query: Incidence of heart failure decreased by 10% in women since 1979.

positive: Trends in heart failure incidence and survival in a community-based population. CONTEXT The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. OBJECTIVE To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis   MAIN OUTCOME MEASURES Incidence of heart failure and survival after heart failure diagnosis. RESULTS The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. CONCLUSION In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.

negative: Clinical epidemiology of heart failure. The aim of this paper is to review the clinical epidemiology of heart failure. The last paper comprehensively addressing the epidemiology of heart failure in Heart appeared in 2000. Despite an increase in manuscripts describing epidemiological aspects of heart failure since the 1990s, additional information is still needed, as indicated by various editorials.

negative: The effect of mass screening on incidence and mortality of squamous and adenocarcinoma of cervix uteri. OBJECTIVE To describe the efficacy of the Finnish mass screening program for cervical squamous carcinoma and adenocarcinoma, as reflected by changes of incidence and mortality rate. METHODS Cervical cancer incidence and mortality data were obtained from the Finnish Cancer Registry. Data were available from the year 1953, when the registry was established. The nationwide mass screening program in Finland was started in the mid-1960s. A centralized organization administers this program. Women age 30-60 years are notified for screening every 5 years. RESULTS The mean incidence of cervical carcinoma in the early 1960s was 15.4 per 10(5) woman-years. In 1991, it was only 2.7 per 10(5) woman-years. The mortality rate has decreased in the same proportion since the mass screening program. In the early 1960s, the mortality was 6.6 and in 1991 1.4 per 10(5) woman-years. However, the decrease of the incidence is seen almost exclusively in squamous cell carcinomas. The mortality caused by adenocarcinoma has decreased in screened birth cohorts, but the incidence rate has remained the same. CONCLUSIONS The Finnish mass screening program has been effective and its continuation is of utmost importance. In the future more attention should be given to glandular cell atypias in cervical smears. Thus, it might be possible to decrease the incidence of cervical adenocarcinoma.

negative: Heart failure admissions in adults with congenital heart disease; risk factors and prognosis. BACKGROUND Heart failure (HF) is a serious complication and often the cause of death in adults with congenital heart disease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess risk factors of first HF-admission and of mortality after first HF-admission in adults with CHD. METHODS The Dutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry to obtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality were assessed using Cox regression models. RESULTS Of 10,808 adult patients (49% male), 274 (2.5%) were admitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, and surgical interventions in childhood were identified as independent risk factors of HF-admission. Patients admitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio (HR)=5.3; 95% confidence interval 4.2-6.9). One- and three-year mortality after first HF-admission were 24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admission were male gender, pacemaker implantation, admission duration, non-cardiac medication use and high serum creatinine. CONCLUSIONS The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years. Mortality risk is substantially increased after HF-admission, which emphasises the importance to identify patients at high risk of HF-admission. These patients might benefit from closer follow-up and earlier medical interventions. The presented risk factors may facilitate surveillance.

negative: Plasma Corin as a Predictor of Cardiovascular Events in Patients With Chronic Heart Failure. OBJECTIVES The aim of this study was to determine the prognostic value of plasma corin in patients with chronic heart failure (CHF). BACKGROUND In recent years, accumulating evidence has indicated that corin plays a critical role in regulating blood pressure and cardiac function. METHODS We enrolled 1,148 consecutive CHF patients in a prospective cohort study and explored the association between plasma corin levels and clinical prognosis using multivariate Cox regression analysis. RESULTS Patients with low corin levels (<458 pg/ml) were more likely to be women and to be hypertensive. Low corin was found to be associated with an increase in New York Heart Association (NYHA) functional class and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and a decrease in left ventricular ejection fraction (LVEF) and the estimated glomerular filtration rate (eGFR). Multivariate Cox regression analysis suggested that log corin was an independent predictor of major adverse cardiac event(s) (MACE) (hazard ratio: 0.62; 95% confidence interval: 0.39 to 0.95), together with age, diabetes, NYHA functional class, LVEF, eGFR, and log NT-proBNP. In addition, log corin was also a significant predictor for cardiovascular death (p = 0.041) and heart failure rehospitalization (p = 0.015) after adjustment for clinical variables and established biomarkers of adverse prognosis. The Kaplan-Meier survival curves showed that low corin was a significant predictor of MACE in patients with NT-proBNP levels above and below the median. CONCLUSIONS Our study demonstrates that plasma corin is a valuable prognostic marker of MACE in patients with CHF, independent of established conventional risk factors.

