percutaneous coronary intervention ( pci ) with drug - eluting stents and pharmacological management such as antiplatelet agents and statins constitutes the therapeutic mainstay for patients with acute coronary syndrome.1 ) however , pci may cause peri - procedural myocardial injury which is associated with adverse in - hospital outcomes and a worse overall prognosis.2)3 ) previous studies suggest that even short - term administration of statins before pci may provide clinical benefit and reduce the incidence of peri - procedural myocardial infarction ( mi).4)5)6 ) however , its mechanism has not been clearly defined . furthermore , recent studies have raised controversy over the effects of high dose statins in the prevention of peri - procedural myocardial injury and the improvement of clinical outcome.7)8 ) the index of microcirculatory resistance ( imr ) is an invasive physiologic index which interrogates the status of coronary microvasculture.9 ) imr can be reliably measured in a cardiac catheterization laboratory and is not influenced by hemodynamic conditions , unlike coronary flow reserve ( cfr ) . recent works have highlighted the clinical usefulness of this index in the evaluation of the coronary microvasculature.9)10 ) in patients with mi , imr has been reported to have prognostic value.10 ) we performed this study to evaluate the effects of pre - pci loading of high dose atorvastatin on peri - procedural myocardial damage by measuring post - pci imr with serial measurement of cardiac enzymes and high sensitivity c - reactive protein levels ( crp ) in patients with non - st - segment elevation acute coronary syndrome ( nste - acs ) . the resist - acs ( pre - treatment with high dose atorvastatin for the prevention of microvascular dysfunction after percutaneous coronary intervention in patients with acute coronary syndrome ) study ( clinicaltrials.gov number , nct01491256 ) is a multicenter , randomized , prospective clinical trial performed in four korean university hospitals ( kangwon national university hospital , keimyung university dongsan medical center , inje university ilsan paik hospital , and seoul national university hospital ) . patients who were scheduled for early coronary angiography ( < 48 hours ) for suspicious nste - acs ( unstable angina or non - st - segment elevation acute myocardial infarction ) between 18 and 85 years old were consecutively included . exclusion criteria were as follows : st - segment elevation acute myocardial infarction , high - risk features needing emergency coronary angiography , any increase in liver enzymes ( alanine aminotransferase and aspartate aminotransferase ) , left ventricular ejection fraction<30% , renal dysfunction with serum creatinine>2.0 mg / dl , total occlusion of culprit vessel , 3-vessel disease , left main stenosis , lesion at distal segments or branches , lesion with marked calcification , presence of definite thrombus or extreme tortuosity , contraindication to adenosine , a history of previous myocardial infarction , a history of coronary artery bypass surgery and a history of previous statin therapy within three months . between march 2010 and may 2012 , 205 patients who underwent coronary angiography were screened according to clinical inclusion and exclusion criteria ( fig . eligible patients were randomized to receive high dose atorvastatin loading ( 80 mg loading given 12 to 24 h before coronary angiography , with a further 40 mg dose 2 h before pci ) or low dose atorvastatin ( 10 mg given 12 to 24 h before pci ) . after coronary angiography , 128 patients ( 65 randomized to high dose arm and 63 to control arm ) were additionally excluded ; 82 patients for no significant stenosis , three for left main lesion , 11 for lesions at branch or distal segment , 10 for total occlusion , 12 for 3-vessel disease , three for failure to cross pressure wire , and seven for markedly calcified or thrombotic lesion . therefore , 77 patients who underwent pci immediately after diagnostic angiography represent the study population . according to the protocol , patients were pre - treated with aspirin ( 300 mg loading dose ) and clopidogrel ( 600 mg loading dose at least three h before the procedure).11 ) before pci , patients received intravenous heparin with a target activated clotting time of > 300 seconds . blood samples were collected before and at six and 12 hours after pci to measure crp , creatine kinase - myocardial band ( ck - mb ) and total