ischemia-reperfusion and increased size of the resulting infarct. PMID:14715513
Effects of central opiate and serotoninergic structures on heart rhythm during acute myocardial ischemia.
Prokop'eva, E V; Pivovarov, Y I
Electrostimulation of the central gray matter in the sylvian aqueduct and nucleus raphe magnus produced an antiarrhythmic effect during acute myocardial ischemia. Stimulation and blockade of opiate receptors in the central amygdaloid nucleus and lateral hypothalamus with dalargin and naloxone induced the same effect. Destruction of the central gray matter in the sylvian aqueduct and nucleus raphe magnus decreased electrical stability of ischemic myocardium. PMID:12152875
Improved myocardial ischemia detection by combined physical and mental stress testing.
Hunziker, P R; Gradel, C; Müller-Brand, J; Buser, P; Pfisterer, M
The hypothesis that addition of mental stress to physical exercise would modify the circulation response to stress and improve noninvasive detection of myocardial ischemia was tested in a randomized, crossover radionuclide angiocardiographic study. Compared with physical exercise or mental stress alone, combined stress led to higher heart rates and rate-pressure products in early stress stages, to more pronounced symptoms, and to a better discrimination of subjects with and without coronary artery disease by radionuclide angiography. PMID:9671017
PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.
Xu, Ya; Gen, Michael; Lu, Li; Fox, Jennifer; Weiss, Sara O; Brown, R Dale; Perlov, Daniel; Ahmad, Hasan; Zhu, Peili; Greyson, Clifford; Long, Carlin S; Schwartz, Gregory G
Peroxisome proliferator-activated receptor (PPAR)-gamma modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-gamma activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-gamma activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both alpha-tocopherol and thiazolidinedione moieties, whether PPAR-gamma activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg x kg(-1) x day(-1)), rosiglitazone (3 mg x kg(-1) x day(-1)), or alpha-tocopherol (73 mg x kg(-1) x day(-1), equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-gamma, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or alpha-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an alpha-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-gamma activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its alpha-tocopherol moiety. These findings, in
Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF
Nakamura, Teruya; Mizuno, Shinya; Matsumoto, Kunio; Sawa, Yoshiki; Matsuda, Hikaru; Nakamura, Toshikazu
Using a rat model of ischemia/reperfusion injury, we demonstrate here that HGF is cardioprotective due to its antiapoptotic effect on cardiomyocytes. Following transient myocardial ischemia and reperfusion, c-Met/HGF receptor expression rapidly increased in the ischemic myocardium, an event accompanied by a dramatic increase in plasma HGF levels in the infarcted rats. When endogenous HGF was neutralized with a specific antibody, the number of myocyte cell deaths increased markedly, the infarct area expanded, and the mortality increased to 50%, as compared with a control group in which there was no mortality. Plasma from the myocardial infarcted rats had cardioprotective effects on primary cultured cardiomyocytes, but these effects were significantly diminished by neutralizing HGF. In contrast, recombinant HGF administration reduced the size of infarct area and improved cardiac function by suppressing apoptosis in cardiomyocytes. HGF rapidly augmented Bcl-xL expression in injured cardiomyocytes both in vitro and in vivo. As apoptosis of cardiomyocytes is one of the major contributors to the pathogenesis in subjects with ischemia/reperfusion injury, prevention of apoptosis may prove to be a reasonable therapeutic strategy. Supplements of HGF, an endogenous cardioprotective factor, may be found clinically suitable in treating subjects with myocardial infarction. PMID:11120758
Ca2+ transient decline and myocardial relaxation are slowed during low flow ischemia in rat hearts.
Camacho, S A; Brandes, R; Figueredo, V M; Weiner, M W
The mechanisms that impair myocardial relaxation during ischemia are believed to involve abnormalities of calcium handling. However, there is little direct evidence to support this hypothesis. Therefore, we sought to determine whether the time constant of cytosolic calcium ([Ca2+]c) decline (tau Ca) was increased during low flow ischemia, and if there was a relationship between the time constant of left ventricular pressure decline (tau P) and tau Ca. Isolated perfused hearts were studied using indo-1 fluorescence ratio as an index of [Ca2+]c.tau P was used as an index of myocardial relaxation. The time constant of decline of the indo-1 ratio increased from 74 +/- 5 ms to 95 +/- 4, 144 +/- 10, and to 204 +/- 16 ms when coronary flow was reduced was reduced to 50, 20, and 10% of control, respectively. Indo-1 transients were calibrated to calculate tau Ca. tau Ca increased from 67 +/- 6 ms to 108 +/- 9 and 158 +/- 19 ms when coronary flow was reduced to 20 and 10% of control, respectively. There was a linear relationship between tau Ca and tau P (r = 0.82). These data support the hypothesis that during low flow ischemia, impaired myocardial relaxation may be caused by slowing of [Ca2+]c decline. PMID:8132781
Titin is a Target of MMP-2: Implications in Myocardial Ischemia/Reperfusion Injury
Ali, Mohammad A.M.; Cho, Woo Jung; Hudson, Bryan; Kassiri, Zamaneh; Granzier, Henk; Schulz, Richard
Background Titin is the largest mammalian (∼3000-4000 kDa) and myofilament protein which acts as a molecular spring in the cardiac sarcomere and determines systolic and diastolic function. Loss of titin in ischemic hearts has been reported, but the mechanism of titin degradation is not well understood. Matrix metalloproteinase-2 (MMP-2) is localized to the cardiac sarcomere and upon activation in ischemia/reperfusion injury proteolyzes specific myofilament proteins. Here we determine whether titin is an intracellular substrate for MMP-2 and if its degradation during ischemia/reperfusion contributes to cardiac contractile dysfunction. Methods and Results Immunohistochemistry and confocal microscopy in rat and human hearts showed discrete co-localization between MMP-2 and titin in the Z-disc region of titin and that MMP-2 is mainly localized to titin near the Z-disc of the cardiac sarcomere. Both purified titin or titin in skinned cardiomyocytes were proteolyzed when incubated with MMP-2 in a concentration-dependent manner and this was prevented by MMP inhibitors. Isolated rat hearts subjected to ischemia/reperfusion injury showed cleavage of titin in ventricular extracts by gel electrophoresis which was confirmed by reduced titin immunostaining in tissue sections. Inhibition of MMP activity with ONO-4817 prevented ischemia/reperfusion-induced titin degradation and improved the recovery of myocardial contractile function. Titin degradation was also reduced in hearts from MMP-2 knockout mice subjected to ischemia/reperfusion in vivo, compared to wild type controls. Conclusions MMP-2 localizes to titin at the Z-disc region of the cardiac sarcomere and contributes to titin degradation in myocardial ischemia/reperfusion injury. PMID:21041693
The Effect of Lipopolysaccharide on Ischemic-Reperfusion Injury of Heart: A Double Hit Model of Myocardial Ischemia and Endotoxemia
Nader, Nader D.; Asgeri, Mehrdad; Davari-Farid, Sina; Pourafkari, Leili; Ahmadpour, Faraz; Porhomayon, Jahan; Javadzadeghan, Hassan; Negargar, Sohrab; Knight, Paul R.
Introduction: Myocardial ischemia may coincide and interact with sepsis and inflammation. Our objective was to examine the effects of bacterial endotoxin on myocardial functions and cell injury during acute ischemia. Methods: Rabbits were pretreated with incremental doses of E. Coli lipopolysaccharide (LPS) or normal saline. Myocardial ischemia was induced by 50-minute occlusion of left anterior descending artery. S-TNFaR was additionally used to block the effects LPS. Results: Ventricular contractility as it was measured by dp/dt during systole decreased from 2445± 1298 to 1422 ± 944 mm Hg/s, P = .019. Isovolumetric relaxation time as an index of diastolic function was prolonged from 50±18 ms to 102± 64 ms following ischemia. Pretreatment with low concentrations of LPS (<1 μg) had no effect on dp/dt, while at higher concentrations it suppressed both contractility and prolonged IVRT. Cell injury as measured by cardiac troponin I level increased to 15.1± 3.2 ng/dL following ischemia and continued to rise with higher doses of LPS. While blocking TNFa did not improve the myocardial contractility after ischemia, it eliminated additional deleterious effects of LPS. Conclusion: Lower doses of LPS had no deleterious effect on myocardial function, whereas higher doses of this endotoxin cause cardiac dysfunction and increased extent of injury. PMID:26430494
Green tea extract given before regional myocardial ischemia-reperfusion in rats improves myocardial contractility by attenuating calcium overload.
Liou, Ying-Ming; Hsieh, Shih-Rong; Wu, Tsu-Juey; Chen, Jan-Yow
There is evidence for a negative correlation between green tea consumption and cardiovascular diseases. The aim of the present study was to examine whether green tea extract (GTE) given before regional myocardial ischemia could improve depression of myocardial contractility by preventing cytosolic Ca(2+) overload. Regional ischemia-reperfusion (IR) was induced in rats by ligating the left anterior descending branch for 20 min, then releasing the ligature. Ligation induced ventricular arrhythmias in rats without GTE pretreatment, but decreased arrhythmogenesis was seen in rats pretreated 30 min earlier with GTE (400 mg/kg). During reperfusion, arrhythmias only occurred during the initial 5 min, and GTE pretreatment had no effect. After overnight recovery, serum cTnI levels were greatly increased in control post-IR rats but only slightly elevated in GTE-pretreated post-IR rats. Myocardial contractility measured by echocardiography was still depressed after 3 days in control post-IR rats, but not in GTE-pretreated post-IR rats. No myocardial ischemic injury was seen in post-IR rats with or without GTE pretreatment. Using freshly isolated single heart myocytes, GTE was found to attenuate the post-IR injury-associated cytosolic Ca(2+) overload and modulate changes in the levels and distribution of myofibril, adherens junction, and gap junction proteins. In summary, GTE pretreatment protects cardiomyocytes from IR injury by preventing cytosolic Ca(2+) overload, myofibril disruption, and alterations in adherens and gap junction protein expression and distribution. PMID:20922441
Effects and Mechanisms of Chinese Herbal Medicine in Ameliorating Myocardial Ischemia-Reperfusion Injury
Liu, Qing; Li, Jiqiang; Wang, Jing; Li, Jianping; Janicki, Joseph S.
Myocardial ischemia-reperfusion (MIR) injury is a major contributor to the morbidity and mortality associated with coronary artery disease, which accounts for approximately 450,000 deaths a year in the United States alone. Chinese herbal medicine, especially combined herbal formulations, has been widely used in traditional Chinese medicine for the treatment of myocardial infarction for hundreds of years. While the efficacy of Chinese herbal medicine is well documented, the underlying molecular mechanisms remain elusive. In this review, we highlight recent studies which are focused on elucidating the cellular and molecular mechanisms using extracted compounds, single herbs, or herbal formulations in experimental settings. These studies represent recent efforts to bridge the gap between the enigma of ancient Chinese herbal medicine and the concepts of modern cell and molecular biology in the treatment of myocardial infarction. PMID:24288571
Clematichinenoside attenuates myocardial infarction in ischemia/reperfusion injury both in vivo and in vitro.
Zhang, Rui; Fang, Weirong; Han, Dan; Sha, Lan; Wei, Jie; Liu, Lifang; Li, Yunman
Clematichinenoside is a triterpenoid saponin isolated from the roots of Clematis chinensis. Oxidative stress and excessive nitric oxide production are thought to play considerable roles in ischemia/reperfusion injury that impairs cardiac function. The present study investigated the protective effect of clematichinenoside on regional and global ischemia/reperfusion injury and ventricular myocytes. In vivo, regional myocardial ischemia/reperfusion injury of rats was induced by the occlusion of the left anterior descending coronary artery, and isolated guinea pigs heart using Langendorff apparatus served as a global ischemia/reperfusion injury model ex vivo. Primary cultured neonatal ventricular myocytes were further applied to explore the anti-ischemia/reperfusion injury property in vitro. Infarct size was measured with TTC stain; enzyme activities such as lactate dehydrogenase, creatine kinase, superoxide dismutase, malondialdehyde, and nitric oxide were analyzed with assay kits; inducible nitric oxide synthase and endothelial nitric oxide synthase expressions were determined by Western blot. Clematichinenoside attenuated infarct size, decreased lactate dehydrogenase, creatine kinase, and malondialdehyde levels and enhanced superoxide dismutase activity. Clematichinenoside improved hemodynamics indexes, such as left ventricular developed pressure, maximum left ventricular developed pressure, and increase/decrease rate (± dp/dtmax) in the isolated guinea pig heart after reperfusion. Clematichinenoside also inhibited excessive production of nitric oxide through downregulating inducible nitric oxide synthase as well as upregulating endothelial nitric oxide synthase during ischemia/reperfusion injury. Clematichinenoside attenuates ischemia/reperfusion injury in vivo, ex vivo, and in vitro via an antioxidant effect and by restoring the balance between inducible nitric oxide synthase and endothelial nitric oxide synthase. PMID:23929248
Mass spectrometry for the measurement of intramyocardial gas tensions: methodology and application to the study of myocardial ischemia.
Khuri, S F; O'Riordan, J; Flaherty, J T; Brawley, R K; Donahoo, J S; Gott, V L
The methodology for use of the mass spectrometer for the measurement of intramyocardial gas tensions in the canine preparation is described. Baseling studies were carried out initially in 36 animals, and control levels for myocardial oxygen tension and myocardial carbon dioxide tension were 19 mm Hg (S.D. 6 mm Hg) and 43 mm Hg (S.D. 10 mm Hg), respectively. Myocardial oxygen tension was not altered significantly by varying the arterial oxygen tension between 65 and 300 mm Hg. However, myocardial carbon dioxide tension increased linearly with increased arterial carbon dioxide tension. In 15 dogs placed on total cardiopulmonary bypass, a perfusion pressure 40-60 mm lower than the control mean arterial pressure resulted in myocardial ischemia with a decrease in myocardial oxygen tension and an increase in myocardial carbon dioxide tension. A subsequent increase in perfusion pressure to control levels resulted in resolution of ischemia and return of myocardial oxygen and carbon dioxide tensions to their control level. In another series of open-chest dogs on cardiopulmonary bypass, a proximal constriction applied to the left coronary circumflex artery resulted in a marked decrease in myocardial oxygen tensions and a marked increase in myocardial carbon dioxide tensions in the region supplied by the constricted vessel. In yet another series of open-chest dogs, it was found that incremental decreases in coronary flow established by constriction of the circumflex artery resulted in an exponential increase in both myocardial carbon dioxide tensions and ST-segment elevation as determined by a 25-gauge multi-contact plunge electrode placed in the posterior left ventricular wall. It appears that mass spectrometry techniques for evaluating myocardial ischemia have several advantages over myocardial biopsy techniques for assay of ATP and lactate, and also over the technique of coronary sinus lactate determination. PMID:1209001
Halothane inhibits calcium accumulation following myocardial ischemia and calcium paradox in guinea pig hearts
Hoka, S.; Bosnjak, Z.J.; Kampine, J.P.
This study was performed to test the hypothesis that halothane inhibits calcium accumulation associated with myocardial ischemia and calcium paradox. Using a Langendorff preparation in isolated guinea pig hearts, tissue /sup 45/Ca was measured after 40 and 60 min of loading with /sup 45/Ca, followed by 20 min of washout period. Myocardial ischemia was produced by a 30-min occlusion of the left anterior descending coronary artery (LAD). LAD occlusion caused an increase in /sup 45/Ca content in the anterior left ventricular muscle (ischemic area) of 215% compared to that of the posterior left ventricular muscle (normal myocardium). The increase in /sup 45/Ca content in the ischemic area was significantly less (P less than 0.05) in the presence of halothane (1%) compared to the non-halothane group. Halothane did not significantly alter /sup 45/Ca content in the non-ischemic myocardium. Myocardial injury associated with calcium paradox, which was produced by a 10-min perfusion of the heart with calcium-free Krebs solution followed by normal calcium repletion, caused a significant increase (P less than 0.05) in the /sup 45/Ca content compared to control. Addition of halothane (1%) significantly depressed (P less than 0.05) the increase in /sup 45/Ca content caused by calcium paradox. It is suggested that halothane might inhibit calcium accumulation associated with myocardial ischemia and calcium paradox under certain experimental situations. The inhibitory effect of halothane on calcium accumulation may be beneficial for the ischemic heart during halothane anesthesia.