negative: Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. PURPOSE Since 1990, overall breast cancer mortality rates in the United States decreased 24%. This decline has been attributed to mammography screening and adjuvant systemic therapy. However, the efficacy of these modalities may depend on estrogen receptor (ER) expression and age. We therefore examined breast cancer mortality trends in the United States according to ER status and age. METHODS Using the Surveillance, Epidemiology, and End Results (SEER) program (1990-2003), we calculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths after diagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors. Relative hazard rates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratified by age at diagnosis. RESULTS During the study period, IBM and annual hazard rates for breast cancer deaths decreased among women with ER-positive and ER-negative tumors, although declines were greater for those with ER-positive tumors. Among women younger than 70 years, relative hazard rates declined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors. Among women 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus no significant decline for those with ER-negative tumors. CONCLUSION In the United States, breast cancer mortality rates have declined among women with ER-positive and ER-negative tumors, with greater declines among younger women and those with ER-positive tumors. Although mortality in all groups remains unacceptably high, additional emphasis should be placed on improving outcomes of breast cancer patients older than 70 years and those of all ages with ER-negative tumors.

negative: Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. BACKGROUND Patients with signs and symptoms of heart failure and a normal left ventricular ejection fraction are said to have diastolic heart failure. It has traditionally been thought that the pathophysiological cause of heart failure in these patients is an abnormality in the diastolic properties of the left ventricle; however, this hypothesis remains largely unproven. METHODS We prospectively identified 47 patients who met the diagnostic criteria for definite diastolic heart failure; all the patients had signs and symptoms of heart failure, a normal ejection fraction, and an increased left ventricular end-diastolic pressure. Ten patients who had no evidence of cardiovascular disease served as controls. Left ventricular diastolic function was assessed by means of cardiac catheterization and echocardiography. RESULTS The patients with diastolic heart failure had abnormal left ventricular relaxation and increased left ventricular chamber stiffness. The mean (+/-SD) time constant for the isovolumic-pressure decline (tau) was longer in the group with diastolic heart failure than in the control group (59+/-14 msec vs. 35+/-10 msec, P=0.01). The diastolic pressure-volume relation was shifted up and to the left in the patients with diastolic heart failure as compared with the controls. The corrected left ventricular passive-stiffness constant was significantly higher in the group with diastolic heart failure than in the control group (0.03+/-0.01 vs. 0.01+/-0.01, P<0.001). CONCLUSIONS Patients with heart failure and a normal ejection fraction have significant abnormalities in active relaxation and passive stiffness. In these patients, the pathophysiological cause of elevated diastolic pressures and heart failure is abnormal diastolic function.

negative: High cardiovascular mortality in Russia cannot be explained by the classical risk factors. The Arkhangelsk study 2000 Since the beginning of the 1990s the public health situation in Russia has been characterized by an extremely high mortality and a significant reduction in life expectancy. Cardiovascular diseases remained the major cause of death. Only a few large population studies were conducted in Russia during this period. A total of 1968 men and 1737 women aged 18–75 years participated in a health survey in Arkhangelsk, Russia, over the period 1999–2000. Investigation included assessment of classic cardiovascular risk factors (family history, smoking, blood pressure, and blood lipids) along with general health variables. The paper presents sex specific data on risk factors for coronary heart disease. Though the cardiovascular mortality is high in Russia, the calculated risk for coronary heart disease (the Framingham risk score and the Norwegian risk score) was lower in all age groups of men and women in Arkhangelsk compared with studies from the Western Europe and USA. Our data suggest that high cardiovascular mortality in Russia may be driven not only by the classic risk factors for coronary heart disease.