creatine kinase ( ck ) levels . after pci , the maintenance dose of atorvastatin was determined at the physician 's discretion . the study complies with the declaration of helsinki and was approved by the institutional review board at each participating center . was measured before and after pci , and cfr , imr and wedge pressure ( pw ) were measured after pci by methods described previously.9)12 ) in brief , a pressure - temperature sensor guide wire ( certus pressure wire , st . paul , mn , usa ) was used for physiologic measurements . with the sensor positioned at the tip of the catheter after intracoronary nitroglycerin administration ( 100 - 200 g ) , three injections of 3 - 4 ml of room - temperature saline were introduced into the coronary artery , and the resting mean transit time ( tmn ) was measured . intravenous infusion of adenosine ( 140 g / kg / min ) was then administered via the femoral vein or large peripheral vein to induce steady state maximal hyperemia . then , three more injections of 3 - 4 ml of room temperature saline were administered , and the hyperemic tmn was measured . simultaneous measurements of mean aortic pressure ( pa , by guiding catheter ) and mean distal coronary pressure ( pd , by pressure wire ) were also made during maximal hyperemia . imr was calculated as the pd at maximal hyperemia divided by the inverse of the hyperemic tmn.9 ) ffr was calculated by the ratio of ( mean pd)/(mean pa ) at maximal hyperemia.12 ) the pw was measured after 60-second balloon occlusion of the target lesion , as well as before and after stent deployment with concurrent measurement of pa . in cases of significant stenosis ( ffr0.75 ) , an expanded formula ( imr = paxtmnx[pd - pw]/[pa - pw ] ) was applied to calculate the true imr that incorporates coronary pw to account for collateral flow.13 ) the primary end point was the post pci imr . microcirculatory impairment was defined as imr25.14)15)16 ) the mean post - pci imr value of patients in the low dose group was expected to be 2612 according to previous study results.9)14)15 ) a 30% reduction of post - pci imr value was hypothesized in the high dose atorvastatin loading group . a total sample size of 76 patients would provide 80% power to detect this difference with a significance level of 0.05 . the distributional assumption of normal populations required for the two sample t - statistic was justified by using the kolmogorov - smirnov test and was visually double - checked by using normal quantile - quantile plots . for categorical variables , chi - square tests were used to test homogeneity between populations . for continuous variables , student 's t - tests or wilcoxon rank - sum tests were used to test for mean differences between populations . the results of statistical tests were summarized as meanstandard deviation for the two sample t - test and median with inter - quartile range for the wilcoxon rank - sum test . multivariable logistic regression analysis was performed to determine the independent predictive factors of microcirculatory impairment after pci . for a two - sided hypothesis test , p - value less than 0.05 is considered significant . statistical analyses were performed using the spss ver . 15.0 ( spss inc . , chicago , il , usa ) . the resist - acs ( pre - treatment with high dose atorvastatin for the prevention of microvascular dysfunction after percutaneous coronary intervention in patients with acute coronary syndrome ) study ( clinicaltrials.gov number , nct01491256 ) is a multicenter , randomized , prospective clinical trial performed in four korean university hospitals ( kangwon national university hospital , keimyung university dongsan medical center , inje university ilsan paik hospital , and seoul national university hospital ) . patients who were scheduled for early coronary angiography ( < 48 hours ) for suspicious nste - acs ( unstable angina or non - st - segment elevation acute myocardial infarction ) between 18 and 85 years old were consecutively included . exclusion criteria were as follows : st - segment elevation acute myocardial infarction , high - risk features needing emergency coronary angiography , any increase in liver enzymes ( alanine aminotransferase and aspartate aminotransferase ) , left ventricular ejection fraction<30% , renal dysfunction with serum creatinine>2.0 mg / dl , total occlusion of culprit vessel , 3-vessel disease , left main stenosis , lesion at distal segments or branches , lesion with