Anti-inflammatory effect of sodium butyrate preconditioning during myocardial ischemia/reperfusion
High mobility group box 1 protein (HMGB1) has an important role in myocardial ischemia/reperfusion (I/R) injury. Sodium butyrate, an inhibitor of histone deacetylase, has been shown to inhibit HMGB1 expression. In the present study, the effect of sodium butyrate on myocardial I/R injury in rats was investigated. Anesthetized male rats were intraperitoneally administered sodium butyrate (100 or 300 mg/kg) 30 min prior to the induction of ischemia. The rats were then subjected to ischemia for 30 min followed by reperfusion for 4 h. Infarct size, lactate dehydrogenase (LDH), creatine kinase (CK) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were then measured. The expression of HMGB1 was assessed using western blot analysis. The results demonstrated that pretreatment with sodium butyrate (300 mg/kg) significantly reduced the infarct size, as well as the levels of LDH and CK (P<0.05). In addition, sodium butyrate (300 mg/kg) was shown to significantly inhibit the I/R-induced increase in the level of MDA and reduction in the level of SOD (P<0.05). Furthermore, treatment with sodium butyrate (300 mg/kg) was found to significantly inhibit the expression of TNF-α, IL-6 and HMGB1 induced by I/R injury (P<0.05). In conclusion, the results from the present study suggest that preconditioning with sodium butyrate may attenuate myocardial I/R injury by inhibition of the expression of inflammatory mediators during myocardial I/R. PMID:24944626
Effect of dexmedetomidine on myocardial ischemia-reperfusion injury
Chen, Shoulin; Hua, Fuzhou; Lu, Jun; Jiang, Yu; Tang, Yanhua; Tao, Lei; Zou, Bing; Wu, Qinghua
Cardiopulmonary bypass (CPB) is associated with a marked systemic inflammatory response. Although dexmedetomidine (Dex) is routinely used in cardiac surgery, the effect in reducing the inflammatory response in coronary artery bypass graft surgery (CABG) with CPB remains unclear. In this study, Dex was administered at a loading dose of 0.5 μg/kg for 10 min, followed by a continuous infusion of 0.5 μg/kg per hour until the completion of CABG with CPB. The levels of inflammatory cytokines in the serum, including tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-8 and IL-10, were measured to explore the inflammatory regulating function of Dex. In addition, troponin-I (cTnI) and creatine kinase (CK-MB) levels were studied to explore the myocardial protection provided by Dex. In this study, we showed Dex inhibited the increase in cTnI and CK-MB, attenuated the production of pro-inflammatory cytokines TNF-alpha, IL-6 and IL-8, and promoted anti-inflammatory cytokine IL-10 production. These findings demonstrate that Dex regulates anti-inflammatory as well as myocardial protection potential in CABG with CPB. PMID:26885050
Rapamycin Treatment of Healthy Pigs Subjected to Acute Myocardial Ischemia-Reperfusion Injury Attenuates Cardiac Functions and Increases Myocardial Necrosis
Lassaletta, Antonio D; Elmadhun, Nassrene Y; Zanetti, Arthus V D; Feng, Jun; Anduaga, Javier; Gohh, Reginald Y.; Sellke, Frank W; Bianchi, Cesario
Background The Mechanistic Target of Rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplants, however, it has other non-immune functions including in the cardiovascular system, where it is a regulator of heart hypertrophy and locally, in coated vascular stents, inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism and survival, we hypothesized that inhibiting it with rapamycin, prior to an acute myocardial ischemia-reperfusion injury (IRI), would confer cardioprotection by virtue of slowing down cardiac function and metabolism. Methods Yorkshire pigs received orally either placebo or 4 mg/day rapamycin for 7 days before the IRI. All animals underwent median sternotomy and the mid-left anterior descending coronary artery was occluded for 60 min followed by 120 min of reperfusion. Left ventricular pressure-volume data was collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by western blotting with specific antibodies against specific substrates phosphorylating sites. Results Rapamycin pre-treatement impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities. Conclusions Pre-treatment of healthy pigs with rapamycin prior to acute myocardial IRI is associated with decreased cardiac function and higher myocardial necrosis. PMID:24266948
Surgical procedure affects physiological parameters in rat myocardial ischemia: need for mechanical ventilation.
Horstick, G; Berg, O; Heimann, A; Darius, H; Lehr, H A; Bhakdi, S; Kempski, O; Meyer, J
Several surgical approaches are being used to induce myocardial ischemia in rats. The present study investigated two different operative procedures in spontaneously breathing and mechanically ventilated rats under sham conditions. A snare around the left coronary artery (LCA) was achieved without occlusion. Left lateral thoracotomy was performed in spontaneously breathing and mechanically ventilated rats (tidal volume 8 ml/kg) with a respiratory rate of 90 strokes/min at different levels of O2 supplementation (room air and 30, 40, and 90% O2). All animals were observed for 60 min after thoracotomy. Rats operated with exteriorization of the heart through left lateral thoracotomy while breathing spontaneously developed severe hypoxia and hypercapnia despite an intrathoracic operation time of <1 min. Arterial O2 content decreased from 18.7 +/- 0.5 to 3.3 +/- 0.9 vol%. Lactate increased from 1.2 +/- 0.1 to 5.2 +/- 0.3 mmol/l. Significant signs of ischemia were seen in the electrocardiogram up to 60 min. Mechanically ventilated animals exhibited a spectrum ranging from hypoxia (room air) to hyperoxia (90% O2). In order not to jeopardize findings in experimental myocardial ischemia-reperfusion injury models, stable physiological parameters can be achieved in mechanically ventilated rats at an O2 application of 30-40% at 90 strokes/min. PMID:9950847
Intravenous Administration of Lycopene, a Tomato Extract, Protects against Myocardial Ischemia-Reperfusion Injury
Tong, Chao; Peng, Chuan; Wang, Lianlian; Zhang, Li; Yang, Xiaotao; Xu, Ping; Li, Jinjin; Delplancke, Thibaut; Zhang, Hua; Qi, Hongbo
Background: Oral uptake of lycopene has been shown to be beneficial for preventing myocardial ischemia-reperfusion (I/R) injury. However, the strong first-pass metabolism of lycopene influences its bioavailability and impedes its clinic application. In this study, we determined an intravenous (IV) administration dose of lycopene protects against myocardial infarction (MI) in a mouse model, and investigated the effects of acute lycopene administration on reactive oxygen species (ROS) production and related signaling pathways during myocardial I/R. Methods: In this study, we established both in vitro hypoxia/reoxygenation (H/R) cell model and in vivo regional myocardial I/R mouse model by ligating left anterior artery descending. TTC dual staining was used to assess I/R induced MI in the absence and presence of acute lycopene administration via tail vein injection. Results: Lycopene treatment (1 μM) before reoxygenation significantly reduced cardiomyocyte death induced by H/R. Intravenous administration of lycopene to achieve 1 μM concentration in circulating blood significantly suppressed MI, ROS production, and JNK phosphorylation in the cardiac tissue of mice during in vivo regional I/R. Conclusion: Elevating circulating lycopene to 1 μM via IV injection protects against myocardial I/R injury through inhibition of ROS accumulation and consequent inflammation in mice. PMID:26950150
Do antioxidant vitamins reduce infarct size following acute myocardial ischemia/reperfusion?
Bellows, S D; Hale, S L; Simkhovich, B Z; Kay, G L; Kloner, R A
There is controversy concerning the ability of antioxidant vitamins to reduce myocardial infarct size. We sought to determine whether a brief prophylactic treatment of vitamin C or vitamin C plus Trolox (a water-soluble form of vitamin E) could reduce myocardial infarct size in an experimental model. We used an anesthetized open-chest rabbit model in which a branch of the circumflex coronary artery was ligated for 30 minutes followed by 4 hours of reperfusion. Experiments were performed in a randomized and blinded fashion. An IV injection of normal saline pH balanced to 7.4 (control group n = 15), vitamin C (150 mg/kg, n = 14), or vitamin C plus Trolox (150 mg/kg plus 100 mg/kg, respectively, n = 15) was administered prior to coronary occlusion. Collateral blood flow during coronary occlusion was measured by radioactive microspheres, myocardial risk zone (AR) was assessed by blue dye injection, and myocardial infarct size (AN) was assessed by triphenyltetrazolium chloride staining. All rabbits received comparable ischemic insult: Collateral blood flow and AR were similar among all three groups. Infarct size, measured as a percent of AR, did not differ significantly among the controls (21%), vitamin C (29%), or the vitamin C plus Trolox (18%) groups. Therefore, in this ischemia/reperfusion model, antioxidant vitamins did not alter myocardial infarct size. PMID:7540423
Toll-Like Receptors: New Players in Myocardial Ischemia/Reperfusion Injury
Ha, Tuanzhu; Liu, Li; Kelley, Jim; Kao, Race; Williams, David
Abstract Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack. Antioxid. Redox Signal. 15, 1875–1893. PMID:21091074
Cardioprotective Effect of Electroacupuncture Pretreatment on Myocardial Ischemia/Reperfusion Injury via Antiapoptotic Signaling
Lu, Sheng-feng; Huang, Yan; Wang, Ning; Shen, Wei-xing; Fu, Shu-ping; Li, Qian; Yu, Mei-ling; Liu, Wan-xin; Chen, Xia; Jing, Xin-yue; Zhu, Bing-mei
Objectives. Our previous study has used RNA-seq technology to show that apoptotic molecules were involved in the myocardial protection of electroacupuncture pretreatment (EAP) on the ischemia/reperfusion (I/R) animal model. Therefore, this study was designed to investigate how EAP protects myocardium against myocardial I/R injury through antiapoptotic mechanism. Methods. By using rats with myocardial I/R, we ligated the left anterior descending artery (LAD) for 30 minutes followed by 4 hr of reperfusion after EAP at the Neiguan (PC6) acupoint for 12 days; we employed arrhythmia scores, serum myocardial enzymes, and cardiac troponin T (cTnT) to evaluate the cardioprotective effect. Heart tissues were harvested for western blot analyses for the expressions of pro- and antiapoptotic signaling molecules. Results. Our preliminary findings showed that EAP increased the survival of the animals along with declined arrhythmia scores and decreased CK, LDH, CK-Mb, and cTnT levels. Further analyses with the heart tissues detected reduced myocardial fiber damage, decreased number of apoptotic cells and the protein expressions of Cyt c and cleaved caspase 3, and the elevated level of Endo G and AIF after EAP intervention. At the same time, the protein expressions of antiapoptotic molecules, including Xiap, BclxL, and Bcl2, were obviously increased. Conclusions. The present study suggested that EAP protected the myocardium from I/R injury at least partially through the activation of endogenous antiapoptotic signaling. PMID:27313648
The emergency department ECG and immediately life-threatening complications in initially uncomplicated suspected myocardial ischemia.
Zalenski, R J; Sloan, E P; Chen, E H; Hayden, R F; Gold, I W; Cooke, D
The emergency physician's disposition of patients with suspected myocardial ischemia is currently debated; some physicians believe that a subgroup of patients can be managed safely outside the coronary care unit. Clinical predictors are needed in assessing the patient with suspected myocardial ischemia to help identify this subgroup. Through a retrospective cohort study, we investigated the value of the initial emergency department ECG in discriminating between chest pain patients with low and high risk for immediately life-threatening complications. Two hundred eleven initially uncomplicated consecutive coronary care unit admissions with suspected unstable angina or myocardial infarction were studied. Patient outcome, including the incidence of myocardial infarction, complications, and mechanical and pharmacologic interventions, was reviewed. Immediately life-threatening complications included ventricular fibrillation, ventricular tachycardia, shock, 2 degrees and 3 degrees block, and death. Mechanical interventions included electrocardioversion or defibrillation, endotracheal intubation, intra-aortic balloon pump, Swan-Ganz catheter, or pacemaker insertion. Pressors, antiarrhythmics, and vasodilators were the reviewed pharmacologic interventions. A positive ECG was defined by the presence of ST elevation or depression, T wave inversion, left ventricular hypertrophy, left bundle branch block, paced rhythm, or new Q waves. All other ECG interpretations were considered negative. Patients were divided into two groups based on this initial emergency physician ECG interpretation and their complication incidences compared. Of the 211 patients, 96 had a positive ECG; 115 had negative ECGs. Patients with positive ECGs were older, had a greater history and concurrent incidence of myocardial infarction, and more complications and intensive interventions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3345014
Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction.
Ekeløf, Sarah V; Halladin, Natalie L; Jensen, Svend E; Zaremba, Tomas; Aarøe, Jens; Kjærgaard, Benedict; Simonsen, Carsten W; Rosenberg, Jacob; Gögenur, Ismail
Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8% (16.1; 24.8) vs. placebo 20.2% (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8% (2.7; 7.1) vs. placebo 3.7% (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32% in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration. PMID:25319673
Epigallocatechin, a Green Tea Polyphenol, Attenuates Myocardial Ischemia Reperfusion Injury in Rats
Aneja, Rajesh; Hake, Paul W; Burroughs, Timothy J; Denenberg, Alvin G; Wong, Hector R; Zingarelli, Basilia
Epigallocatechin-3-gallate (EGCG) is the most prominent catechin in green tea. EGCG has been shown to modulate numerous molecular targets in the setting of inflammation and cancer. These molecular targets have also been demonstrated to be important participants in reperfusion injury, hence this study examines the effects of EGCG in myocardial reperfusion injury. Male Wistar rats were subjected to myocardial ischemia (30 min) and reperfusion (up to 2 h). Rats were treated with EGCG (10 mg/kg intravenously) or with vehicle at the end of the ischemia period followed by a continuous infusion (EGCG 10 mg/kg/h) during the reperfusion period. In vehicle-treated rats, extensive myocardial injury was associated with tissue neutrophil infiltration as evaluated by myeloperoxidase activity, and elevated levels of plasma creatine phosphokinase. Vehicle-treated rats also demonstrated increased plasma levels of interleukin-6. These events were associated with cytosol degradation of inhibitor κB-α, activation of IκB kinase, phosphorylation of c-Jun, and subsequent activation of nuclear factor-κB and activator protein-1 in the infarcted heart. In vivo treatment with EGCG reduced myocardial damage and myeloperoxidase activity. Plasma IL-6 and creatine phosphokinase levels were decreased after EGCG administration. This beneficial effect of EGCG was associated with reduction of nuclear factor-κB and activator protein-1 DNA binding. The results of this study suggest that EGCG is beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the NF-κB and AP-1 pathway. PMID:15502883
Myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway
Li, Chun-Mei; Shen, Shu-Wen; Wang, Tao; Zhang, Xing-Hua
Objectives: To investigate whether myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway. Design: Forty-five male Sprague-Dawley rats were randomly divided into three groups: Sham, Ischemia reperfusion (I/R) and Ischemic post-conditioning (IPost) group. After the experiment finished, myocardial infarction area was examined. Serum creatine phosphokinase and lactate dehydrogenase activity were detected at baseline and the end of reperfusion. The protein levels of PTEN, Akt, p-Akt, Bax and Bcl-2 were measured by Western blot method. Results: Myocardial infarct size was significantly reduced in IPost as compared to I/R. Results were confirmed by serum creatine phosphokinase and lactate dehydrogenase activity. In addition, PTEN and Bax protein expression were inhibited and the p-Akt and bcl-2 protein expression were enhanced in IPost compared with I/R (P < 0.05). At the same time, the ratio of Bax and Bcl-2 was decreased in IPost (P < 0.05). However, ischemic post conditioning did not affect the total Akt level (P > 0.05). Conclusions: We confirmed that ischemic post-conditioning protects the heart against reperfusion injury. It is important that we demonstrated that the cardioprotective effect of ischemic post-conditioning was involved in the inhibition of PTEN, activation of the PI3K/Akt pathway and reduction of the cardiomyocyte apoptosis. PMID:26629079
Rho-kinase activation in leukocytes plays a pivotal role in myocardial ischemia/reperfusion injury.
Kitano, Katsunori; Usui, Soichiro; Ootsuji, Hiroshi; Takashima, Shin-ichiro; Kobayashi, Daisuke; Murai, Hisayoshi; Furusho, Hiroshi; Nomura, Ayano; Kaneko, Shuichi; Takamura, Masayuki
The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome. PMID:24638037
Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury
Kitano, Katsunori; Usui, Soichiro; Ootsuji, Hiroshi; Takashima, Shin-ichiro; Kobayashi, Daisuke; Murai, Hisayoshi; Furusho, Hiroshi; Nomura, Ayano; Kaneko, Shuichi; Takamura, Masayuki
The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome. PMID:24638037
Early detection of acute transmural myocardial ischemia by the phasic systolic-diastolic changes of local tissue electrical impedance.
Jorge, Esther; Amorós-Figueras, Gerard; García-Sánchez, Tomás; Bragós, Ramón; Rosell-Ferrer, Javier; Cinca, Juan
Myocardial electrical impedance is influenced by the mechanical activity of the heart. Therefore, the ischemia-induced mechanical dysfunction may cause specific changes in the systolic-diastolic pattern of myocardial impedance, but this is not known. This study aimed to analyze the phasic changes of myocardial resistivity in normal and ischemic conditions. Myocardial resistivity was measured continuously during the cardiac cycle using 26 different simultaneous excitation frequencies (1 kHz-1 MHz) in 7 anesthetized open-chest pigs. Animals were submitted to 30 min regional ischemia by acute left anterior descending coronary artery occlusion. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow were recorded simultaneously. Baseline myocardial resistivity depicted a phasic pattern during the cardiac cycle with higher values at the preejection period (4.19 ± 1.09% increase above the mean, P < 0.001) and lower values during relaxation phase (5.01 ± 0.85% below the mean, P < 0.001). Acute coronary occlusion induced two effects on the phasic resistivity curve: 1) a prompt (5 min ischemia) holosystolic resistivity rise leading to a bell-shaped waveform and to a reduction of the area under the LV pressure-impedance curve (1,427 ± 335 vs. 757 ± 266 Ω·cm·mmHg, P < 0.01, 41 kHz) and 2) a subsequent (5-10 min ischemia) progressive mean resistivity rise (325 ± 23 vs. 438 ± 37 Ω·cm at 30 min, P < 0.01, 1 kHz). The structural and mechanical myocardial dysfunction induced by acute coronary occlusion can be recognized by specific changes in the systolic-diastolic myocardial resistivity curve. Therefore these changes may become a new indicator (surrogate) of evolving acute myocardial ischemia. PMID:26608340
Penehyclidine Hydrochloride Preconditioning Provides Cardioprotection in a Rat Model of Myocardial Ischemia/Reperfusion Injury
Lin, Duomao; Ma, Jun; Xue, Yanyan; Wang, Zhaoqi
To investigate the impacts and related mechanisms of penehyclidine hydrochloride (PHC) on ischemia/reperfusion (I/R)-induced myocardial injury. A rat model of myocardial I/R injury was established by the ligation of left anterior descending coronary artery for 30 min followed by 3 h perfusion. Before I/R, the rats were pretreated with or without PHC. Cardiac function was measured by echocardiography. The activities/levels of myocardial enzymes, oxidants and antioxidant enzymes were detected. Evans blue/TTC double staining was performed to assess infarct size. Cardiomyocyte apoptosis was evaluated by TUNEL assay. The release of inflammatory cytokines and inflammatory mediators was detected by ELISA. Western blot was performed to analyze the expression of COX-2, IκB, p-IκB and NF-κB. Meanwhile, the rats were given a single injection of H-PHC before I/R. The effects of PHC on myocardial infarct and cardiac function were investigated after 7 days post-reperfusion. We found that PHC remarkably improved cardiac function, alleviated myocardial injury by decreasing myocardial enzyme levels and attenuated oxidative stress in a dose-dependent manner. Additionally, PHC preconditioning significantly reduced infarct size and the apoptotic rate of cardiomyocytes. Administration of PHC significantly decreased serum TNF-α, IL-1β, IL-6 and PGE2 levels and myocardium COX-2 level. Meanwhile, the expression levels of p-IκB and NF-κB were downregulated, while IκB expression was upregulated. H-PHC also exerted long-term cardioprotection in a rat model of I/R injury by decreasing infarct size and improving cardiac function. These results suggest that PHC can efficiently protect the rats against I/R-induced myocardial injury. PMID:26632817
Plasma catecholamine concentrations at onset of myocardial ischemia during supine bicycle exercise
Sung, B.H.; Robinson, C.; Thadani, U.; Lee, R.; Wilson, M.F.