negative: Quality of life in patients with advanced heart failure. Although evaluation of the treatment of congestive heart failure is usually based on objective clinical outcomes, patient self-assessment is increasingly recognized as an important component of evaluation. A study was designed to measure the quality of life of 134 patients with symptoms of advanced heart failure who were being evaluated for possible heart transplantation. The patients' quality of life was assessed using a mix of subjective and objective measures, including functional status, physical symptoms, emotional state, and psychosocial adaptation. There was no significant relationship between patients' cardiac ejection fraction and any quality-of-life measures; however, the results of a 6-minute walking test, New York Heart Association classification, and self-reported functional status were all significantly correlated with psychosocial adjustment. Self-reported functional status, depression, and hostility accounted for 43% of the variance in total psychosocial adjustment to illness. These findings support the inclusion of quality of life as an outcome measure in any evaluation of treatment efficacy and suggest that interventions to improve the quality of life of patients with advanced heart failure need to be targeted at reducing depression and hostility and increasing daily activity levels.

negative: Mass screening programmes and trends in cervical cancer in Finland and the Netherlands. With respect to cervical cancer management, Finland and the Netherlands are comparable in relevant characteristics, e.g., fertility rate, age-of-mother at first birth and a national screening programme for several years. The aim of this study is to compare trends in incidence of and mortality from cervical cancer in Finland and the Netherlands in relation to the introduction and intensity of the screening programmes. Therefore, incidence and mortality rates were calculated using the Cancer Registries of Finland and the Netherlands. Data on screening intensity were obtained from the Finnish Cancer Registry and the Dutch evaluation centre at ErasmusMC-Rotterdam. Women aged 30-60 have been screened every 5 years, in Finland since 1992 and in the Netherlands since 1996. Screening protocols for smear taking and referral to the gynaecologist are comparable. Incidence and mortality rates have declined more in Finland. In 2003, age-adjusted incidence and mortality in Finland were 4.0 and 0.9 and in the Netherlands 4.9 and 1.4 per 100,000 woman-years, respectively. Excess smear use in the Netherlands was estimated to be 24 per 1,000 women during a 5-year interval compared to 121 in Finland. The decline in mortality in Finland seems to be almost completely related to the screening programme whereas in the Netherlands it was initially considered to be a natural decline. Differences in risk factors might also play a role: the Netherlands has higher population density and higher percentages of immigrants and (female) smokers. The greater excess smear use in Finland might also have affected incidence.

negative: Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

negative: Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease. The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response. Normotensive women with a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) were studied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA). The BP, HR, and MSNA responses to the CPT were similar between groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p < 0.05). MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31 ± 13 vs. 23 ± 13 bursts/min; p for group = 0.06). Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history. This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events.

negative: Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models. The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure. However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart. This review discusses new insights into metabolic adaptations in heart failure. A particular focus lies on data obtained from mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolic pathway and how these differently affect cardiac function. Based on studies in which these mouse models were exposed to ischaemic and non-ischaemic heart failure, we discuss whether and when modulations in FA metabolism are protective against heart failure.

negative: An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. BACKGROUND Readmission soon after hospital discharge is an expensive and often preventable event for patients with heart failure. We present a model approved by the National Quality Forum for the purpose of public reporting of hospital-level readmission rates by the Centers for Medicare & Medicaid Services. METHODS AND RESULTS We developed a hierarchical logistic regression model to calculate hospital risk-standardized 30-day all-cause readmission rates for patients hospitalized with heart failure. The model was derived with the use of Medicare claims data for a 2004 cohort and validated with the use of claims and medical record data. The unadjusted readmission rate was 23.6%. The final model included 37 variables, had discrimination ranging from 15% observed 30-day readmission rate in the lowest predictive decile to 37% in the upper decile, and had a c statistic of 0.60. The 25th and 75th percentiles of the risk-standardized readmission rates across 4669 hospitals were 23.1% and 24.0%, with 5th and 95th percentiles of 22.2% and 25.1%, respectively. The odds of all-cause readmission for a hospital 1 standard deviation above average was 1.30 times that of a hospital 1 standard deviation below average. State-level adjusted readmission rates developed with the use of the claims model are similar to rates produced for the same cohort with the use of a medical record model (correlation, 0.97; median difference, 0.06 percentage points). CONCLUSIONS This claims-based model of hospital risk-standardized readmission rates for heart failure patients produces estimates that may serve as surrogates for those derived from a medical record model.