marked calcification , presence of definite thrombus or extreme tortuosity , contraindication to adenosine , a history of previous myocardial infarction , a history of coronary artery bypass surgery and a history of previous statin therapy within three months . between march 2010 and may 2012 , 205 patients who underwent coronary angiography were screened according to clinical inclusion and exclusion criteria ( fig . eligible patients were randomized to receive high dose atorvastatin loading ( 80 mg loading given 12 to 24 h before coronary angiography , with a further 40 mg dose 2 h before pci ) or low dose atorvastatin ( 10 mg given 12 to 24 h before pci ) . after coronary angiography , 128 patients ( 65 randomized to high dose arm and 63 to control arm ) were additionally excluded ; 82 patients for no significant stenosis , three for left main lesion , 11 for lesions at branch or distal segment , 10 for total occlusion , 12 for 3-vessel disease , three for failure to cross pressure wire , and seven for markedly calcified or thrombotic lesion . therefore , 77 patients who underwent pci immediately after diagnostic angiography represent the study population . according to the protocol , patients were pre - treated with aspirin ( 300 mg loading dose ) and clopidogrel ( 600 mg loading dose at least three h before the procedure).11 ) before pci , patients received intravenous heparin with a target activated clotting time of > 300 seconds . blood samples were collected before and at six and 12 hours after pci to measure crp , creatine kinase - myocardial band ( ck - mb ) and total creatine kinase ( ck ) levels . after pci , the maintenance dose of atorvastatin was determined at the physician 's discretion . the study complies with the declaration of helsinki and was approved by the institutional review board at each participating center . was measured before and after pci , and cfr , imr and wedge pressure ( pw ) were measured after pci by methods described previously.9)12 ) in brief , a pressure - temperature sensor guide wire ( certus pressure wire , st . paul , mn , usa ) was used for physiologic measurements . with the sensor positioned at the tip of the catheter , after intracoronary nitroglycerin administration ( 100 - 200 g ) , three injections of 3 - 4 ml of room - temperature saline were introduced into the coronary artery , and the resting mean transit time ( tmn ) was measured . intravenous infusion of adenosine ( 140 g / kg / min ) was then administered via the femoral vein or large peripheral vein to induce steady state maximal hyperemia . then , three more injections of 3 - 4 ml of room temperature saline were administered , and the hyperemic tmn was measured . simultaneous measurements of mean aortic pressure ( pa , by guiding catheter ) and mean distal coronary pressure ( pd , by pressure wire ) were also made during maximal hyperemia . imr was calculated as the pd at maximal hyperemia divided by the inverse of the hyperemic tmn.9 ) ffr was calculated by the ratio of ( mean pd)/(mean pa ) at maximal hyperemia.12 ) the pw was measured after 60-second balloon occlusion of the target lesion , as well as before and after stent deployment with concurrent measurement of pa . in cases of significant stenosis ( ffr0.75 ) , an expanded formula ( imr = paxtmnx[pd - pw]/[pa - pw ] ) was applied to calculate the true imr that incorporates coronary pw to account for collateral flow.13 ) the mean post - pci imr value of patients in the low dose group was expected to be 2612 according to previous study results.9)14)15 ) a 30% reduction of post - pci imr value was hypothesized in the high dose atorvastatin loading group . a total sample size of 76 patients would provide 80% power to detect this difference with a significance level of 0.05 . the distributional assumption of normal populations required for the two sample t - statistic was justified by using the kolmogorov - smirnov test and was visually double - checked by using normal quantile - quantile plots . for categorical variables , chi - square tests were used to test homogeneity between populations . for continuous variables , student 's t - tests or wilcoxon rank - sum tests the results of statistical tests were summarized as meanstandard deviation for the two sample t - test and median with inter - quartile range for the wilcoxon rank - sum test . multivariable logistic regression analysis was performed to determine the independent predictive factors of