To assess plasma norepinephrine (NE) and epinephrine (E) concentrations at onset of exercise induced myocardial ischemia the authors studied 10 male patients (PTS), age = 56 +/- 8, with angiographically proven coronary disease during multistage supine bicycle exercise (BEX). All drugs were stopped 7 days before study. Data were obtained at rest and each BEX stage. End points were angina or fatigue. Plasma NE and E were measured by radioenzymatic assay and hemodynamic responses and left ventricular ejection fraction (LVEF) were measured by quantitative cardiac blood pool scintigraphy. Ischemia was defined by 1 mm ST depression ( ) and/or less than 5% increase of LVEF. Seven had ST, 9 abnormal LVEF response and 6 angina. Changes from rest to onset of ischemia for individual PTS ranged from 18 to 122% for NE, 10 to 118% for E. Conclusion: Plasma NE and E levels at onset of exercise induced ischemia were, 1) mildly elevated thus can be reached with mild to moderate stress in daily activity, 2) varied widely from patient to patient, and 3) reflected cardiac workload more than contractability.
Pathogenesis of Myocardial Ischemia-Reperfusion Injury and Rationale for Therapy
Turer, Aslan T.; Hill, Joseph A.
Since the initial description of the phenomenon by Jennings et al 50 years ago, our understanding of the underlying mechanisms of reperfusion injury has grown significantly. Its pathogenesis reflects the confluence of multiple pathways, including ion channels, reactive oxygen species, inflammation, and endothelial dysfunction. This complexity should not deter our efforts to intervene in this process, however, since nearly 2 million patients annually undergo either spontaneous (in the form of acute myocardial infarction) or iatrogenic (in the context of cardioplegic arrest) ischemia-reperfusion. The purpose of this review is to examine our current state of understanding of ischemia-reperfusion injury and highlight recent interventions aimed at this heretofore elusive target. PMID:20643246
FMLP provokes coronary vasoconstriction and myocardial ischemia in rabbits
Gillespie, M.N.; Booth, D.C.; Friedman, B.J.; Cunningham, M.R.; Jay, M.; De Maria, A.N. )
Recent pathological studies of coronary arteries from humans with suspected coronary spasm have revealed an augmented intramural burden of inflammatory cells. To test the hypothesis than inappropriate activation of inflammatory cells participates in the evolution of coronary vasospasm, the present experiment employed a newly developed coronary arteriographic technique for use in pentobarbital-anesthetized rabbits to evaluate the coronary vasomotor actions of the nonselective inflammatory cell stimulant, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). In 10 of 10 animals, selective left intracoronary injection of 200 ng fMLP evoked profound left coronary narrowing accompanied in all cases by ST segment deviation and dysrhythmias. Thallium-201 scintigraphy demonstrated hypoperfusion of the left ventricular free wall and septum supplied by the spastic coronary artery. The fMLP-induced epicardial vasoconstriction, ischemic electrocardiogram (ECG) changes, and thallium perfusion defects were reversed by intravenous nitroglycerin. Neither the right coronary artery nor its distribution were influenced by left coronary injection of fMLP. Additional experiments in isolated, salt solution-perfused rabbit hearts demonstrated that fMLP failed to exert direct coronary vasoconstrictor effects. These observations indicate that the nonselective inflammatory cell stimulant, fMLP, provokes arteriographically demonstrable coronary spasm with attendant myocardial hypoperfusion and ischemic ECG changes in anesthetized rabbits. Such a model may be useful in exploring the dynamic role of inflammatory cells in development of coronary spasm.
Inhalation of concentrated ambient air particles exacerbates myocardial ischemia in conscious dogs.
Wellenius, Gregory A; Coull, Brent A; Godleski, John J; Koutrakis, Petros; Okabe, Kazunori; Savage, Sara T; Lawrence, Joy E; Murthy, G G Krishna; Verrier, Richard L
Short-term increases in ambient air pollution have been associated with an increased incidence of acute cardiac events. We assessed the effect of inhalation exposure to concentrated ambient particles (CAPs) on myocardial ischemia in a canine model of coronary artery occlusion. Six mongrel dogs underwent thoracotomy for implantation of a vascular occluder around the left anterior descending coronary artery and tracheostomy to facilitate particulate exposure. After recovery (5-13 weeks), pairs of subjects were exposed for 6 hr/day on 3 or 4 consecutive days. Within each pair, one subject was randomly assigned to breathe CAPs on the second exposure day and filtered air at other times. The second subject breathed CAPs on the third exposure day and filtered air at other times. Immediately after each exposure, subjects underwent 5-min coronary artery occlusion. We determined ST-segment elevation, a measure of myocardial ischemia heart rate, and arrhythmia incidence during occlusion from continuous electrocardiograms. Exposure to CAPs (median, 285.7; range, 161.3-957.3 microg/m3) significantly (p = 0.007) enhanced occlusion-induced peak ST-segment elevation in precordial leads V4 (9.4 +/- 1.7 vs. 6.2 +/- 0.9 mm, CAPs vs. filtered air, respectively) and V5 (9.2 +/- 1.3 vs. 7.5 +/- 0.9 mm). ST-segment elevation was significantly correlated with the silicon concentration of the particles and other crustal elements possibly associated with urban street dust (p = 0.003 for Si). No associations were found with CAPs mass or number concentrations. Heart rate was not affected by CAPs exposure. These results suggest that exacerbation of myocardial ischemia during coronary artery occlusion may be an important mechanism of environmentally related acute cardiac events. PMID:12676590
Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin–oxygen affinity
Weiss, Robert G.; Mejia, Marco A.; Kass, David A.; DiPaula, Anthony F.; Becker, Lewis C.; Gerstenblith, Gary; Chacko, V.P.
Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin–oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin–oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment–length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin–oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia. J. Clin. Invest. 103:739–746 (1999) PMID:10074492
Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity.
Weiss, R G; Mejia, M A; Kass, D A; DiPaula, A F; Becker, L C; Gerstenblith, G; Chacko, V P
Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia. PMID:10074492
Silent and Malignant Early Repolarization Syndrome Mimicking Hyper-Acute ST Elevation Myocardial Infarction
Tam, Weng-Chio; Hsieh, Ming-Hsiung; Lin, Yung-Kuo; Yeh, Jong-Shiuan
A 55-year-old male with underlying type 2 diabetes mellitus and hypertension presented at our emergency department with ventricular fibrillation-related cardiac arrest. Hyper-acute ST elevation myocardial infarction was the preliminary diagnosis by 12-lead electrocardiography, which simultaneously showed J point ST elevation and tall T waves. However, the echocardiography showed concentric left ventricle hypertrophy and preserved left ventricular systolic function with no regional wall motion abnormalities, and coronary angiography did not show any critical coronary artery lesion. Malignant early repolarization syndrome was diagnosed, and an implantable cardioverter defibrillator was implanted. Early repolarization syndrome is associated with J point elevation, and more involved leads and an increased J point elevation amplitude can increase the risk of arrhythmogenicity. In summary, we report a case with asymptomatic type 3 early repolarization syndrome-induced idiopathic ventricular fibrillation mimicking hyper-acute ST elevation myocardial infarction. PMID:27471366
Silent and Malignant Early Repolarization Syndrome Mimicking Hyper-Acute ST Elevation Myocardial Infarction.
Tam, Weng-Chio; Hsieh, Ming-Hsiung; Lin, Yung-Kuo; Yeh, Jong-Shiuan
A 55-year-old male with underlying type 2 diabetes mellitus and hypertension presented at our emergency department with ventricular fibrillation-related cardiac arrest. Hyper-acute ST elevation myocardial infarction was the preliminary diagnosis by 12-lead electrocardiography, which simultaneously showed J point ST elevation and tall T waves. However, the echocardiography showed concentric left ventricle hypertrophy and preserved left ventricular systolic function with no regional wall motion abnormalities, and coronary angiography did not show any critical coronary artery lesion. Malignant early repolarization syndrome was diagnosed, and an implantable cardioverter defibrillator was implanted. Early repolarization syndrome is associated with J point elevation, and more involved leads and an increased J point elevation amplitude can increase the risk of arrhythmogenicity. In summary, we report a case with asymptomatic type 3 early repolarization syndrome-induced idiopathic ventricular fibrillation mimicking hyper-acute ST elevation myocardial infarction. PMID:27471366
PPAR-γ activation fails to provide myocardial protection in ischemia and reperfusion in pigs
Xu, Ya; Gen, Michael; Lu, Li; Fox, Jennifer; Weiss, Sara O.; Brown, R. Dale; Perlov, Daniel; Ahmad, Hasan; Zhu, Peili; Greyson, Clifford; Long, Carlin S.; Schwartz, Gregory G.
Peroxisome proliferator-activated receptor (PPAR)-γ modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-γ activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-γ activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both α-tocopherol and thiazolidinedione moieties, whether PPAR-γ activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg·kg−1 ·day−1), rosiglitazone (3 mg·kg−1 ·day−1), or α-tocopherol (73 mg·kg−1 ·day−1, equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-γ, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or α-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an α-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-γ activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its α-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest
The Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited
Kurian, Gino A.; Rajagopal, Rashmi; Vedantham, Srinivasan; Rajesh, Mohanraj
Oxidative and reductive stress are dual dynamic phases experienced by the cells undergoing adaptation towards endogenous or exogenous noxious stimulus. The former arises due to the imbalance between the reactive oxygen species production and antioxidant defenses, while the latter is due to the aberrant increase in the reducing equivalents. Mitochondrial malfunction is the common denominator arising from the aberrant functioning of the rheostat that maintains the homeostasis between oxidative and reductive stress. Recent experimental evidences suggest that the maladaptation during oxidative stress could play a pivotal role in the pathophysiology of major cardiovascular diseases such as myocardial infraction, atherosclerosis, and diabetic cardiovascular complications. In this review we have discussed the role of oxidative and reductive stress pathways in the pathogenesis of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy (DCM). Furthermore, we have provided impetus for the development of subcellular organelle targeted antioxidant drug therapy for thwarting the deterioration of the failing myocardium in the aforementioned cardiovascular conditions. PMID:27313825
The Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited.
Kurian, Gino A; Rajagopal, Rashmi; Vedantham, Srinivasan; Rajesh, Mohanraj
Oxidative and reductive stress are dual dynamic phases experienced by the cells undergoing adaptation towards endogenous or exogenous noxious stimulus. The former arises due to the imbalance between the reactive oxygen species production and antioxidant defenses, while the latter is due to the aberrant increase in the reducing equivalents. Mitochondrial malfunction is the common denominator arising from the aberrant functioning of the rheostat that maintains the homeostasis between oxidative and reductive stress. Recent experimental evidences suggest that the maladaptation during oxidative stress could play a pivotal role in the pathophysiology of major cardiovascular diseases such as myocardial infraction, atherosclerosis, and diabetic cardiovascular complications. In this review we have discussed the role of oxidative and reductive stress pathways in the pathogenesis of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy (DCM). Furthermore, we have provided impetus for the development of subcellular organelle targeted antioxidant drug therapy for thwarting the deterioration of the failing myocardium in the aforementioned cardiovascular conditions. PMID:27313825
Internal countershock produces myocardial damage and lactate production without myocardial ischemia in anesthetized dogs
Gaba, D.M.; Maxwell, M.S.; Merlone, S.; Smith, C.
The global myocardial extraction of lactate was measured in 13 halothane anesthetized dogs to assess the effect of electric countershock applied directly to the heart. Seven animals received two countershocks of 30 delivered joules each, while six animals were not shocked but were atrially paced to a rate of 190-200, both with and without occlusion of the vena cava to produce a mean arterial pressure of 40-50 mmHg. All animals had substantially positive lactate extraction in the baseline state (36 +/- 10% for countershock group vs. 41 +/- 3% for pacing group). Myocardial lactate extraction reached a markedly negative nadir 2.5 min after countershock (-19 +/- 15%), but returned toward normal by 6 min (10 +/- 6%). Lactate extraction was not significantly changed from baseline in the pacing group. The relationship between changes in regional myocardial blood flow (radiolabeled microspheres) and post-countershock myocardial damage (technetium pyrophosphate uptake) was assessed in six dogs shocked as above. Mean myocardial blood flow was increased minimally immediately after countershock (0.78 +/- 0.08 ml X min-1 X g-1 vs. 1.16 +/- 0.3), but there was no difference in blood flow between damaged and undamaged tissue at either time point. The epicardial-to-endocardial ratio of blood flow was unchanged after countershock (0.97 +/- 0.05 vs. 0.99 +/- 0.08). There was no relationship between myocardial damage and either the absolute amount of blood flow after countershock (r = -0.03) or the change in blood flow compared with the pre-shock period (r = 0.01).
Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice
Muzumdar, Radhika H.; Huffman, Derek M.; Calvert, John W.; Jha, Saurabh; Weinberg, Yoni; Cui, Lingguang; Nemkal, Anjana; Atzmon, Gil; Klein, Laura; Gundewar, Susheel; Ji, Sang Yong; Lavu, Madhav; Predmore, Benjamin L.; Lefer, David J.
Objective Humanin, an endogenous anti-apoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of humanin, HNG, in an in vivo murine model of myocardial ischemia and reperfusion (MI-R). Methods Male C57BL6/J mice (8–10 week old) were subjected to 45 min of left coronary artery occlusion followed by 24 hr reperfusion. HNG or vehicle was administered intra-peritoneally one hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hrs using Evans Blue dye and 2,3,5 triphenyltetrazolium chloride (TTC) staining. Left ventricular (LV) function was evaluated at one week post ischemia using high-resolution, 2- D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0–24 hrs) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. Results HNG reduced infarct size relative to the area-at-risk in a dose dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced LV ejection fraction and preserved post-ischemic LV dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased the expression of pAMPK and p-eNOS in the heart and attenuated Bax and Bcl-2 levels following MI-R. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. Conclusions These data show that HNG provides cardioprotection in a mouse model of MI-R potentially through activation of AMPK-eNOS mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction. PMID:20651283
Both Castration and Goserelin Acetate Ameliorate Myocardial Ischemia Reperfusion Injury and Apoptosis in Male Rats
Hadi, Najah R.; Yusif, Fadhil G.; Yousif, Maitham; Jaen, Karrar K.
Although reperfusion of an ischemic organ is essential to prevent irreversible tissue damage, it may amplify tissue injury. This study investigates the role of endogenous testosterone in myocardial ischemia reperfusion and apoptosis in male rats. Material and method. Twenty four male rats were randomized into 4 equal groups: Group (1), sham group, rats underwent the same anesthetic and surgical procedure as the control group except for LAD ligation; Group (2), Active control group, rats underwent LAD ligation; Group (3), castrated, rats underwent surgical castration, left 3wks for recovery, and then underwent LAD ligation; and Group (4), Goserelin acetate treated, rats received 3.6 mg of Goserelin 3 wks before surgery and then underwent LAD ligation. At the end of experiment, plasma cTn I, cardiac TNF-α, IL1-β, ICAM-1, and Apoptosis level were measured and histological examination was made. Results. Compared to sham group, the levels of myocardial TNF-α, IL-1β, ICAM-1, apoptosis, and plasma cTn I were significantly increased (P < 0.05) in control group and all rats showed significant myocardial injury (P < 0.05). Castration and Goserelin acetates significantly counteract the increase in myocardial levels of TNF-α, IL-1β, ICAM-1, plasma cTn I, and apoptosis (P < 0.05) and significantly reduce (P < 0.05) the severity of myocardial injury. We conclude that castration and Goserelin acetates ameliorate myocardial I/R injury and apoptosis in rats via interfering with inflammatory reactions. PMID:24729888
Plumbagin Mediates Cardioprotection Against Myocardial Ischemia/Reperfusion Injury Through Nrf-2 Signaling
Wang, Shi-Xun; Wang, Jian; Shao, Jing-Bo; Tang, Wei-ning; Zhong, Jing-Quan
Background Plumbagin is a potent antioxidant with anti-inflammatory and anti-carcinogenic action. Myocardial ischemia/reperfusion injury results in organ damage through oxidative stress and inflammatory mechanisms. In this study, we analyzed the potential role of plumbagin against myocardial I/R injury in Wistar rats. Material/Methods Oxidative stress was measured through ROS, lipid peroxide content, and antioxidant enzyme activities. The expression of redox signaling and inflammatory proteins was analyzed through Western blotting. Inflammatory cytokine expressions were determined through ELISA. Results Oxidative stress status was reduced by plumbagin by decreasing ROS and lipid peroxide levels in rats with myocardial I/R (MI/R) injury. Plumbagin regulated redox imbalance induced by I/R injury by modulating the transcription factors NF-κB and Nrf-2. Further, downstream targets of NF-κB (COX-2, iNOS) and Nrf-2 (HO-1, NQO1 and GST) expression were significantly downregulated by plumbagin treatment. Pro-inflammatory cytokine expressions were significantly abrogated by plumbagin treatment. Conclusions This study shows the protective role of plumbagin against myocardial I/R injury by regulating antioxidant and inflammatory mechanisms. PMID:27078001
Pramipexole pretreatment attenuates myocardial ischemia/reperfusion injury through upregulation of autophagy.