negative: Risk of hospitalization or death from ischemic heart disease among British vegetarians and nonvegetarians: results from the EPIC-Oxford cohort study. BACKGROUND Few previous prospective studies have examined differences in incident ischemic heart disease (IHD) risk between vegetarians and nonvegetarians. OBJECTIVE The objective was to examine the association of a vegetarian diet with risk of incident (nonfatal and fatal) IHD. DESIGN A total of 44,561 men and women living in England and Scotland who were enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% consumed a vegetarian diet at baseline, were part of the analysis. Incident cases of IHD were identified through linkage with hospital records and death certificates. Serum lipids and blood pressure measurements were available for 1519 non cases, who were matched to IHD cases by sex and age. IHD risk by vegetarian status was estimated by using multivariate Cox proportional hazards models. RESULTS After an average follow-up of 11.6 y, there were 1235 IHD cases (1066 hospital admissions and 169 deaths). Compared with nonvegetarians, vegetarians had a lower mean BMI [in kg/m(2); -1.2 (95% CI: -1.3, -1.1)], non-HDL-cholesterol concentration [-0.45 (95% CI: -0.60, -0.30) mmol/L], and systolic blood pressure [-3.3 (95% CI: -5.9, -0.7) mm Hg]. Vegetarians had a 32% lower risk (HR: 0.68; 95% CI: 0.58, 0.81) of IHD than did nonvegetarians, which was only slightly attenuated after adjustment for BMI and did not differ materially by sex, age, BMI, smoking, or the presence of IHD risk factors. CONCLUSION Consuming a vegetarian diet was associated with lower IHD risk, a finding that is probably mediated by differences in non-HDL cholesterol, and systolic blood pressure.

negative: Breathing more with weaker respiratory muscles in pulmonary arterial hypertension. Exertional fatigue and dyspnoea limit the daily activities of patients with pulmonary arterial hypertension 1. These symptoms are usually explained by the inability of the overloaded right ventricle to perfuse the lungs and to adapt systemic oxygen delivery to oxygen demand. Accordingly, pulmonary hypertension patients present with reductions in peak oxygen uptake, anaerobic threshold, oxygen pulse, ventilatory efficiency and 6-min walk distance 2–8. This ergospirometric profile is strikingly similar to that of congestive heart failure 8–12, further supporting the notion of impaired cardiac output adaptation to peripheral oxygen requirements as the main cause of decreased exercise capacity. However, in both pulmonary hypertension and heart failure, ergospirometric variables and walk distances are better correlated to functional class and prognosis than to haemodynamic function 3, 6, 7, 10–12. In addition, impaired skeletal muscle function has been repeatedly reported in heart failure, fuelling a “muscle hypothesis” relating dyspnoea and fatigue symptoms to skeletal muscle metaboreceptor and/or ergoreceptor reflexes 13. The muscle hypothesis implies a persistent sympathetic nervous system activation, which has indeed been shown to occur in heart failure 14 and also, more recently, in pulmonary hypertension 15. Until now, there have been no studies on skeletal muscle function in pulmonary arterial hypertension. In the present issue of the European Respiratory Journal , Meyer et al. 16 report data suggesting that respiratory muscle strength is decreased in pulmonary arterial hypertension. In a prospective study on 37 patients with idiopathic pulmonary hypertension, significant decreases in maximal inspiratory (MIP) and expiratory pressures (MEP) were measured, together with an increased mouth occlusion pressure within first 0.1 s of inspiration ( P 0.1), suggesting inadequate muscle …