microcirculatory impairment after pci . for a two - sided hypothesis test , p - value less than 0.05 is considered significant . clinical and procedural features in the high dose ( 39 patients ) and low dose ( 38 patients ) groups are shown in table 1 . there were no significant differences between the two groups in age , gender , prevalence of cardiovascular risk factors , current medications , metabolic profiles , left ventricular function , and clinical presentation . angiographic and procedural characteristics were also comparable in both groups for coronary anatomy , lesion type , procedural characteristics , diameter and length of implanted stents , and the use of glycoprotein iib / iiia inhibitors ( table 2 ) . procedural success was obtained in all patients and there were no procedure - related complications in either group . no patient experienced statin - related adverse events , such as liver enzyme elevation or myopathy . after pci , physiological parameters such as ffr , cfr , imr , and pw were successfully obtained in all patients . post pci imr value , the primary end point of this study , was significantly lower in the high dose group than in the low dose group ( 14.15.0 u vs. 19.29.3 u , p=0.003 ) ( fig . 2 ) . incidence of microcirculatory impairment was also lower in the high dose group ( 2.6% vs. 23.7% , p=0.007 ) ( table 3 ) . post - pci ffr , cfr , and pw values were similar between the two groups . pre - pci ffr , cfr , imr , and pw values were also comparable , but pre - pci physiological values were measured in only 38 patients ( 17 in the study group and 21 in the low dose group ) since measurement before pci was not protocol - mandated . the baseline levels of total ck , ck - mb and crp were comparable between the two groups . post - pci ck - mb ( median 1.40 [ interquartile range ( iqr ) : 0.75 to 3.45 ] vs. 4.00 ng / ml [ iqr : 1.70 to 7.37 ] , p=0.002 ) and crp ( 0.09 [ iqr : 0.04 to 0.16 ] vs. 0.22 mg / dl [ iqr : 0.08 to 0.60 ] , p=0.001 ) were significantly lower in the high dose group ( table 4 ) . when ck , ck - mb and crp levels before and after pci were compared , ck - mb ( 1.70 [ iqr : 1.09 to 2.73 ] vs. 4.00 ng / ml [ 1.70 to 7.37 ] , p=0.001 ) and crp ( 0.12 [ iqr : 0.04 to 0.30 ] vs. 0.22 [ 0.08 to 0.60 ] , p<0.001 ) levels showed significant elevation after pci in the low dose group , but not in the high dose group ( fig . the ck - mb levels showed a weak positive correlation with post - pci imr values ( r=0.238 , p=0.041 ) ( fig . ( odd ratio [ or ] 0.117 , 95% confidence interval [ ci ] 0.014 to 0.999 ; p=0.050 ) and pre - dilatation balloon pressure ( or 1.353 , 95% ci 0.945 to 1.938 ; p=0.099 ) were explored as potential predictors of post - pci microcirculatory impairment . multivariable logistic regression analysis identified pretreatment with high dose atorvastatin as the only independent predictor ( or 0.089 , 95% ci 0.009 to 0.843 ; p=0.035 ) for post - pci microcirculatory impairment . clinical and procedural features in the high dose ( 39 patients ) and low dose ( 38 patients ) groups are shown in table 1 . there were no significant differences between the two groups in age , gender , prevalence of cardiovascular risk factors , current medications , metabolic profiles , left ventricular function , and clinical presentation . angiographic and procedural characteristics were also comparable in both groups for coronary anatomy , lesion type , procedural characteristics , diameter and length of implanted stents , and the use of glycoprotein iib / iiia inhibitors ( table 2 ) . procedural success was obtained in all patients and there were no procedure - related complications in either group . no patient experienced statin - related adverse events , such as liver enzyme elevation or myopathy . after pci , physiological parameters such as ffr , cfr , imr , and pw were successfully obtained in all patients . post pci imr value , the primary end point of this study , was significantly lower in the high dose group than in the low dose group ( 14.15.0 u vs. 19.29.3 u , p=0.003 ) ( fig . 