Mo, Yingli; Tang, Lu; Ma, Yi; Wu, Saizhu
This article investigated the effects of pramipexole on myocardial ischemia reperfusion (I/R) injury and its underlying mechanisms. We utilized an in vivo mouse model of myocardial I/R injury and an in vitro H9c2 cell model of hypoxia/reoxygenation (H/R) injury. Pramipexole pretreatment in male C57BL/6 mice significantly reduced the myocardial infarction size, decreased the CK and LDH activities at the serum level and enhanced autophagy. In the in vitro study, the pramipexole treatment significantly elevated the survival rate, decreased the LDH activity, reduced ROS generation and restored the ΔΨm in H9C2 cells during H/R. Additionally, its use could increase the autophagy flux level in H9c2 cells. The underlying mechanisms were determined by measuring the expression of the autophagic protein levels. These results further indicated that pramipexole treatment modulated H/R-induced autophagy via an AMPK-dependent pathway. All of these data indicate that pramipexole exerted protective effects against myocardial I/R injury and enhanced autophagy in part through the AMPK-mediated pathway. PMID:27063800
Traditional Chinese Medicine Shuang Shen Ning Xin Attenuates Myocardial Ischemia/Reperfusion Injury by Preserving of Mitochondrial Function
Li, Xueli; Liu, Jianxun; Lin, Li; Guo, Yujie; Lin, Chengren; Zhang, Cuixiang; Yang, Bin
To investigate the potential cardioprotective effects of Shuang Shen Ning Xin on myocardial ischemia/reperfusion injury. Wistar rats were treated with trimetazidine (10 mg/kg/day, ig), Shuang Shen Ning Xin (22.5, 45 mg/kg/day, ig), or saline for 5 consecutive days. Myocardial ischemia/reperfusion injury was induced by ligation of the left anterior descending coronary artery for 40 min and reperfusion for 120 min on the last day of administration. It is found that Shuang Shen Ning Xin pretreatment markedly decreased infarct size and serum LDH levels, and this observed protection was associated with reduced myocardial oxidative stress and cardiomyocyte apoptosis after myocardial ischemia/reperfusion injury. In addition, further studies on mitochondrial function showed that rats treated with Shuang Shen Ning Xin displayed decreased mitochondrial swelling and cytosolic cytochrome c levels, which were accompanied by a preservation of complex I activities and inhibition of mitochondrial permeability transition. In conclusion, the mitochondrial protective effect of Shuang Shen Ning Xin could be a new mechanism, by which Shuang Shen Ning Xin attenuates myocardial ischemia/reperfusion injury. PMID:25031602
Traditional chinese medicine shuang shen ning xin attenuates myocardial ischemia/reperfusion injury by preserving of mitochondrial function.
Li, Xueli; Liu, Jianxun; Lin, Li; Guo, Yujie; Lin, Chengren; Zhang, Cuixiang; Yang, Bin
To investigate the potential cardioprotective effects of Shuang Shen Ning Xin on myocardial ischemia/reperfusion injury. Wistar rats were treated with trimetazidine (10 mg/kg/day, ig), Shuang Shen Ning Xin (22.5, 45 mg/kg/day, ig), or saline for 5 consecutive days. Myocardial ischemia/reperfusion injury was induced by ligation of the left anterior descending coronary artery for 40 min and reperfusion for 120 min on the last day of administration. It is found that Shuang Shen Ning Xin pretreatment markedly decreased infarct size and serum LDH levels, and this observed protection was associated with reduced myocardial oxidative stress and cardiomyocyte apoptosis after myocardial ischemia/reperfusion injury. In addition, further studies on mitochondrial function showed that rats treated with Shuang Shen Ning Xin displayed decreased mitochondrial swelling and cytosolic cytochrome c levels, which were accompanied by a preservation of complex I activities and inhibition of mitochondrial permeability transition. In conclusion, the mitochondrial protective effect of Shuang Shen Ning Xin could be a new mechanism, by which Shuang Shen Ning Xin attenuates myocardial ischemia/reperfusion injury. PMID:25031602
The PPAR-α activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs
Xu, Ya; Lu, Li; Greyson, Clifford; Rizeq, Mona; Nunley, Karin; Wyatt, Beata; Bristow, Michael R.; Long, Carlin S.; Schwartz, Gregory G.
Rodent studies suggest that peroxisome proliferator-activated receptor-α (PPAR-α) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-α activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-α activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg·kg−1 ·day−1 orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-α in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-α mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-α in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-α activator does not alter myocardial metabolic or contractile responses to I/R in pigs. PMID:16339839
Cellular and molecular mechanisms of endothelial ischemia/reperfusion injury: perspectives and implications for postischemic myocardial protection
Yang, Qin; He, Guo-Wei; Underwood, Malcolm John; Yu, Cheuk-Man
Ischemia/reperfusion (I/R) injury is a major cause of myocardial damage. Despite continuous efforts, minimizing I/R injury still represents a great challenge in standard medical treatments of ischemic heart disease, i.e., thrombolytic therapy, primary percutaneous coronary intervention, and coronary arterial bypass grafting. Development of effective interventions and strategies to prevent or reduce myocardial I/R injury is therefore of great clinical significance. Endothelial dysfunction plays a significant role in myocardial I/R injury, which renders endothelial cells an attractive target for postischemic myocardial protection. The rapidly evolving knowledge of the mechanisms of endothelial I/R injury helps broaden perspective for future development of novel strategies targeting endothelium for alleviating myocardial I/R damage. This review provides a comprehensive summary of the cellular and molecular mechanisms of endothelial I/R injury. Current perspectives and future directions for developing endothelium targeting therapeutics for postischemic myocardial protection are further discussed. PMID:27158368
Cellular and molecular mechanisms of endothelial ischemia/reperfusion injury: perspectives and implications for postischemic myocardial protection.
Yang, Qin; He, Guo-Wei; Underwood, Malcolm John; Yu, Cheuk-Man
Ischemia/reperfusion (I/R) injury is a major cause of myocardial damage. Despite continuous efforts, minimizing I/R injury still represents a great challenge in standard medical treatments of ischemic heart disease, i.e., thrombolytic therapy, primary percutaneous coronary intervention, and coronary arterial bypass grafting. Development of effective interventions and strategies to prevent or reduce myocardial I/R injury is therefore of great clinical significance. Endothelial dysfunction plays a significant role in myocardial I/R injury, which renders endothelial cells an attractive target for postischemic myocardial protection. The rapidly evolving knowledge of the mechanisms of endothelial I/R injury helps broaden perspective for future development of novel strategies targeting endothelium for alleviating myocardial I/R damage. This review provides a comprehensive summary of the cellular and molecular mechanisms of endothelial I/R injury. Current perspectives and future directions for developing endothelium targeting therapeutics for postischemic myocardial protection are further discussed. PMID:27158368
Myocardial protection against global ischemia with Krebs-Henseleit buffer-based cardioplegic solution
Background The Krebs-Henseleit buffer is the best perfusion solution for isolated mammalian hearts. We hypothesized that a Krebs-Henseleit buffer-based cardioplegic solution might provide better myocardial protection than well-known crystalloid cardioplegic solutions because of its optimal electrolyte and glucose levels, presence of buffer systems, and mild hyperosmolarity. Methods Isolated Langendorff-perfused rat hearts were subjected to either global ischemia without cardioplegia (controls) or cardioplegic arrest for either 60 or 180 min, followed by 120 min of reperfusion. The modified Krebs-Henseleit buffer-based cardioplegic solution (mKHB) and St. Thomas' Hospital solution No. 2 (STH2) were studied. During global ischemia, the temperatures of the heart and the cardioplegic solutions were maintained at either 37°C (60 min of ischemia) or 22°C (moderate hypothermia, 180 min of ischemia). Hemodynamic parameters were registered throughout the experiments. The infarct size was determined through histochemical examination. Results Cardioplegia with the mKHB solution at moderate hypothermia resulted in a minimal infarct size (5 ± 3%) compared to that in the controls and STH2 solution (35 ± 7% and 19 ± 9%, respectively; P < 0.001, for both groups vs. the mKHB group). In contrast to the control and STH2-treated hearts, no ischemic contracture was registered in the mKHB group during the 180-min global ischemia. At normothermia, the infarct sizes were 4 ± 3%, 72 ± 6%, and 70 ± 12% in the mKHB, controls, and STH2 groups, respectively (P < 0.0001). In addition, cardioplegia with mKHB at normothermia prevented ischemic contracture and improved the postischemic functional recovery of the left ventricle (P < 0.001, vs. STH2). Conclusions The data suggest that the Krebs-Henseleit buffer-based cardioplegic might be superior to the standard crystalloid solution (STH2). PMID:23547937
Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury
Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N.; Chaudhary, Uma; Bhatia, Jagriti; Ojha, Shreesh; Arya, Dharamvir Singh
Kaempferol (KMP), a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR) model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p.) was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB), inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3), TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2). In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway. PMID:27087891
Transduction of PEP-1-heme oxygenase-1 fusion protein reduces myocardial ischemia/reperfusion injury in rats.
He, Xiang-Hu; Wang, Yun; Yan, Xue-Tao; Wang, Yan-Lin; Wang, Cheng-Yao; Zhang, Zong-Ze; Li, Hui; Jiang, Hai-Xing
Recent studies have uncovered that overexpression of heme oxygenase-1 (HO-1) by induction or gene transfer provides myocardial protection. In the present study, we investigated whether HO-1 protein mediated by cell-penetrating peptide PEP-1 could confer cardioprotection in a rat model of myocardial ischemia/reperfusion (I/R) injury. Male Sprague-Dawley rats were subjected to 30 minutes of ischemia by occluding the left anterior descending coronary artery and to 120 minutes of reperfusion to prepare the model of I/R. Animals were randomized to receive PEP-1-HO-1 fusion protein or saline 30 minutes before a 30-minute occlusion. I/R increased myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor alpha, and interleukin 6 and reduced myocardial superoxide dismutase activity. Administration of PEP-1-HO-1 reduced myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor alpha, and interleukin 6 and increased myocardial superoxide dismutase and HO-1 activities. His-probe protein was only detected in PEP-1-HO-1-transduced hearts. In addition, transduction of PEP-1-HO-1 markedly reduced elevated myocardial tissue nuclear factor-κB induced by I/R. The results suggested that transduction of PEP-1-HO-1 fusion protein decreased myocardial reperfusion injury, probably by attenuating the production of oxidants and proinflammatory cytokines regulated by nuclear factor-κB. PMID:23921302
CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis.
Zhang, Ting; Zhang, Yan; Cui, Mingyao; Jin, Li; Wang, Yimei; Lv, Fengxiang; Liu, Yuli; Zheng, Wen; Shang, Haibao; Zhang, Jun; Zhang, Mao; Wu, Hongkun; Guo, Jiaojiao; Zhang, Xiuqin; Hu, Xinli; Cao, Chun-Mei; Xiao, Rui-Ping
Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure. PMID:26726877
Effects of Glucose Concentration on Propofol Cardioprotection against Myocardial Ischemia Reperfusion Injury in Isolated Rat Hearts.
Yao, Xinhua; Li, Yalan; Tao, Mingzhe; Wang, Shuang; Zhang, Liangqing; Lin, Jiefu; Xia, Zhengyuan; Liu, Hui-Min
The anesthetic propofol confers cardioprotection against myocardial ischemia-reperfusion injury (IRI) by reducing reactive oxygen species (ROS). However, its cardioprotection on patients is inconsistent. Similarly, the beneficial effect of tight glycemic control during cardiac surgery in patients has recently been questioned. We postulated that low glucose (LG) may promote ROS formation through enhancing fatty acid (FA) oxidation and unmask propofol cardioprotection during IRI. Rat hearts were isolated and randomly assigned to be perfused with Krebs-Henseleit solution with glucose at 5.5 mM (LG) or 8 mM (G) in the absence or presence of propofol (5 μg/mL) or propofol plus trimetazidine (TMZ). Hearts were subjected to 35 minutes of ischemia followed by 60 minutes of reperfusion. Myocardial infarct size (IS) and cardiac CK-MB were significantly higher in LG than in G group (P < 0.05), associated with reduced left ventricular developed pressure and increases in postischemic cardiac contracture. Cardiac 15-F2t-isoprostane was higher, accompanied with higher cardiac lipid transporter CD36 protein expression in LG. Propofol reduced IS, improved cardiac function, and reduced CD36 in G but not in LG. TMZ facilitated propofol cardioprotection in LG. Therefore, isolated heart with low glucose lost sensitivity to propofol treatment through enhancing FA oxidation and TMZ supplementation restored the sensitivity to propofol. PMID:26491698
Effects of Glucose Concentration on Propofol Cardioprotection against Myocardial Ischemia Reperfusion Injury in Isolated Rat Hearts
Yao, Xinhua; Li, Yalan; Tao, Mingzhe; Wang, Shuang; Zhang, Liangqing; Lin, Jiefu; Xia, Zhengyuan; Liu, Hui-min
The anesthetic propofol confers cardioprotection against myocardial ischemia-reperfusion injury (IRI) by reducing reactive oxygen species (ROS). However, its cardioprotection on patients is inconsistent. Similarly, the beneficial effect of tight glycemic control during cardiac surgery in patients has recently been questioned. We postulated that low glucose (LG) may promote ROS formation through enhancing fatty acid (FA) oxidation and unmask propofol cardioprotection during IRI. Rat hearts were isolated and randomly assigned to be perfused with Krebs-Henseleit solution with glucose at 5.5 mM (LG) or 8 mM (G) in the absence or presence of propofol (5 μg/mL) or propofol plus trimetazidine (TMZ). Hearts were subjected to 35 minutes of ischemia followed by 60 minutes of reperfusion. Myocardial infarct size (IS) and cardiac CK-MB were significantly higher in LG than in G group (P < 0.05), associated with reduced left ventricular developed pressure and increases in postischemic cardiac contracture. Cardiac 15-F2t-isoprostane was higher, accompanied with higher cardiac lipid transporter CD36 protein expression in LG. Propofol reduced IS, improved cardiac function, and reduced CD36 in G but not in LG. TMZ facilitated propofol cardioprotection in LG. Therefore, isolated heart with low glucose lost sensitivity to propofol treatment through enhancing FA oxidation and TMZ supplementation restored the sensitivity to propofol. PMID:26491698
Endogenous glycogen prevents Ca2+ overload and hypercontracture in harp seal myocardial cells during simulated ischemia.
Henden, Thale; Aasum, Ellen; Folkow, Lars; Mjøs, Ole D; Lathrop, David A; Larsen, Terje S
The purpose of this study was to determine if elevated myocardial glycogen content could obviate Ca(2+) overload and subsequent myocardial injury in the setting of low oxygen and diminished exogenous substrate supplies. Isolated harp seal cardiomyocytes, recognized as having large glycogen stores, were incubated under conditions simulating ischemia (oxygen and substrate deprivation) for 1 h. Rat cardiomyocytes were used for comparison. Freshly isolated seal cardiomyocytes contained approximately 10 times more glycogen than those from rats (479 +/- 39 vs. 48 +/- 5 nmol glucose/mg dry weight (dry wt), mean +/- S.E., n = 6), and during ischemia lactate production was significantly greater in seal compared to rat cardiomyocytes (660 +/- 99 vs. 97 +/- 14 nmol/mg dry wt), while glycogen content decreased both in seal (from 479 +/- 39 to 315 +/- 58 nmol glucose/mg dry wt) and rat cardiomyocytes (from 48 +/- 5 to 18 +/- 5 nmol glucose/mg dry wt). Cellular ATP was well maintained in ischemic seal cardiomyocytes, whereas it showed a 65% decline (from 31 +/- 3 to 11 +/- 1 nmol ATP/mg dry wt) in rat cardiomyocytes. Similarly, total seal cardiomyocyte Ca(2+) content was not affected by ischemia, while Ca(2+) increased from 8.5 +/- 2.0 to 13.3 +/- 2.0 nmol/mg dry wt in ischemic rat myocytes. Rat cardiomyocytes also showed a notable decline in the percentage of rod-shaped cells in response to ischemia (from 66 +/- 4% to 30 +/- 3%), and cell morphology was unaffected in seal incubations. Addition of iodoacetate (IAA, an inhibitor of glycolysis) to seal cardiomyocytes, on top of substrate and oxygen deprivation, reduced the cellular content of ATP by 52.9 +/- 4.4% (from 25 +/- 4 to 11 +/- 2 nmol ATP/mg dry wt) and the percentage of rod-shaped myocytes from 51 +/- 3% to 28 +/- 4%, while total Ca(2+) content was unchanged by these conditions. Seal cardiomyocytes thus tolerate low oxygen conditions better than rat cardiomyocytes. This finding is most likely due to a higher glycolysis
Relation between regional myocardial uptake of /sup 82/Rb and perfusion: absolute reduction of cation uptake in ischemia
Selwyn, A.P.; Allan, R.M.; L'Abbate, A.; Horlock, P.; Camici, P.; Clark, J.; O'Brien, H.A.; Grant, P.M.