negative: Blocking caspase-activated apoptosis improves contractility in failing myocardium. Cardiac myocyte apoptosis has been demonstrated in end-stage failing human hearts. The therapeutic utility of blocking apoptosis in congestive heart failure (CHF) has not been elucidated. This study investigated the role of caspase activation in cardiac contractility and sarcomere organization in the development of CHF. In a rabbit model of heart failure obtained by rapid ventricular pacing, we demonstrate, using in vivo transcoronary adenovirus-mediated gene delivery of the potent caspase inhibitor p35, that caspase activation is associated with a reduction in contractile force of failing myocytes by destroying sarcomeric structure. In this animal model gene transfer of p35 prevented the rise in caspase 3 activity and DNA-histone formation. Genetically manipulated hearts expressing p35 had a significant improvement in left ventricular pressure rise (+dp/dt), decreased end-diastolic chamber pressure (LVEDP), and the development of heart failure was delayed. To better understand this benefit, we examined the effects of caspase 3 on cardiomyocyte dysfunction in vitro. Microinjection of activated caspase 3 into the cytoplasm of intact myocytes induced sarcomeric disorganization and reduced contractility of the cells. These results demonstrate a direct impact of caspases on cardiac function and may lead to novel therapeutic strategies via antiapoptotic regimens.

negative: Physician knowledge levels and barriers to coronary risk prevention in women: survey results from the Women and Heart Disease Physician Education Initiative. BACKGROUND Few studies have examined whether physician knowledge, attitudes, or practice patterns might contribute to gender disparities in the primary prevention of coronary heart disease (CHD), including among physicians caring for the largest number of reproductive-age women, obstetricians and gynecologists (OB/GYNs). We sought to identify barriers affecting the provision of recommended coronary risk factor therapies in women. METHODS We surveyed internists and OB/GYNs who attended Grand Rounds presentations developed for the New York State Women and Heart Disease Physician Education Initiative. This program was designed to improve screening and management of coronary risk factors in women. Attendees were asked to complete a 7-minute questionnaire. RESULTS The mean age of the 529 respondents was 40.3 years (standard deviation = 12.3), 75.1% were internists (n=378), and 42.7% (n=226) were women. Physicians correctly responded to 71.5% of the 13 questions assessing knowledge of coronary risk prevention (range, 4-13). Almost one third of internists and half of the OB/GYNs did not know that tobacco use was the leading cause of myocardial infarction in young women. For patients who smoked tobacco, only two thirds of internists and 55.4% of OB/GYNs reported suggesting a quit date (p=.007). After controlling for covariates, physicians who did not perceive time as a barrier were more likely to discuss smoking cessation (odds ratio=1.7 [1.1-2.7]). CONCLUSIONS Among the internists and OB/GYNs surveyed, time was perceived as a barrier to implementing risk prevention. These physicians also underestimated the impact of tobacco use as a risk factor for CHD in young women. To lessen gender disparities in CHD prevention, both specialties need time-efficient educational programs that reflect specialty differences.

negative: Cardiovascular risk and events in 17 low-, middle-, and high-income countries. BACKGROUND More than 80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-income countries, but the reasons are unknown. METHODS We enrolled 156,424 persons from 628 urban and rural communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) and assessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years. RESULTS The mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P=0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001). CONCLUSIONS Although the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in high-income countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.).

negative: Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. CONTEXT The long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown. OBJECTIVES To estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk. DESIGN, SETTING, AND PARTICIPANTS Community-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998). MAIN OUTCOME MEASURES Residual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications. RESULTS The residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (greater-than-or-equal to 140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving antihypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (greater-than-or-equal to 160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure. CONCLUSION The residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension.

negative: Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. OBJECTIVE To assess whether sex differences exist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS). METHODS The study comprised 7638 women and 19 117 men with ACS who underwent coronary angiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006. Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced disease was defined as >or=one vessel with >or=50% stenosis. RESULTS Women were older than men and had higher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however, jaw pain and nausea were more frequent among women. Women were more likely to have normal/mild disease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and men with normal and mild disease were treated less aggressively than those with advanced disease. Women with advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age and extent of disease, women were more likely to have adverse outcomes (death, myocardial infarction, stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval 1.14 to 1.34); however, sex differences in mortality were no longer statistically significant. CONCLUSIONS Women with ACS were more likely to have cardiovascular disease risk factors and atypical symptoms such as nausea compared with men, but were more likely to have normal/mild angiographic coronary artery disease. Further study regarding sex differences related to disease severity is warranted.