Experiments were undertaken using /sup 82/Rb and position tomography to examine the relation between myocardial perfusion and cation uptake during acute ischemia. /sup 82/Rb was repeatedly eluted from a /sup 82/Sr-/sup 82/Rb generator. In six dogs emission tomograms were used to measure the delivered arterial and myocardial concentrations at rest and after coronary stenosis, stress and ischemia. There was a poor overall relation between regional myocardial uptake and flow measured by microspheres and a large individual variability. Extraction of /sup 82/Rb was inversely related to flow. Significant regional reduction of cation uptake was detected in the tomograms when regional flow decreased by more than 35 percent. This reduction was significantly greater when ischemia was present. A small but significantly greater when ischemia was present. A small but significant decrease (33.0 +/- 9.1 percent, mean +/- standard deviation) in the myocardial uptake of /sup 82/Rb was detected only when flow was increased by more than 120 percent in relation to a control area after administration of dypiridamole. The technique using /sup 82/Rb and tomography was applied in five volunteers and five patients with angina pectoris and coronary artery disease. Myocardial tomograms recorded at rest and after exercise in the volunteers showed homogeneous uptake of cation in reproducible and repeatable scans. In contrast, the patients with coronary artery disease showed an absolute mean decrease of 36 +/- 14 percent in regional myocardial uptake of /sup 82/Rb after exercise. These abnormalities persisted in serial tomograms for more than 20 minutes after the symptoms and electrocardiographic signs of ischemia.
Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats
Takhtfooladi, Hamed Ashrafzadeh; Asl, Adel Haghighi Khiabanian; Shahzamani, Mehran; Takhtfooladi, Mohammad Ashrafzadeh; Allahverdi, Amin; Khansari, Mohammadreza
Background Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries. Objective This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR. Methods Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination. Results The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II. Conclusion From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model. PMID:26039663
7-oxo-PGI2 induced late protective action from arrhythmias due to local myocardial ischemia.
Udvary, E; Végh, A; Szekeres, L
In our earlier experiments administration of the stable PGI2 analogue: 7-oxo-PGI2-ephedrine salt to dogs resulted in a late appearing and long-lasting protection from coronary ligation induced ischemia and subsequent postocclusion and reperfusion arrhythmias. Objective of the present study was to evaluate the extent and duration of antiischemic and antiarrhythmic action induced by a single dose 50 micrograms/kg i.m. 7-oxo-PGI2 in dogs subjected to myocardial ischemia evoked by left anterior descending coronary (LAD) ligation at different intervals (2, 6, 24, 48, 72 hours and 2 weeks) after treatment. In the 2 weeks prolonged treatment group treatment started with 50 micrograms/kg i.m. dose, followed every third day by administration of 25 micrograms/kg 7-oxo-PGI2. After anesthesia and thoracotomy the electrophysiological parameters (SCL, CSNRT, AFRP, VFRP and A-V ERP) were determined by means of computer controlled programmed electrical stimulation. Then the animals were subjected to LAD occlusion for 25 min and subsequent reperfusion. 7-oxo-PGI2 pretreatment considerably protected against myocardial ischemia, i.e. there was a marked reduction in ST-segment elevation, the number of ES and the incidence of VF. The maximal antiischemic action and the most striking reduction in ventricular arrhythmias could be observed 48 hours after a single dose of 7-oxo-PGI2 and also after prolonged treatment of two weeks. In this latter group CSNRT showed the most expressed prolongation, however, AFRP and to lesser degree VFRP was also prolonged. PMID:2029655
Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury
Conklin, Daniel J.; Guo, Yiru; Jagatheesan, Ganapathy; Kilfoil, Peter; Haberzettl, Petra; Hill, Bradford G.; Baba, Shahid P.; Guo, Luping; Wetzelberger, Karin; Obal, Detlef; Rokosh, D. Gregg; Prough, Russell A.; Prabhu, Sumanth D.; Velayutham, Murugesan; Zweier, Jay L.; Hoetker, David; Riggs, Daniel W.; Srivastava, Sanjay; Bolli, Roberto; Bhatnagar, Aruni
Rationale Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. Objective We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury. Methods and Results In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type (WT) mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism 4-hydroxy-trans-2-nonenal (HNE) or trans-2-hexanal; and, upon ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than WT hearts. GSTP-deficiency did not affect I/R-induced free radical generation, JNK activation or depletion of reduced glutathione. Acrolein-exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na+/Ca++ exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than WT myocytes to acrolein-induced protein crosslinking and cell death. Conclusions GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes such as acrolein. PMID:26169370
Cardioprotective effect of total paeony glycosides against isoprenaline-induced myocardial ischemia in rats.
Long, Jiangang; Gao, Meili; Kong, Yu; Shen, Xian; Du, Xiaoyang; Son, Young-Ok; Shi, Xianglin; Liu, Jiankang; Mo, Xiaoyan
Paeoniae radix is a traditional Chinese medicinal herb for treating some diseases; important components are total paeony glycosides (TPGs), an approved drug by the State Food and Drug Administration (SFDA) for the therapy of rheumatoid arthritis (RA). We firstly reported myocardial benefits of TPGs previously, and the present study is to further investigate the underlying mechanisms for preventing oxidative damage in cardiomyopathy. We measured the capacity of TPGs to scavenge free radicals in vitro. Then 60 SD rats were randomly divided into five groups: (1) a normal control group, (2) an isoprenaline (ISO)-induced myocardial ischemic model group, (3) a TPG treatment group (TPGs 269.4 mg/kg delivered by intragastric administration for 3 days before ISO administration and TPGs 449 mg/kg delivered for 3 days after ISO administration), (4) a TPG therapy group (TPGs 449 mg/kg delivered for 3 days after ISO administration), and (5) a positive control group (propranolol 15 mg/kg for 3 days after ISO administration). The ISO-induced myocardial ischemic model was established by subcutaneous injection of 1mg/kg/8h ISO (2 times). The activities of myocardial enzymes, including glutamic oxaloacetic transaminase (GOT), creatine kinase (CK), lactate dehydrogenase (LDH), antioxidant enzyme superoxide dismutase (SOD) as well as the content of lipid peroxidation product malondialdehyde (MDA) were detected. We found that TPGs potently eliminated hydroxyl radicals and superoxide in vitro using ESR assays. Compared with model rats, TPG treatment, TPG therapy and the positive control treatment exhibited significantly reduced activities of GOT, LDH, and CK (p < 0.01), increased activity of SOD (p < 0.01) and lower levels of MDA (p < 0.05). More interestingly, the protective effect of TPG treatment was even better than that of propranolol. These results suggest that TPGs significantly ameliorate ISO-induced myocardial ischemia and their action might be through reducing oxidative stress
Silent broken heart (Can shortness of breath be the only presentation of myocardial infarction?).
Waleed, Mohammad; Sachpekidis, Vasileios; Bragadeesh, Thanjavur; Clark, Andrew L
A 55-year-old previously healthy man was referred to our cardiology outpatient department (by the respiratory team) due to shortness of breath that started 2-3 months prior. He suddenly became breathless after changing a car wheel with no other associated symptoms. Specifically, he denied ever having had chest pain. His breathlessness got gradually worse preventing him from performing simple everyday activities, such as climbing stairs, and a couple of weeks before presentation, the patient noticed ankle oedema. He was an ex-smoker and drank 3-4 units of alcohol daily. There was a family history of hypertension. He worked as a contract manager in the construction industry. After clinical examination, a transthoracic echocardiogram was performed and the patient was admitted for further investigations. Clinical examination and investigation confirmed missed myocardial infarction with a complication of ventricular aneurysm. The patient was referred to cardiothoracic surgeons for surgical correction of the defect. PMID:26113615
Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart
Napoli, Claudio; Cicala, Carla; Wallace, John L.; de Nigris, Filomena; Santagada, Vincenzo; Caliendo, Giuseppe; Franconi, Flavia; Ignarro, Louis J.; Cirino, Giuseppe
Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor α (TNFα) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFα and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFα may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury. PMID:10737808
Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart.
Napoli, C; Cicala, C; Wallace, J L; de Nigris, F; Santagada, V; Caliendo, G; Franconi, F; Ignarro, L J; Cirino, G
Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor alpha (TNFalpha) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFalpha and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFalpha may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury. PMID:10737808
Myocardial ischemia, reperfusion, and infarction in chronically instrumented, intact, conscious, and unrestrained mice
Lujan, Heidi L.; Janbaih, Hussein; Feng, Han-Zhong; Jin, Jian-Ping
In the United States alone, the National Heart, Lung, and Blood Institute (NHLBI) has invested several hundred million dollars in pursuit of myocardial infarct-sparing therapies. However, due largely to methodological limitations, this investment has not produced any notable clinical application or cardioprotective therapy. Among the major methodological limitations is the reliance on animal models that do not mimic the clinical situation. In this context, the limited use of conscious animal models is of major concern. In fact, whenever possible, studies of cardiovascular physiology and pathophysiology should be conducted in conscious, complex models to avoid the complications associated with the use of anesthesia and surgical trauma. The mouse has significant advantages over other experimental models for the investigation of infarct-sparing therapies. The mouse is inexpensive, has a high throughput, and presents the ability of one to create genetically modified models. However, successful infarct-sparing therapies in anesthetized mice or isolated mouse hearts may not be successful in more complex models, including conscious mice. Accordingly, a conscious mouse model of myocardial ischemia and reperfusion has the potential to be of major importance for advancing the concepts and methods that drive the development of infarct-sparing therapies. Therefore, we describe, for the first time, the use of an intact, conscious, and unrestrained mouse model of myocardial ischemia-reperfusion and infarction. The conscious mouse model permits occlusion and reperfusion of the left anterior descending coronary artery in an intact, complex model free of the confounding influences of anesthetics and surgical trauma. This methodology may be adopted for advancing the concepts and ideas that drive cardiovascular research. PMID:22538514
Critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient.
Bruni, C; Bellando-Randone, S; Gargani, L; Picano, E; Pingitore, A; Matucci-Cerinic, M; Guiducci, S
Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment. PMID:27608801
Different effects of interventions suppressing free fatty acid metabolism on myocardial ischemia.
Kahles, H; Hellige, G; Hunnemann, D H; Junggeburth, J; Kochsiek, K
We studied the effects of different metabolic interventions, which stimulate oxidative myocardial carbohydrate metabolism, on ischemic stress during repeated coronary occlusions of three minutes in open-chest dog hearts. Increase of glucose concentration in plasma and decrease of peripheral lipolysis by glucose-insulin-potassium (n = 6) had no substantial beneficial effects on myocardial damage indicated by hemodynamic, electrocardiographic, and metabolic parameters. Infusion of lactate and pyruvate (10 mM, n = 6) was detrimental. Only activation of pyruvate dehydrogenase by dichloroacetate (n = 6) without influence on plasma osmolality reduced epicardial ST-segment elevations (-42%) and myocardial release of potassium (-36%), phosphate (-58%), and lactate (-39%). Elevations of plasma osmolalities by 10 and 20 mOsm with the metabolically inert mannitol increased ECG changes, functional loss and release of potassium, phosphate, and lactate during ischemia in our model. It is suggested, that the oxygen-saving potency of metabolic interventions can exert univocal beneficial effects in experimental and in clinical conditions only when systemic hyperosmolality and hypervolemia are avoided. PMID:6430618
Cardioprotective Effects of Astragalin against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart
Qu, Daoxu; Ren, Huanhuan; Yang, Wenxiao; Zhang, Xinjie; Zheng, Qiusheng; Wang, Dong
This study aims to evaluate the cardioprotective effects of astragalin against myocardial ischemia/reperfusion (I/R) injury in isolated rat heart. The cardioprotective effects of astragalin on myocardial I/R injury were investigated on Langendorff apparatus. Adult male Sprague-Dawley rats were randomly divided into five groups. The results showed that astragalin pretreatment improved myocardial function. Compared with I/R group, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in coronary flow decreased in astragalin pretreatment groups, whereas superoxide dismutase (SOD) activity and glutathione/glutathione disulfide (GSH/GSSG) ratio significantly increased. The levels of malondialdehyde (MDA), intracellular reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) decreased in astragalin-treated groups. The infarct size (IS) and apoptosis rate in hearts from astragalin-treated groups were lower than those in hearts from the I/R group. Western blot analysis also revealed that astragalin preconditioning significantly reduced Bax level, whereas Bcl-2 was increased in the myocardium. Therefore, astragalin exhibited cardioprotective effects via its antioxidative, antiapoptotic, and anti-inflammatory activities. PMID:26788251
Pathophysiology and time course of silent myocardial ischaemia during mental stress: clinical, anatomical, and physiological correlates.
Legault, S. E.; Freeman, M. R.; Langer, A.; Armstrong, P. W.
OBJECTIVE--To define the prevalence and pathophysiology of myocardial ischaemia induced by mental stress in patients with coronary artery disease and exercise inducible ischaemia, and to determine the correlation between the severity of coronary artery disease and ischaemia induced by speech. DESIGN--Prospective cohort study. SETTING--Tertiary care academic institution. PATIENTS AND PROTOCOL--47 patients with coronary artery disease and 20 normal controls were studied using standardised exercise and mental stress. The ambulatory nuclear vest provided continuous measures of left ventricular ejection fraction and relative volume changes: an ischaemic response to mental stress was defined as a decrease in ejection fraction of > or = 5% for > or = 60 s. Severity of coronary artery disease was assessed by the extent of thallium reversibility on exercise testing and the severity of angiographic disease. RESULTS--23 (49%) of 47 patients with coronary artery disease had an ischaemic response to mental stress which occurred early, was sustained throughout the task and associated with an increase in end systolic volume. In contrast, the pattern of left ventricular response in the remaining 24 patients (51%) resembled that in the normal controls. Patients with mental stress induced ischaemia tended to have greater severity of coronary disease (mean (SD) total number of diseased vessels 1.9 (0.8) v 1.4 (0.9), P = 0.07), more frequent exercise induced angina (17/23 v 7/24, P = 0.003) and lower increases in heart rate (36 (11) v 49 (23) beats per min, P = 0.023) and systolic blood pressure (32 (19) v 45 (18) mm Hg, P = 0.03) during exercise. Left ventricular responses to speech and exercise were compared in the 23 patients with mental stress induced ischaemia: mental stress was associated with a greater decrease in ejection fraction at comparable increases in rate pressure product (-6.5 (6.3)% v 4.7 (11.2)%, P = 0.0001). CONCLUSIONS--These findings suggest that mental stress
Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo.
Motoki, Atsuko; Merkel, Matthias J; Packwood, William H; Cao, Zhiping; Liu, Lijuan; Iliff, Jeffrey; Alkayed, Nabil J; Van Winkle, Donna M
Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury. PMID:18835921
Silent myocardial infarction secondary to cardiac autonomic neuropathy in a patient with rheumatoid arthritis.
Unnikrishnan, Dileep; Jacob, Aasems; Anthony Diaz, Mark; Lederman, Jeffrey
An 83-year-old female patient with rheumatoid arthritis and hypertension presented to the emergency department with fever and chills of 1 day duration. On examination, temperature was 100.9 F, heart rate 111/min and she had orthostatic hypotension. Laboratory tests showed elevated blood urea nitrogen and white cell count. The patient underwent treatment for symptomatic urinary tract infection and while her fever and leucocytosis resolved, tachycardia persisted. An EKG done showed T inversions in leads II, III, arteriovenous fistula, V2 and V3. Troponin-I was elevated. Nuclear stress test revealed apical wall motion abnormality confirming myocardial infarction. Ewing's tests were carried out at bedside and these diagnosed severe autonomic neuropathy. Rheumatoid arthritis can cause cardiac autonomic neuropathy from chronic inflammation. This case entails the importance of assessing and detecting cardiac autonomic neuropathy in chronic inflammatory conditions, and the need to be cautious of acute coronary events in these patients, even for minimal or no symptoms. PMID:27489064
Selective Cyclooxygenase-2 Inhibition Protects Against Myocardial Damage in Experimental Acute Ischemia
Carnieto, Alberto; Dourado, Paulo Magno Martins; da Luz, Protásio Lemos; Chagas, Antonio Carlos Palandri
BACKGROUND Acute myocardial infarction is associated with tissue inflammation. Early coronary reperfusion clearly improves the outcome but may help propagate the inflammatory response and enhance tissue damage. Cyclooxygenase-2 is an enzyme that catalyzes the initial step in the formation of inflammatory prostaglandins from arachidonic acid. Cyclooxygenase-2 levels are increased when ischemic cardiac events occur. The overall function of COX-2 in the inflammatory process generated by myocardial ischemic damage has not yet been elucidated. GOAL The objective of this study was to determine whether a selective cyclooxygenase-2 inhibitor (rofecoxib) could alter the evolution of acute myocardial infarction after reperfusion. METHODS AND RESULTS This study was performed with 48 mongrel dogs divided into two groups: controls and those treated with the drug. All animals were prepared for left anterior descending coronary artery occlusion. The dogs then underwent 180 minutes of coronary occlusion, followed by 30 minutes of reperfusion. Blood samples were collected from the venous sinus immediately before coronary occlusion and after 30 minutes of reperfusion for measurements of CPK-MB, CPK-MBm and troponin I. During the experiment we observed the mean blood pressure, heart rate and coronary flow. The coronary flow and heart rate did not change, but in the control group, there was blood pressure instability, in addition to maximal levels of CPK-MB post-infarction. The same results were observed for CPK-MBm and troponin I. CONCLUSION In a canine model of myocardial ischemia-reperfusion, selective inhibition of Cyclooxygenase-2 with rofecoxib was not associated with early detrimental effects on the hemodynamic profile or the gross extent of infarction; in fact, it may be beneficial by limiting cell necrosis. PMID:19330252
Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function
Dixon, Jennifer A.; Gaillard, William F.; Rivers, William T.; Koval, Christine N.; Stroud, Robert E.; Mukherjee, Rupak
After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process. PMID:20935147
pH-Controlled Hydrogen Sulfide Release for Myocardial Ischemia-Reperfusion Injury.
Kang, Jianming; Li, Zhen; Organ, Chelsea L; Park, Chung-Min; Yang, Chun-Tao; Pacheco, Armando; Wang, Difei; Lefer, David J; Xian, Ming
Hydrogen sulfide (H2S) is a critical signaling molecule that regulates many physiological and/or pathological processes. Modulation of H2S levels could have potential therapeutic value. In this work, we report the rational design, synthesis, and biological evaluation of a class of phosphonamidothioate-based H2S-releasing agents (i.e., H2S donors). A novel pH-dependent intramolecular cyclization was employed to promote H2S release from the donors. These water-soluble compounds showed slow, controllable, and pH-sensitive production of H2S in aqueous solutions. The donors also showed significant cytoprotective effects in cellular models of oxidative damage. Most importantly, the donors were found to exhibit potent cardioprotective effects in an in vivo murine model of myocardial ischemia-reperfusion (MI/R) injury through a H2S-related mechanism. PMID:27172143
Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms.
Shi, Zhenwei; Fu, Feng; Yu, Liming; Xing, Wenjuan; Su, Feifei; Liang, Xiangyan; Tie, Ru; Ji, Lele; Zhu, Miaozhang; Yu, Jun; Zhang, Haifeng
Diabetes mellitus increases morbidity/mortality of ischemic heart disease. Although atrial natriuretic peptide and C-type natriuretic peptide reduce the myocardial ischemia-reperfusion damage in nondiabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of atrial natriuretic peptide and C-type natriuretic peptide, confers cardioprotective effects against ischemia-reperfusion injury, especially in diabetic patients, is still unclear. This study was designed to investigate the effects of VNP on ischemia-reperfusion injury in diabetic rats and to further elucidate its mechanisms. The high-fat diet-fed streptozotocin-induced diabetic Sprague-Dawley rats were subjected to ischemia-reperfusion operation. VNP treatment (100 μg/kg iv, 10 min before reperfusion) significantly improved the instantaneous first derivation of left ventricle pressure (±LV dP/dtmax) and LV systolic pressure and reduced LV end-diastolic pressure, apoptosis index, caspase-3 activity, plasma creatine kinase (CK), and lactate dehydrogenase (LDH) activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). These effects were mimicked by 8-bromine-cyclic guanosinemonophosphate (8-Br-cGMP), a cGMP analog, whereas they were inhibited by KT-5823, the selective inhibitor of PKG. In addition, pretreatment with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress, could not further promote the VNP's cardioprotective effect in diabetic rats. In vitro H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation and incubated with or without VNP (10(-8) mol/l). Gene knockdown of PKG1α with siRNA blunted VNP inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis. VNP protects the diabetic heart against ischemia-reperfusion injury by inhibiting ER stress via the cGMP-PKG signaling pathway. These
Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway.
Yang, Jian; Jiang, Hong; Yang, Jun; Ding, Jia-Wang; Chen, Li-Hua; Li, Song; Zhang, Xiao-Dong
Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-kappaB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-kappaB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-kappaB signaling pathway. PMID:19370315
Myocardial ischemia and reperfusion: the role of oxygen radicals in tissue injury.
Werns, S W; Lucchesi, B R
Thrombolytic therapy has gained widespread acceptance as a means of treating coronary artery thrombosis in patients with acute myocardial infarction. Although experimental data have demonstrated that timely reperfusion limits the extent of infarction caused by regional ischemia, there is growing evidence that reperfusion is associated with an inflammatory response to ischemia that exacerbates the tissue injury. Ischemic myocardium releases archidonate and complement-derived chemotactic factors, e.g., leukotriene B4 and C5a, which attract and activate neutrophils. Reperfusion of ischemic myocardium accelerates the influx of neutrophils, which release reactive oxygen products, such as superoxide anion and hydrogen peroxide, resulting in the formation of a hydroxyl radical and hypochlorous acid. The latter two species may damage viable endothelial cells and myocytes via the peroxidation of lipids and oxidation of protein sulfhydryl groups, leading to perturbations of membrane permeability and enzyme function. Neutrophil depletion by antiserum and inhibition of neutrophil function by drugs, e.g., ibuprofen, prostaglandins (prostacyclin and PGE1), or a monoclonal antibody, to the adherence-promoting glycoprotein Mo-1 receptor, have been shown to limit the extent of canine myocardial injury due to coronary artery occlusion/reperfusion. Recent studies have challenged the hypothesis that xanthine-oxidase-derived oxygen radicals are a cause of reperfusion injury. Treatment with allopurinol or oxypurinol may exert beneficial effects on ischemic myocardium that are unrelated to the inhibition of xanthine oxidase. Furthermore, the human heart may lack xanthine oxidase activity. Further basic research is needed, therefore, to clarify the importance of xanthine oxidase in the pathophysiology of reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2488090
Platelet Aggregation and Mental Stress Induced Myocardial Ischemia: Results from the REMIT Study
Jiang, Wei; Boyle, Stephen H.; Ortel, Thomas L.; Samad, Zainab; Velazquez, Eric J.; Harrison, Robert W.; Wilson, Jennifer; Kuhn, Cynthia; Williams, Redford B.; O'Connor, Christopher M.; Becker, Richard C.
BACKGROUND Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and associated with a poorer cardiovascular prognosis. Platelet hyperactivity is an important factor in acute coronary syndrome. This study examined associations between MSIMI and resting and mental stress-induced platelet activity. METHODS Eligible patients with clinically stable IHD underwent a battery of 3 mental stress tests during the recruitment phase of REMIT (Responses of Myocardial Ischemia to Escitalopram Treatment) study. MSIMI was assessed by echocardiography and electrocardiography. Ex vivo platelet aggregation in response to ADP, epinephrine, collagen, serotonin, and combinations of serotonin plus ADP, epinephrine, and collagen were evaluated as was platelet serotonin transporter expression. RESULTS Of the 270 participants who completed mental stress testing, and had both resting and post-stress platelet aggregation evaluation, 43.33% (N=117) met criteria for MSIMI and 18.15% (N=49) had normal left ventricular response to stress (NLVR). The MSIMI group, relative to the NLVR groups, demonstrated heightened mental stress-induced aggregation responses, as measured by area under the curve, to collagen 10 μM (6.95[5.54] vs. −14.23[8.75].; p=0.045), epinephrine 10 μM (12.84[4.84] vs. −6.40[7.61].; p=0.037) and to serotonin 10 μM plus ADP 1 μM (6.64[5.29] vs. −27.34[8.34]; p < .001). The resting platelet aggregation and serotonin transporter expression, however, were not different between the two groups. CONCLUSIONS These findings suggest that the dynamic change of platelet aggregation caused by mental stress may underlie MSIMI. While the importance of these findings requires additional investigation, they raise concern given the recognized relationship between mental stress-induced platelet hyperactivity and cardiovascular events in patients with IHD. PMID:25819856
Thioredoxin-interacting protein and myocardial mitochondrial function in ischemia-reperfusion injury.
Yoshioka, Jun; Lee, Richard T
Cellular metabolism and reactive oxygen species (ROS) formation are interrelated processes in mitochondria and are implicated in a variety of human diseases including ischemic heart disease. During ischemia, mitochondrial respiration rates fall. Though seemingly paradoxical, reduced respiration has been observed to be cardioprotective due in part to reduced generation of ROS. Enhanced myocardial glucose uptake is considered beneficial for the myocardium under stress, as glucose is the primary substrate to support anaerobic metabolism. Thus, inhibition of mitochondrial respiration and uncoupling oxidative phosphorylation can protect the myocardium from irreversible ischemic damage. Growing evidence now positions the TXNIP/thioredoxin system at a nodal point linking pathways of antioxidant defense, cell survival, and energy metabolism. This emerging picture reveals TXNIP's function as a regulator of glucose homeostasis and may prove central to regulation of mitochondrial function during ischemia. In this review, we summarize how TXNIP and its binding partner thioredoxin act as regulators of mitochondrial metabolism. While the precise mechanism remains incompletely defined, the TXNIP-thioredoxin interaction has the potential to affect signaling that regulates mitochondrial bioenergetics and respiratory function with potential cardioprotection against ischemic injury. PMID:23891554
Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion
Lee, Hsin-Ling; Chen, Chwen-Lih; Yeh, Steve T.; Zweier, Jay L.
Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R. Rat hearts were subjected to ischemia for 30 min followed by reperfusion for 1 h. Studies of mitochondrial function indicated a biphasic modulation of electron transfer activity (ETA) and ETC protein expression during I/R. Analysis of ETAs in the isolated mitochondria indicated that complexes I, II, III, and IV activities were diminished after 30 min of ischemia but increased upon restoration of flow. Immunoblotting analysis and ultrastructural analysis with transmission electron microscopy further revealed marked downregulation of ETC in the ischemic heart and then upregulation of ETC upon reperfusion. No significant difference in the mRNA expression level of ETC was detected between ischemic and postischemic hearts. However, reperfusion-induced ETC biosynthesis in myocardium can be inhibited by cycloheximide, indicating the involvement of translational control. Immunoblotting analysis of tissue homogenates revealed a similar profile in peroxisome proliferator-activated receptor-γ coactivator-1α expression, suggesting its essential role as an upstream regulator in controlling ETC biosynthesis during I/R. Significant impairment caused by ischemic and postischemic injury was observed in the complexes I- III. Analysis of NADH ferricyanide reductase activity indicated that injury of flavoprotein subcomplex accounts for 50% decline of intact complex I activity from ischemic heart. Taken together, our findings provide a new insight into the molecular mechanism of I/R-induced mitochondrial dysfunction. PMID:22268109
Osteoprotegerin concentrations in patients with suspected reversible myocardial ischemia: observations from the Akershus Cardiac Examination (ACE) 1 Study.
Røysland, Ragnhild; Røsjø, Helge; Høiseth, Arne Didrik; Gullestad, Lars; Badr, Pirouz; Kravdal, Gunnhild; Omland, Torbjørn
Increased circulating osteoprotegerin (OPG) levels have been associated with the prevalence and severity of coronary artery disease and the risk of cardiovascular death. OPG is a cytokine of the tumor necrosis factor receptor superfamily and is expressed in various cell types in the body, including osteoblasts, inflammatory cells, vascular smooth muscle cells/endothelial cells and cardiomyocytes. The main sources determining OPG levels in the circulation however, are not well understood, and whether reversible myocardial ischemia influences OPG levels are not known. Accordingly, OPG levels were measured in 198 patients referred for exercise stress testing and myocardial perfusion imaging (MPI). In addition OPG levels were measured in 8 healthy control subjects performing a maximal bicycle stress test. Plasma samples were collected before, immediately after, 1.5h and 4.5h after exercise stress testing with MPI. OPG levels at baseline were not different in patient with reversible myocardial ischemia (n=19) and patients without reversible ischemia (n=179) (4.7 [3.6-5.5]pmol/L vs. 4.3 [3.4-5.2]pmol/L, p=0.21), and there was an increase in OPG levels immediately after exercise regardless of whether or not the patient had reversible ischemia on MPI (absolute increase: 0.2 [0-0.55]pmol/L vs. 0.3 [0-0.5]pmol/L, p=0.72). OPG levels also increased immediately after stress in the 8 control subjects (3.5 (3.2-3.8)pmol/L at baseline to 3.8 (3.5-4.7), p=0.008). In conclusion, OPG levels increase acutely during exercise stress testing, but this increase is likely caused by mechanisms other than myocardial ischemia. PMID:25748834
Protective Effects of Berberine on Isoproterenol-Induced Acute Myocardial Ischemia in Rats through Regulating HMGB1-TLR4 Axis
Zhang, Tianzhu; Yang, Shihai; Du, Juan
Berberine, an isoquinoline alkaloid originally isolated from the Chinese herb Coptis chinensis (Huanglian), has been shown to display a wide array of pharmacological activities. The present study was to investigate the effects of berberine against myocardial ischemia produced in rats by isoproterenol. 50 male Sprague-Dawley rats were randomized equally into five groups: a control group, an untreated model group, berberine (30, 60 mg/kg) treatment, or propranolol (30 mg/kg). Rats were treated for 12 days and then given isoproterenol, 85 mg/kg for 2 consecutive days by subcutaneous injection. ST-segment elevation was measured after the last administration. Serum levels of creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured after the rats were sacrificed. The hearts were excised for determining heart weight index, microscopic examination, high mobility group box 1 (HMGB1), toll-like receptor (TLR4), prodeath protein (Bax), antideath protein (Bcl-2), and tumor necrosis factor (TNF-α) protein were determined by western blot. Berberine decreased the ST elevation induced by acute myocardial ischemia, and decreased serum levels of CK-MB, LDH, TNF-α, and IL-6. Berberine increased total superoxide dismutase (T-SOD) activity and decreased malondialdehyde (MDA) content in myocardial tissue. Berberine can regulate HMGB1-TLR4 axis to protect myocardial ischemia. PMID:25477998
The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial Ischemia/Reperfusion Injury
Tang, Xilan; Liu, Jianxun; Dong, Wei; Li, Peng; Li, Lei; Lin, Chengren; Zheng, Yongqiu; Hou, Jincai; Li, Dan
Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L-malic acid significantly reduced myocardial infarct size, serum levels of TNF-α, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. PMID:23737849
Polymeric electrospun scaffolds: neuregulin encapsulation and biocompatibility studies in a model of myocardial ischemia.
Simón-Yarza, Teresa; Rossi, Angela; Heffels, Karl-Heinz; Prósper, Felipe; Groll, Jürgen; Blanco-Prieto, Maria J
Cardiovascular disease represents one of the major health challenges in modern times and is the number one cause of death globally. Thus, numerous studies are under way to identify effective cell- and/or growth factor (GF)-based therapies for repairing damaged cardiac tissue. In this regard, improving the engraftment or survival of regenerative cells and prolonging GF exposure have become fundamental goals in advancing these therapeutic approaches. Biomaterials have emerged as innovative scaffolds for the delivery of both cells and proteins in tissue engineering applications. In the present study, electrospinning was used to generate smooth homogenous polymeric fibers, which consisted of a poly(lactic-co-glycolic acid) (PLGA)/NCO-sP(EO-stat-PO) polymer blend encapsulating the cardioactive GF, Neuregulin-1 (Nrg). We evaluated the biocompatibility and degradation of this Nrg-containing biomaterial in a rat model of myocardial ischemia. Histological analysis revealed the presence of an initial acute inflammatory response after implantation, which was followed by a chronic inflammatory phase, characterized by the presence of giant cells. Notably, the scaffold remained in the heart after 3 months. Furthermore, an increase in the M2:M1 macrophage ratio following implantation suggested the induction of constructive tissue remodeling. Taken together, the combination of Nrg-encapsulating scaffolds with cells capable of inducing cardiac regeneration could represent an ambitious and promising therapeutic strategy for repairing diseased or damaged myocardial tissue. PMID:25707939
Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.
Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi
The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes. PMID:27574914
Lipoxin A4 Preconditioning and Postconditioning Protect Myocardial Ischemia/Reperfusion Injury in Rats
Zhao, Qifeng; Shao, Lan; Hu, Xingti; Wu, Guowei; Du, Jie; Xia, Jie; Qiu, Huixian
This study aims to investigate the pre- and postconditioning effects of lipoxin A4 (LXA4) on myocardial damage caused by ischemia/reperfusion (I/R) injury. Seventy-two rats were divided into 6 groups: sham groups (C1 and C2), I/R groups (I/R1 and I/R2), and I/R plus LXA4 preconditioning and postconditioning groups (LX1 and LX2). The serum levels of IL-1β, IL-6, IL-8, IL-10, TNF-α, and cardiac troponin I (cTnI) were measured. The content and the activity of Na+-K+-ATPase as well as the superoxide dismutase (SOD), and malondialdehyde (MDA) levels were determined. Along with the examination of myocardium ultrastructure and ventricular arrhythmia scores (VAS), connexin 43 (Cx43) expression were also detected. Lower levels of IL-1β, IL-6, IL-8, TNF-α, cTnI, MDA content, and VAS and higher levels of IL-10, SOD activity, Na+-K+-ATPase content and activity, and Cx43 expression appeared in LX groups than I/R groups. Besides, H&E staining, TEM examination as well as analysis of gene, and protein confirmed that LXA4 preconditioning was more effective than postconditioning in preventing arrhythmogenesis via the upregulation of Cx43. That is, LXA4 postconditioning had better protective effect on Na+-K+-ATPase and myocardial ultrastructure. PMID:23956501
Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation
Vassalli, Giuseppe; Milano, Giuseppina; Moccetti, Tiziano
In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion. PMID:22530110
Study of baicalin on sympathoexcitation induced by myocardial ischemia via P2X3 receptor in superior cervical ganglia.
Zhang, Jun; Liu, Shuangmei; Xu, Baohua; Li, Guodong; Li, Guilin; Huang, An; Wu, Bing; Peng, Lichao; Song, Miaomiao; Xie, Qiuyu; Lin, Weijian; Xie, Wei; Wen, Shiyao; Zhang, Zhedong; Xu, Xiaoling; Liang, Shangdong
After the myocardial ischemia, injured myocardial tissues released large quantity of ATP, which activated P2X3 receptor in superior cervical ganglia and made the SCG postganglionic neurons excited. Excitatory of sympathetic postganglionic efferent neurons increased the blood pressure and heart rates, which aggravated the myocardial ischemic injury. Baicalin has anti-inflammatory and anti-oxidant properties. Our study showed that baicalin reduced the incremental concentration of serum CK-MB, cTn-T, epinephrine and ATP, decreased the up-regulated expression levels of P2X3 mRNA and protein in SCG after MI, and then inhibited the sympathetic excitatory activity triggered by MI injury. These results indicated that baicalin acted on P2X3 receptor was involved in the transmission of sympathetic excitation after the myocardial ischemic injury. Baicalin might decrease sympathetic activity via inhibiting P2X3 receptor in rat SCG to protect the myocardium. PMID:25554221
Increased myocardial ischemia-reperfusion injury in renal failure involves cardiac adiponectin signal deficiency.