negative: Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. BACKGROUND This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope. METHODS AND RESULTS Patients from 14 centers were randomized to receive either a DDD pacemaker provided with rate-drop response function or the beta-blocker atenolol at the dosage of 100 mg once a day. Inclusion criteria were age >35 years, >/=3 syncopal spells in the preceding 2 years, and positive response to tilt table testing with syncope occurring in association with relative bradycardia. The primary outcome was the first recurrence of syncope after randomization. Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1+/-14.3 years) had been enrolled and randomized, although follow-up data were available for all patients (46 patients in the pacemaker arm, 47 patients in the pharmacological arm). The interim analysis showed a significant effect in favor of permanent cardiac pacing (recurrence of syncope in 2 patients [4.3%] after a median of 390 days) compared with medical treatment (recurrence of syncope in 12 patients [25.5%] after a median of 135 days; OR, 0.133; 95% CI, 0.028 to 0.632; P=0.004). Consequently, enrollment and follow-up were terminated. CONCLUSIONS DDD pacing with rate-drop response function is more effective than beta-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope.

negative: Sex-based differences in the effect of digoxin for the treatment of heart failure. BACKGROUND The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated. METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables. RESULTS There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, -1.6 percent; 95 percent confidence interval, -4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction). CONCLUSIONS The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.

negative: Incidence of cancer after immunosuppressive treatment for heart transplantation. Prolonged or intensive immunosuppressive therapy used after organ transplantation is complicated by an increased incidence of cancer. Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients. The most significant increase was in the incidence of lymphomas in cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account for these differences. In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy.

negative: Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. RATIONALE Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population. OBJECTIVES To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. METHODS Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke. MEASUREMENTS AND MAIN RESULTS A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. CONCLUSIONS The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.

negative: Sympathetic baroreflex gain in normotensive pregnant women. Muscle sympathetic nerve activity is increased during normotensive pregnancy while mean arterial pressure is maintained or reduced, suggesting baroreflex resetting. We hypothesized spontaneous sympathetic baroreflex gain would be reduced in normotensive pregnant women relative to nonpregnant matched controls. Integrated muscle sympathetic burst incidence and total sympathetic activity (microneurography), blood pressure (Finometer), and R-R interval (ECG) were assessed at rest in 11 pregnant women (33 ± 1 wk gestation, 31 ± 1 yr, prepregnancy BMI: 23.5 ± 0.9 kg/m(2)) and 11 nonpregnant controls (29 ± 1 yr; BMI: 25.2 ± 1.7 kg/m(2)). Pregnant women had elevated baseline sympathetic burst incidence (43 ± 2 vs. 33 ± 2 bursts/100 heart beats, P = 0.01) and total sympathetic activity (1,811 ± 148 vs. 1,140 ± 55 au, P < 0.01) relative to controls. Both mean (88 ± 3 vs. 91 ± 2 mmHg, P = 0.4) and diastolic (DBP) (72 ± 3 vs. 73 ± 2 mmHg, P = 0.7) pressures were similar between pregnant and nonpregnant women, respectively, indicating an upward resetting of the baroreflex set point with pregnancy. Baroreflex gain, calculated as the linear relationship between sympathetic burst incidence and DBP, was reduced in pregnant women relative to controls (-3.7 ± 0.5 vs. -5.4 ± 0.5 bursts·100 heart beats(-1)·mmHg(-1), P = 0.03), as was baroreflex gain calculated with total sympathetic activity (-294 ± 24 vs. -210 ± 24 au·100 heart beats(-1)·mmHg(-1); P = 0.03). Cardiovagal baroreflex gain (sequence method) was not different between nonpregnant controls and pregnant women (49 ± 8 vs. 36 ± 8 ms/mmHg; P = 0.2). However, sympathetic (burst incidence) and cardiovagal gains were negatively correlated in pregnant women (R = -0.7; P = 0.02). Together, these data indicate that the influence of the sympathetic nervous system over arterial blood pressure is reduced in normotensive pregnancy, in terms of both long-term and beat-to-beat regulation of arterial pressure, likely through a baroreceptor-dependent mechanism.