Song, Yanbin; Yu, Qiujun; Zhang, Junyi; Huang, Weidong; Liu, Yi; Pei, Haifeng; Liu, Jingyi; Sun, Lu; Yang, Lu; Li, Congye; Li, Yan; Zhang, Fuyang; Qu, Yan; Tao, Ling
Plasma levels of adiponectin (APN) are significantly increased in patients with renal dysfunction and are inversely related to the risk of cardiovascular mortality. The present study was designed to determine the role of APN in myocardial ischemia-reperfusion (MI/R) injury in mice with renal failure and delineate the underlying mechanisms. Renal failure was induced by subtotal nephrectomy (SN). Human recombinant globular domain of adiponectin (gAd) or full-length adiponectin (fAd) was administered via intraperitoneal injection once daily for 7 consecutive days after SN, and in vivo MI/R was introduced 3 wk later. Both plasma and urinary levels of APN increased significantly in SN mice. Compared with sham-operated mice, cardiac function was significantly depressed, and myocardial infarct size and apoptosis increased in SN mice following MI/R. The aggravated MI/R injury was further intensified in APN-knockout mice and markedly ameliorated by treatment with gAd but not fAd. Moreover, SN increased myocardial NO metabolites, superoxide, and their cytotoxic reaction product peroxynitrite, upregulated inducible NO synthase expression, and decreased endothelial NOS phosphorylation. In addition, SN mice also exhibited reduced APN receptor-1 (AdipoR1) expression and AMPK activation. All these changes were further amplified in the absence of APN but reversed by gAd treatment. The present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic-reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the protective role of exogenous supplement of gAd on MI/R outcomes in renal failure. PMID:24595307
The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury.
He, Ben; Zhao, Yichao; Xu, Longwei; Gao, Lingchen; Su, Yuanyuan; Lin, Nan; Pu, Jun
Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors RORs are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of RORs in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion (MI/R) injury pathogenesis. RORα and RORγ subtypes were detected in the adult mouse heart, and RORα but not RORγ was downregulated after MI/R. To determine the pathological consequence of MI/R-induced reduction of RORα, we subjected RORα-deficient staggerer mice and wild-type (WT) littermates to MI/R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, RORα deficiency promoted MI/R-induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, RORα deficiency augmented MI/R-induced oxidative/nitrative stress. Given the emerging evidence of RORα as an essential melatonin effects mediator, we further investigated the RORα roles in melatonin-exerted cardioprotection, in particular against MI/R injury, which was significantly attenuated in RORα-deficient mice, but negligibly affected by cardiac-specific silencing of RORγ. Finally, to determine cell type-specific effects of RORα, we generated mice with cardiomyocyte-specific RORα overexpression and they were less vulnerable to MI/R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor RORα is a novel endogenous protective receptor against MI/R injury and an important mediator of melatonin-exerted cardioprotection; melatonin-RORα axis signaling thus appears important in protection against ischemic heart injury. PMID:26797926
Gender specific effect of progesterone on myocardial ischemia/reperfusion injury in rats.
Dhote, Vipin V; Balaraman, R
The study was designed to investigate the effect of progesterone and its gender based variation on myocardial ischemia/reperfusion (I/R) injury in rats. Adult Sprague Dawley rats were divided into vehicle treated reperfusion injury group male (I/R-M), female (I/R-F), ovariectomised (I/R-OVR) and progesterone treatment (I/R-M+PG, I/R-F+PG, I/R-OVR+PG) groups, respectively. I/R injury was produced by occluding the left descending coronary artery (LCA) for 1 h and followed by re-opening for 1 h. Progesterone (2 mg kg(-1) i.p.) was administered 30 min after induction of ischemia. Hemodynamic parameters (+/-dp/dt, MAP), heart rate, ST-segment elevation and occurrence of ventricular tachycardia (VT) were measured during the I/R period. The myocardial infarct area, oxidative stress markers, activities of myeloperoxidase (MPO) and creatine kinase (CK) were determined after the experiment along with the assessment of the effect on apoptotic activity by using DNA fragmentation analysis. Histological observations were carried out on heart tissue. Treatment with progesterone significantly (P<0.05) reduced infarct area, lipid peroxidation (LPO) level and activity of MPO in females (I/R-F+PG) as compared to ischemic females (I/R-F). Progesterone significantly (P<0.001, P<0.05) inhibited serum CK activity and incidences of VT in female rats. Superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels were significantly elevated (P<0.05) in I/R-F+PG group. Internucleosomal DNA fragmentation was less in I/R-F+PG group when compared to I/R-F group. The ischemic male and ovariectomised (I/R-M and I/R-OVR) counterparts did not show any significant change after progesterone treatment. In conclusion, the cardioprotective effect of progesterone on myocardial I/R injury induced damage is based on gender of the animal. The protective effect could be mediated by attenuation of inflammation and its possible interaction with endogenous estrogen. PMID:17585947
In vivo gene delivery of XIAP protects against myocardial apoptosis and infarction following ischemia/reperfusion in conscious rabbits
Kim, Song-Jung; Kuklov, Alex; Crystal, George J.
Aims We tested the hypothesis that an in vivo gene delivery of the pro-survival protein XIAP (X-chromosome linked inhibitor of apoptosis protein) protects against myocardial apoptosis and infarction following ischemia/reperfusion. Main Methods Nineteen rabbits were chronically instrumented with an hydraulic occluder placed around the circumflex coronary artery. Adenovirus harboring XIAP (Ad.XIAP; 1×1010 pfu/ml) or β-galactosidase (5×109 pfu/ml), as a control, was constructed and transfected into the heart using a catheter place into the left ventricle accompanied by cross-clamping. 1-2 weeks after gene delivery, myocardial ischemia was induced by a 30-min occlusion followed by reperfusion for four days. Protein expression was determined by Western blot and Apoptosis (% of myocytes) was quantified by TUNEL staining. Key Findings Myocardial infarct size, expressed as a fraction of the area at risk, was reduced in Ad.XIAP (n=5) compared to control (n=7) rabbits (21±3% vs. 30±2%, p<0.05). Apoptosis was reduced in Ad.XIAP rabbits compared to control rabbits (2.96±0.68% vs. 8.98±1.84%, p<0.01). This was associated with an approximate 60% decrease in the cleaved caspase-3 level in Ad.XIAP rabbits compared to control rabbits. Significances The current findings demonstrate that overexpression of XIAP via in vivo delivery in an adenovirus can reduce both myocardial apoptosis and infarction following ischemia/reperfusion, at least in part, due to the ability of XIAP to inhibit caspase-3. These findings confirm previous work suggesting a link between myocardial apoptosis and infarction i.e., anti-apoptotic therapy was effective in reducing myocardial infarct size. PMID:21277870
Disrupting the EMMPRIN-Cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion
Seizer, Peter; Ochmann, Carmen; Schönberger, Tanja; Zach, Sebastian; Rose, Melanie; Borst, Oliver; Klingel, Karin; Kandolf, Reinhard; MacDonald, H. Robson; Nowak, Romana A.; Engelhardt, Stefan; Lang, Florian; Gawaz, Meinrad; May, Andreas E.
Introduction Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) and its ligand Cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury. Methods and results Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections from human autopsies of patients who had died from acute myocardial infarction and from mice at 24 hours after I/R. At 24 hours and 7 days after I/R, the infarct size was reduced in CD147+/− mice versus CD147+/+ mice (C57Bl/6), in mice (C57Bl/6) treated with mAb anti-CD147 vs. control mAb, and in CyPA−/− mice vs. CyPA+/+ mice (129S6/SvEv), all of which being associated with reduced monocyte and neutrophil recruitment at 24h and with a preserved systolic function at 7 days. Combination of CyPA−/− mice with anti-CD147 treatment did not yield further protection in comparison to either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147- and PI3-kinase dependent manner and induced monocyte rolling and adhesion to endothelium (HUVEC) under flow in a CD147-dependent manner. Conclusion CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury. PMID:21441138
Evolution of myocardial ischemia and left ventricular function in patients with angina pectoris without myocardial infarction and total occlusion of the left anterior descending coronary artery and collaterals from other coronary arteries
Juilliere, Y.; Marie, P.Y.; Danchin, N.; Karcher, G.; Bertrand, A.; Cherrier, F. )
Repeated episodes of myocardial ischemia might lead to progressive impairment of left ventricular (LV) function. This radionuclide study assessed myocardial ischemia and LV function several years after documented coronary occlusion without myocardial infarction. Over 5 years, 24 consecutive patients, who underwent cardiac catheterization for angina pectoris without myocardial infarction, had isolated total occlusion of the left anterior descending coronary artery with well-developed collateral vessels. Five patients were successfully treated by coronary bypass grafting and 3 by coronary angioplasty. Among the 16 medically treated patients, 1 was lost to follow-up and 1 died (extracardiac death). The mean (+/- standard deviation) follow-up (14 patients) was 48 +/- 15 months. At follow-up, 8 patients still had clinical chest pain, 11 received antianginal therapy, 4 patients had no stress ischemia and the other 10 had greater than or equal to 1 sign of stress ischemia. All patients had a normal LV ejection fraction at rest (mean 60 +/- 3%; range 55 to 65%). Collateral circulation preserves LV function at the time of occlusion and, in some cases, prevents the development of myocardial ischemia; in patients with persisting myocardial ischemia after well-collateralized coronary occlusion, LV function is not impaired at long-term follow-up.
Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules
Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu
Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT–activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI. PMID:26010537
Coxsackie and adenovirus receptor (CAR) is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia
Marsman, Roos F.J.; Bezzina, Connie R.; Freiberg, Fabian; Verkerk, Arie O.; Adriaens, Michiel E.; Podliesna, Svitlana; Chen, Chen; Purfürst, Bettina; Spallek, Bastian; Koopmann, Tamara T.; Baczko, Istvan; dos Remedios, Cristobal G.; George, Alfred L.; Bishopric, Nanette H.; Lodder, Elisabeth M.; de Bakker, Jacques M.T.; Fischer, Robert; Coronel, Ruben; Wilde, Arthur A.M.; Gotthardt, Michael; Remme, Carol Ann
Objectives To investigate the modulatory effect of the Coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Background A heritable component in risk for ventricular fibrillation (VF) during myocardial infarction (MI) has been well established. A recent genome-wide association study (GWAS) for VF during acute MI has led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the coxsackie and adenovirus receptor (CAR), a cell adhesion molecule predominantly located at intercalated discs of the cardiomyocyte. Methods The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed CAR haploinsufficient mice (CAR+/−). Results In human left ventricular samples, the risk allele at the chr21q21 GWAS locus was associated with lower CXADR mRNA levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced VF. Hearts from CAR+/− mice displayed ventricular conduction slowing in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia following LAD ligation. Connexin43 expression and distribution was unaffected, but CAR+/− hearts displayed increased arrhythmia susceptibility upon pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR+/− myocytes showed reduced sodium current magnitude specifically at the intercalated disc. Moreover, CAR co-precipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. Conclusion We identify CAR as a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk
Association of Vitamin D Status With Mental Stress Induced Myocardial Ischemia in Patients With Coronary Artery Disease
Ramadan, Ronnie; Vaccarino, Viola; Esteves, Fabio; Sheps, David S.; Bremner, James Douglas; Raggi, Paolo; Quyyumi, Arshed A.
Background Mental stress-induced (MSIMI) or physical stress-induced (PSIMI) myocardial ischemia portends a worse prognosis in CAD patients. Vitamin D insufficiency is associated with adverse cardiovascular outcomes, but its relationship to myocardial ischemia remains unclear. We hypothesized that vitamin D insufficiency will be associated with a higher prevalence of myocardial ischemia in CAD patients. Methods In 255 patients with stable CAD, myocardial perfusion imaging was performed to assess ischemia in response to mental and physical stress protocols. Vitamin D insufficiency was defined as serum 25-hydroxyvitamin-D [25(OH)D] levels below 30 ng/ml, collected on the day of stress testing. Results Mean 25(OH)D level was 30.8±12.8 ng/ml, and 139 (55%) patients had vitamin D insufficiency. MSIMI occurred in 30 (12%) patients and PSIMI in 67 (27%). Individuals with MSIMI had significantly lower levels of 25(OH)D as compared to those without MSIMI (24.0±8.6 vs. 31.7±12.9, p=0.002). The prevalence of MSIMI was higher in those with as compared to those without vitamin D insufficiency (17% vs. 6%, p=0.009). Moreover, low 25(OH)D levels remained independently associated with MSIMI after adjusting for potential confounders. Conversely, 25(OH)D levels were similar between those with or without PSIMI (29.8±13.0 vs. 31.4±12.7; p=0.37), as was the prevalence of PSIMI in those with or without vitamin D insufficiency (29% vs. 24%, p=0.42). Conclusions Vitamin D insufficiency is associated with a higher prevalence of MSIMI, but not PSIMI among stable CAD patients. Whether this association serves as a potential mechanism linking low vitamin D status to adverse cardiovascular outcomes warrants further investigation. PMID:25222601
Identification of Left Ventricular Myocardial Ischemia and Cardiac Prognosis with Cardiovascular Magnetic Resonance: Updates from 2008 to 2010
Chotenimitkhun, Runyawan
Noninvasive imaging modalities are often used to manage patients with cardiovascular disease. Cardiovascular magnetic resonance (CMR) is increasingly used for diagnosing and evaluating myocardial ischemia and viability; moreover, stress CMR study results can be used to determine cardiac prognosis. In this article, we review recently published material regarding the performance of stress testing with CMR including a brief update regarding techniques, stress agents, diagnostic accuracy, prognosis, economic implications, and ongoing trials and future developments. PMID:21125353
LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation.
Li, Dayuan; Williams, Victor; Liu, Ling; Chen, Hongjiang; Sawamura, Tatsuya; Antakli, Tamim; Mehta, Jawahar L
A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury. PMID:12384456
Imaging of Receptors for Advanced Glycation End Products in Experimental Myocardial Ischemia and Reperfusion Injury
Tekabe, Yared; Luma, Joane; Li, Qing; Schmidt, Ann Marie; Ramasamy, Ravichandran; Johnson, Lynne L.
OBJECTIVES The aim of this study was to image expression of receptor for advanced glycation end products (RAGE) in a mouse model of myocardial reperfusion injury. BACKGROUND RAGE and its ligands are implicated in the pathogenesis of ischemia/reperfusion injury and infarction. We hypothesized that RAGE-directed quantitative imaging of myocardial uptake of technetium-99m (99mTc)-anti-RAGE F(ab′)2 in a mouse model of myocardial ischemic injury can detect RAGE expression and show quantitative differences between early (18 to 20 h) and later times (48 h) after reperfusion. METHODS Twenty-five wild-type (WT) mice underwent left anterior descending coronary artery occlusion for 30 min. Mice were injected with 19.98 ± 1.78 MBq of 99mTc anti-RAGE F(ab′)2 at 2 time points after reperfusion (at 18 to 20 h [n = 8] and at 48 h [n = 12]) and 5 h later with 6.14 ± 2.0 MBq of thallium-201 (201Tl). Five WT mice were injected with nonspecific F(ab′)2 and 201Tl 18 to 20 h after reperfusion. Six WT mice underwent sham operation without coronary intervention. After injection with 201Tl, all mice immediately underwent dual isotope single-photon emission computed tomography/computed tomography. At completion of imaging, hearts were counted and sectioned. RESULTS The uptake of 99mTc-anti-RAGE F(ab′)2 in the ischemic zone from the scans as mean percentage injected dose was significantly greater at 18 to 20 h (5.7 ± 2.1 × 10−3%) as compared with at 48 h (1.4 ± 1.1 × 10−3%; p < 0.001) after reperfusion. Disease and antibody controls showed no focal uptake in the infarct. Gamma well counting of the myocardium supported the quantitative scan data. By immunohistochemical staining there was greater caspase-3 and RAGE staining at 18 to 20 h versus at 48 h (p = 0.04 and p = 0.01, respectively). On dual immunofluorescence, RAGE colocalized mainly with injured cardiomyocytes undergoing apoptosis. CONCLUSIONS RAGE expression in myocardial ischemic injury can be imaged in vivo using
Wang, Meijing; Wang, Yue; Abarbanell, Aaron; Tan, Jiangjing; Weil, Brent; Herrmann, Jeremy; Meldrum, Daniel R.
Background Signal transducer and activator of transduction 3 (STAT3) pathway has been shown to be cardioprotective. We observed decreased STAT3/suppressor of cytokine signaling 3 (SOCS3) in male hearts, which was associated with worse post-ischemic myocardial function compared to females. However, it is unclear whether this down-regulation of myocardial STAT3/SOCS3 is due to testosterone in males. We hypothesized that following ischemia/reperfusion (I/R): 1) endogenous testosterone decreases myocardial STAT3 and SOCS3 in males; 2) administration of exogenous testosterone reduces myocardial STAT3/SOCS3 in female and castrated male hearts. Methods To study this, hearts from I/R injury (Langendorff) were homogenized and assessed for phosphorylated-STAT3 (p-STAT3), total-STAT3 (T-STAT3), SOCS3 and GAPDH by western blot. Groups: age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide implantation, females and castrated males with chronic (3-week) 5alpha-dihydrotestosterone (DHT) release pellet implantation or acute (5-minute) testosterone infusion (ATI) prior to ischemia (n=5–9/group). Results Castration or flutamide treatment significantly increased SOCS3 expression in male hearts after I/R. However, only castration increased myocardial STAT3 activation. Notably, DHT replacement or ATI markedly decreased myocardial STAT3/SOCS3 in castrated males and females subjected to I/R. Conclusion These results suggest that endogenous and exogenous testosterone decrease myocardial STAT3 activation and SOCS3 expression following I/R. This represents the initial demonstration of testosterone-downregulated STAT3/SOCS3 signaling in myocardium. PMID:19628067
Can myocardial ischemia be recognized by the exercise electrocardiogram in coronary disease patients with abnormal resting Q waves
Ahnve, S.; Savvides, M.; Abouantoun, S.; Atwood, J.E.; Froelicher, V.
This study was performed in order to determine whether exercise-induced myocardial ischemia demonstrated by thallium-201 imaging could be detected by ST segment shifts in patients with abnormal Q waves at rest. Fifty-four patients with coronary artery disease and exercise-induced thallium-201 defects were compared to 22 patients with similar Q wave patterns but without thallium-201 exercise defects and to 14 normal subjects. Exercise data were analyzed visually in the 12-lead ECG and for spatial ST vector shifts. Both ST segment depression observed on the 12-lead ECG and spatial criteria were reasonably sensitive and specific for ischemia when the resting ECG showed no Q waves or inferior Q waves (range 69% to 93%). However, when anterior Q waves were present, ST segment shifts could not distinguish patients with ischemia from those with normal perfusion as determined by thallium imaging.
In-vivo determination of myocardial pH during regional ischemia using near-infrared spectroscopy
NASA Astrophysics Data System (ADS)
Zhang, Songbiao; Soller, Babs R.
pH electrodes have been used during open heart surgery to ensure adequate delivery of blood and oxygen to the myocardium during the surgical procedure. The electrodes are cumbersome and suffer from motion artifacts. Near infrared spectroscopy was evaluated as a noninvasive method of measuring myocardial pH during regional ischemia in seven beating dog hearts. Two pH microelectrodes were implanted in the distribution area of the left anterior descending (LAD) coronary artery. The LAD was occluded to stop the myocardial blood flow and to initialize regional ischemia. Ischemia was maintained for 20 minutes before the LAD was released to resume blood flow. A fiber-optic probe was used to collect the reflected NIR light over the spectral region of 575 nm to 1100 nm from the heart muscle. Partial least-squares multivariate calibration technique was applied to relate the myocardial pH changes to the NIR spectral changes in the region of 700 to 1100 nm. Calibration models based on data collected on each individual dog heart had an average of 7 factors with an R2 of 0.84. The standard error of prediction (SEP) averaged 0.09 pH units for a mean pH change of 0.73 pH units, adequate for monitoring pH changes during cardiac surgery.
Novel curcumin analogue 14p protects against myocardial ischemia reperfusion injury through Nrf2-activating anti-oxidative activity
Li, Weixin; Wu, Mingchai; Tang, Longguang; Pan, Yong; Liu, Zhiguo; Zeng, Chunlai; Wang, Jingying; Wei, Tiemin; Liang, Guang
Background: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. Methods: H9c2 cells challenged with H{sub 2}O{sub 2} or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H{sub 2}O{sub 2} and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. Results: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H{sub 2}O{sub 2}-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2–caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10 mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100 mg/kg). Conclusion: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2. - Highlights: • Mono-carbonyl analogue of curcumin, 14p, exhibited better chemical stability. • Compound 14p inhibited TBHP-induced apoptosis through activating Nrf2 in vitro. • Compound 14p limited myocardial ischemia
Effect of collateral flow on epicardial and endocardial lysosomal hydrolases in acute myocardial ischemia.
Gottwik, M G; Kirk, E S; Hoffstein, S; Weglicki, W B
Early changes in lysosomal enzymes must occur if their role is significant in irreversible myocardial injury. Therefore, we ligated the anterior descending coronary artery in 14 dogs and after 60 min excised epicardial and endocardial samples from the ischemic and adjacent normal heart. The collateral flow measured with radioactive microspheres in the endocardial samples averaged 19% of control. The muscle was disrupted and fractionated by ultracentrifugation into nuclear pellet (NP), heavy lysosomal pellet (HL), light lysosomal pellet (LL), microsomal pellet (M) and supernate (S). Electron microscopy demonstrated changes characteristic of sichemia in whole tissues and sedimented fractions. Acid phosphatase reaction product was present in residual bodies in the HL fraction and membrane-bound vesicles in the LL fraction and in the intact tissue. Significant decreases in the specific activity of N-acetyl-beta-glucosaminidase and beta-glucuronidase occurred in the endocardial LL fraction, while significant increases in both were found in the ts fraction (P less than 0.05). Losses of acid phosphatase occurred in both LL and S fractions. Moreover, decreases of total N-acetyl-beta-glucosaminidase in the HL fraction and of total beta-glucuronidase and acid phosphatase in the LL fraction were positively correlated (P less than 0.01) with the degree of ischemia measured with radioactive microspheres. Only insignificant enzymatic changes were found when the collateral flow was greater than 40%, and the differences were less significant in epicardial samples where the flow averaged 29%. The early loss of enzymes from the lysosomal fractions in severe ischemia suggests a role for lysosomal hydrolases in the necrosis that follows coronary occlusion. Images PMID:1159094
Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats.
Xu, Meijuan; Hao, Haiping; Jiang, Lifeng; Wei, Yidan; Zhou, Fang; Sun, Jianguo; Zhang, Jingwei; Ji, Hui; Wang, Guangji; Ju, Wenzheng; Li, Ping
Accumulating data suggest that epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid, both cytochrome P450 (P450) enzyme metabolites of arachidonic acid (AA), play important roles in cardiovascular diseases. For many years, the cardiotonic pill (CP), an herbal preparation derived from Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum, has been widely used in China for the treatment of coronary artery disease. However, its pharmacological mechanism has not been well elucidated. The purpose of this study was to investigate the chronic effects of the CP on myocardial ischemia-reperfusion injury (MIRI) and AA P450 enzyme metabolism in rats (in vivo) and H9c2 cells (in vitro). The results showed that CP dose dependently (10, 20, and 40 mg/kg/d; 7 days) mitigated MIRI in rats. The plasma concentrations of EETs in CP-treated ischemia-reperfusion (I/R) rats (40 mg/kg/d; 7 days) were significantly higher (P < 0.05) than those in controls. Cardiac Cyp1b1, Cyp2b1, Cyp2e1, Cyp2j3, and Cyp4f6 were significantly induced (P < 0.05); CYP2J and CYP2C11 proteins were upregulated (P < 0.05); and AA-epoxygenases activity was significantly increased (P < 0.05) after CP (40 mg/kg/d; 7 days) administration in rats. In H9c2 cells, the CP also increased (P < 0.05) the EET concentrations and showed protection in hypoxia-reoxygenation (H/R) cells. However, an antagonist of EETs, 14,15-epoxyeicosa-5(Z)-enoic acid, displayed a dose-dependent depression of the CP's protective effects in H/R cells. In conclusion, upregulation of cardiac epoxygenases after multiple doses of the CP-leading to elevated concentrations of cardioprotective EETs after myocardial I/R-may be the underlying mechanism, at least in part, for the CP's cardioprotective effect in rats. PMID:27149899
Total saponins from Aralia taibaiensis protect against myocardial ischemia/reperfusion injury through AMPK pathway
It was previously shown that total saponins extracted from Aralia taibaiensis (sAT) have potent antioxidant activities for treating diabetes mellitus and attenuate D-galactose-induced aging. Since diabetes mellitus and aging are closely associated with cardiac dysfunction, particularly ischemic heart disease, sAT may have potential protective activity against myocardial ischemia/reperfusion injury (MI/RI). However, the anti-MI/RI effects of sAT have yet to be examined, and the possible molecular mechanisms remain to be determined. The present study was undertaken to investigate the anti-MI/RI activities of sAT and to elucidate the mechanisms underlying these effects in rats using TUNEL and Hoechst 33258 staining. The results confirmed the cardioprotective effects in vivo and elucidated the potential molecular mechanisms of sAT in vitro. Pretreatment with sAT significantly reduced infarct size, decreased the levels of lactate dehydrogenase and creatine kinase in the serum and blocked apoptosis. In addition, sAT inhibited A/R-induced apoptosis by decreasing DNA strand breaks, caspase-3 activity and cytochrome c release in H9c2 cells. Furthermore, sAT markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase and elevated the Bcl2/Bcl-2-associated X protein ratio. These effects were blocked by compound C. The results suggested that sAT pretreatment exerts protective effects on myocardial cells in vitro and in vivo against MI/RI-induced apoptosis by activating AMPK pathway. PMID:26498380
Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury.
Jiang, Wei; Hall, Sean R; Moos, Michael P W; Cao, Richard Yang; Ishii, Satoshi; Ogunyankin, Kofo O; Melo, Luis G; Funk, Colin D
Cysteinyl leukotrienes (CysLTs) have been implicated as inflammatory mediators of cardiovascular disease. Three distinct CysLT receptor subtypes transduce the actions of CysLTs but the role of the endothelial CysLT2 receptor (CysLT2R) in cardiac function is unknown. Here, we investigated the role of CysLT2R in myocardial ischemia-reperfusion (I/R) injury using transgenic (tg) mice overexpressing human CysLT2R in vascular endothelium and nontransgenic (ntg) littermates. Infarction size in tg mice increased 114% compared with ntg mice 48 hours after I/R; this increase was blocked by the CysLT receptor antagonist BAY-u9773. Injection of 125 I-albumin into the systemic circulation revealed significantly enhanced extravasation of the label in tg mice, indicating increased leakage of the coronary endothelium, combined with increased incidence of hemorrhage and cardiomyocyte apoptosis. Expression of proinflammatory genes such as Egr-1, VCAM-1, and ICAM was significantly increased in tg mice relative to ntg controls. Echocardiographic assessment 2 weeks after I/R revealed decreased anterior wall thickness in tg mice. Furthermore, the postreperfusion time constant tau of isovolumic relaxation was significantly increased in tg animals, indicating diastolic dysfunction. These results reveal that endothelium-targeted overexpression of CysLT2R aggravates myocardial I/R injury by increasing endothelial permeability and exacerbating inflammatory gene expression, leading to accelerated left ventricular remodeling, induction of peri-infarct zone cellular apoptosis, and impaired cardiac performance. PMID:18276782
Endothelial Cysteinyl Leukotriene 2 Receptor Expression Mediates Myocardial Ischemia-Reperfusion Injury
Jiang, Wei; Hall, Sean R.; Moos, Michael P.W.; Cao, Richard Yang; Ishii, Satoshi; Ogunyankin, Kofo O.; Melo, Luis G.; Funk, Colin D.
Cysteinyl leukotrienes (CysLTs) have been implicated as inflammatory mediators of cardiovascular disease. Three distinct CysLT receptor subtypes transduce the actions of CysLTs but the role of the endothelial CysLT2 receptor (CysLT2R) in cardiac function is unknown. Here, we investigated the role of CysLT2R in myocardial ischemia-reperfusion (I/R) injury using transgenic (tg) mice overexpressing human CysLT2R in vascular endothelium and nontransgenic (ntg) littermates. Infarction size in tg mice increased 114% compared with ntg mice 48 hours after I/R; this increase was blocked by the CysLT receptor antagonist BAY-u9773. Injection of 125I-albumin into the systemic circulation revealed significantly enhanced extravasation of the label in tg mice, indicating increased leakage of the coronary endothelium, combined with increased incidence of hemorrhage and cardiomyocyte apoptosis. Expression of proinflammatory genes such as Egr-1, VCAM-1, and ICAM was significantly increased in tg mice relative to ntg controls. Echocardiographic assessment 2 weeks after I/R revealed decreased anterior wall thickness in tg mice. Furthermore, the postreperfusion time constant τ of isovolumic relaxation was significantly increased in tg animals, indicating diastolic dysfunction. These results reveal that endothelium-targeted overexpression of CysLT2R aggravates myocardial I/R injury by increasing endothelial permeability and exacerbating inflammatory gene expression, leading to accelerated left ventricular remodeling, induction of peri-infarct zone cellular apoptosis, and impaired cardiac performance. PMID:18276782
Uncoupling of increased cellular oxidative stress and myocardial ischemia reperfusion injury by directed sarcolemma stabilization
Martindale, Joshua J.; Metzger, Joseph M.
Myocardial ischemia/reperfusion (I/R) injury is a major clinical problem leading to cardiac dysfunction and myocyte death. It is widely held that I/R causes damage to membrane phospholipids, and is a significant mechanism of cardiac I/R injury. Molecular dissection of sarcolemmal damage in I/R, however, has been difficult to address experimentally. We studied here cardiac I/R injury under conditions targeting gain- or loss-of sarcolemma integrity. To implement gain-in-sarcolemma integrity during I/R, synthetic copolymer-based sarcolemmal stabilizers (CSS), including Poloxamer 188 (P188), were used as a tool to directly stabilize the sarcolemma. Consistent with the hypothesis of sarcolemmal stabilization, cellular markers of necrosis and apoptosis evident in untreated myocytes were fully blocked in sarcolemma stabilized myocytes. Unexpectedly, sarcolemmal stabilization of adult cardiac myocytes did not affect the status of myocyte-generated oxidants or lipid peroxidation in two independent assays. We also investigated the loss of sarcolemmal integrity using two independent genetic mouse models, dystrophin-deficient mdx or dysferlin knockout (Dysf KO) mice. Both models of sarcolemmal loss-of-function were severely affected by I/R injury ex vivo, and this was lessened by CSS. In vivo studies also showed that infarct size was significantly reduced in CSS-treated hearts. Mechanistically, these findings support a model whereby I/R-mediated increased myocyte oxidative stress is uncoupled from myocyte injury. Because the sarcolemma stabilizers used here do not transit across the myocyte membrane this is evidence that intracellular targets of oxidants are not sufficiently altered to affect cell death when sarcolemma integrity is preserved by synthetic stabilizers. These findings, in turn, suggest that sarcolemma destabilization, and consequent Ca2+ mishandling, as a focal initiating mechanism underlying myocardial I/R injury. PMID:24362314
Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2—dependent mechanisms
Shibata, Rei; Sato, Kaori; Pimentel, David R; Takemura, Yukihiro; Kihara, Shinji; Ohashi, Koji; Funahashi, Tohru; Ouchi, Noriyuki; Walsh, Kenneth
Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-α expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-α production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-α production. Adiponectin induced cyclooxygenase (COX)-2–dependent synthesis of prostaglandin E2 in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2–dependent mechanisms. PMID:16155579
Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs.
Stark, Christoffer K-J; Tarkia, Miikka; Kentala, Rasmus; Malmberg, Markus; Vähäsilta, Tommi; Savo, Matti; Hynninen, Ville-Veikko; Helenius, Mikko; Ruohonen, Saku; Jalkanen, Juho; Taimen, Pekka; Alastalo, Tero-Pekka; Saraste, Antti; Knuuti, Juhani; Savunen, Timo; Koskenvuo, Juha
The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI. PMID:27199757
Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs
Stark, Christoffer K.-J.; Tarkia, Miikka; Kentala, Rasmus; Malmberg, Markus; Vähäsilta, Tommi; Savo, Matti; Hynninen, Ville-Veikko; Helenius, Mikko; Ruohonen, Saku; Jalkanen, Juho; Taimen, Pekka; Alastalo, Tero-Pekka; Saraste, Antti; Knuuti, Juhani; Savunen, Timo; Koskenvuo, Juha
The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI. PMID:27199757
Berberine attenuates myocardial ischemia reperfusion injury by suppressing the activation of PI3K/AKT signaling
Berberine (BBR), an isoquinoline alkaloid originally isolated from the Chinese herb Coptis chinensis (Huanglian), exhibits anti-inflammatory and immunosuppressive properties. Since myocardial ischemia/reperfusion (I/R) injury is associated with an excessive immune response, the current study was conducted to investigate the impact of BBR on myocardial I/R injury, a common disorder in clinical settings. Preconditioning of Sprague-Dawley rats with BBR (100 mg/kg/day, by gavage) for 14 days prior to the induction of I/R significantly attenuated myocardial I/R injury as manifested by a reduction in the incidence of ventricular arrhythmia and the amelioration of myocardial histological changes. These effects were found to be associated with the suppression of the phosphoinositide 3-kinase/AKT signaling pathway and the subsequent reduction of the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in the serum and myocardial tissue. These results indicate that BBR has the potential be an effective alternative therapy for the prevention and treatment of myocardial I/R injury in clinical practice. PMID:26998023
Diagnosis of Coronary Heart Diseases Using Gene Expression Profiling; Stable Coronary Artery Disease, Cardiac Ischemia with and without Myocardial Necrosis
Kazmi, Nabila; Gaunt, Tom R.
Cardiovascular disease (including coronary artery disease and myocardial infarction) is one of the leading causes of death in Europe, and is influenced by both environmental and genetic factors. With the recent advances in genomic tools and technologies there is potential to predict and diagnose heart disease using molecular data from analysis of blood cells. We analyzed gene expression data from blood samples taken from normal people (n = 21), non-significant coronary artery disease (n = 93), patients with unstable angina (n = 16), stable coronary artery disease (n = 14) and myocardial infarction (MI; n = 207). We used a feature selection approach to identify a set of gene expression variables which successfully differentiate different cardiovascular diseases. The initial features were discovered by fitting a linear model for each probe set across all arrays of normal individuals and patients with myocardial infarction. Three different feature optimisation algorithms were devised which identified two discriminating sets of genes, one using MI and normal controls (total genes = 6) and another one using MI and unstable angina patients (total genes = 7). In all our classification approaches we used a non-parametric k-nearest neighbour (KNN) classification method (k = 3). The results proved the diagnostic robustness of the final feature sets in discriminating patients with myocardial infarction from healthy controls. Interestingly it also showed efficacy in discriminating myocardial infarction patients from patients with clinical symptoms of cardiac ischemia but no myocardial necrosis or stable coronary artery disease, despite the influence of batch effects and different microarray gene chips and platforms. PMID:26930047