negative: The Incidence and Repetition of Hospital-Treated Deliberate Self Harm: Findings from the World's First National Registry BACKGROUND Suicide is a significant public health issue with almost one million people dying by suicide each year worldwide. Deliberate self harm (DSH) is the single most important risk factor for suicide yet few countries have reliable data on DSH. We developed a national DSH registry in the Republic of Ireland to establish the incidence of hospital-treated DSH at national level and the spectrum and pattern of presentations with DSH and repetition. METHODS AND FINDINGS Between 2003 and 2009, the Irish National Registry of Deliberate Self Harm collected data on DSH presentations to all 40 hospital emergency departments in the country. Data were collected by trained data registration officers using standard methods of case ascertainment and definition. The Registry recorded 75,119 DSH presentations involving 48,206 individuals. The total incidence rate fell from 209 (95% CI: 205-213) per 100,000 in 2003 to 184 (95% CI: 180-189) per 100,000 in 2006 and increased again to 209 (95% CI: 204-213) per 100,000 in 2009. The most notable annual changes were successive 10% increases in the male rate in 2008 and 2009. There was significant variation by age with peak rates in women in the 15-19 year age group (620 (95% CI: 605-636) per 100,000), and in men in the 20-24 age group (427 (95% CI: 416-439) per 100,000). Repetition rates varied significantly by age, method of self harm and number of previous episodes. CONCLUSIONS Population-based data on hospital-treated DSH represent an important index of the burden of mental illness and suicide risk in the community. The increased DSH rate in Irish men in 2008 and 2009 coincided with the advent of the economic recession in Ireland. The findings underline the need for developing effective interventions to reduce DSH repetition rates as a key priority for health systems.

negative: Incidence of childhood distal forearm fractures over 30 years: a population-based study. CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase.

negative: Pregnancy in dialysis patients: a review of outcomes, complications, and management. Although uncommon, pregnancy occurs in women on chronic dialysis. In 1980 the incidence of pregnancy in women on dialysis was 0.9%. Studies from 1992 to 2003 indicate that pregnancy occurred in 1-7% of women on chronic dialysis. Half of the infants born to women on chronic dialysis survive. Of importance is that "intensive dialysis" of 16-24 hr/week is associated with improved infant survival. In this article, the incidence, duration, fetal and maternal complications, and outcomes of pregnancy in women on chronic dialysis are reviewed. The management of anemia, hypertension, electrolytes, bone minerals, and acid-base parameters in the pregnant dialysis patient is also summarized. Recommendations regarding the dialysis prescription for the pregnant woman on hemodialysis (HD) or peritoneal dialysis (PD) are also made. The complex and precarious condition of the pregnant woman on dialysis requires close collaboration between the patient, nephrologist, dialysis staff, obstetrician, and neonatologist to maximize the chance of a successful pregnancy.

negative: Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110alpha isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110alpha) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic mice with increased or decreased PI3K(p110alpha) activity to the DCM model, and subjected PI3K(p110alpha) transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110alpha) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110alpha) activity drastically shortened lifespan by approximately 50%. Increased PI3K(p110alpha) activity had a favorable effect on cardiac function and fibrosis in the pressure-overload model and attenuated pathological growth. PI3K(p110alpha) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110gamma) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110alpha) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.

negative: Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. BACKGROUND Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. METHODS AND RESULTS Thirty patients with PH (21 women; mean age, 50+/-13 years; mean pulmonary artery pressure, 50+/-15 mm Hg; mean World Health Organization [WHO] class, 2.9+/-0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61+/-18 to 54+/-18 mm Hg) within the training group. CONCLUSIONS This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.

negative: Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort. OBJECTIVE To compare the incidence of cancer among women with and without a history of pre-eclampsia. DESIGN Cohort study. SETTING Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalem during 1964-76. PARTICIPANTS 37 033 women. MAIN OUTCOME MEASURES Age adjusted and multivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who were primiparous at study entry. RESULTS Cancer developed in 91 women who had pre-eclampsia and 2204 who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancers was increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence of cancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women at study entry who had a history pre-eclampsia. CONCLUSIONS A history of pre-eclampsia is associated with increases in overall risk of cancer and incidence at several sites. This may be explained by environmental and genetic factors common to the development of pre-eclampsia and cancer in this population.

negative: Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. CONTEXT Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. OBJECTIVE To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN, SETTING, AND PATIENTS A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. RESULTS Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. CONCLUSIONS In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01087996.