2 ) . incidence of microcirculatory impairment was also lower in the high dose group ( 2.6% vs. 23.7% , p=0.007 ) ( table 3 ) . post - pci ffr , cfr , and pw values were similar between the two groups . pre - pci ffr , cfr , imr , and pw values were also comparable , but pre - pci physiological values were measured in only 38 patients ( 17 in the study group and 21 in the low dose group ) since measurement before pci was not protocol - mandated . the baseline levels of total ck , ck - mb and crp were comparable between the two groups . post - pci ck - mb ( median 1.40 [ interquartile range ( iqr ) : 0.75 to 3.45 ] vs. 4.00 ng / ml [ iqr : 1.70 to 7.37 ] , p=0.002 ) and crp ( 0.09 [ iqr : 0.04 to 0.16 ] vs. 0.22 mg / dl [ iqr : 0.08 to 0.60 ] , p=0.001 ) were significantly lower in the high dose group ( table 4 ) . when ck , ck - mb and crp levels before and after pci were compared , ck - mb ( 1.70 [ iqr : 1.09 to 2.73 ] vs. 4.00 ng / ml [ 1.70 to 7.37 ] , p=0.001 ) and crp ( 0.12 [ iqr : 0.04 to 0.30 ] vs. 0.22 [ 0.08 to 0.60 ] , p<0.001 ) levels showed significant elevation after pci in the low dose group , but not in the high dose group ( fig . the ck - mb levels showed a weak positive correlation with post - pci imr values ( r=0.238 , p=0.041 ) ( fig . by univariate analyses , high dose atorvastatin loading ( odd ratio [ or ] 0.117 , 95% confidence interval [ ci ] 0.014 to 0.999 ; p=0.050 ) and pre - dilatation balloon pressure ( or 1.353 , 95% ci 0.945 to 1.938 ; p=0.099 ) were explored as potential predictors of post - pci microcirculatory impairment . multivariable logistic regression analysis identified pretreatment with high dose atorvastatin as the only independent predictor ( or 0.089 , 95% ci 0.009 to 0.843 ; p=0.035 ) for post - pci microcirculatory impairment . the results of resist - acs trial indicate that a short - term pre - treatment with high - dose atorvastatin loading before pci can reduce peri - procedural myocardial injury verified by post - pci imr in patients with nste - acs compared to low dose statin therapy . as the high dose group had lower imr and lower crp than the low dose group , this effect seems to be mediated improved microvascular function and less inflammation . microcirculatory impairment is closely related with myocardial damage and adverse outcomes in various clinical situations . gibson et al . demonstrated that patients with impaired thrombolysis in myocardial infarction ( timi ) perfusion grade had a 10-fold - higher incidence of post - procedural ck - mb elevation.17 ) bolognese et al . found using a combination of timi flow grade , corrected timi frame count , timi perfusion grade , and myocardial contrast echocardiography , that post - pci cardiac troponin i elevation in high - risk patients with acs was associated with an abnormal tissue - level perfusion.18 ) recently , imr has been shown to be a reliable and reproducible index to evaluate coronary microvascular function with less interference by other hemodynamic changes.19 ) fearon et al . reported that high imr measured after primary pci was associated with low left ventricular function at three month follow - up and reduced long - term survival.14 ) furthermore , pepine et al . reported that a limited coronary microvascular response to adenosine is associated with increased risk for major adverse outcomes , even in the absence of significant obstructive coronary artery disease.20 ) in agreement with previous findings , our study showed that the assessment of microvascular function using imr during the invasive procedure can be helpful in the evaluation of acs patients . the low post - pci imr in the high dose atorvastatin group was associated with less myocardial damage , represented by less ck - mb elevation . as expected , there was no difference in ffr between the two groups ; however , there was also no difference in cfr and pw / pa between the two groups in our study , in contrast to imr . previous randomized controlled trials demonstrated that pretreatment with atorvastatin can reduce pci induced myocardial damage,4)5 ) while a recent study by jang et al.6 ) showed that a high loading dose of atorvastatin did not translate into clinical benefit over the usual atorvastatin administration ( 40 mg / day ) in patients with nste - acs . when we compared the incidence of post - pci myocardial infarction defined as ck - mb>3 times the upper limit of normal , there was no significant difference between the two groups . however , we conducted this randomized trial focused on coronary microvascular function after pci and showed the beneficial effect of high - dose atorvastatin loading on preventing microvascular dysfunction in patients with nste - acs . despite the significant difference of post - pci imr between the two groups , post - pci cfr , and pw values were comparable . this may be due to cfr being influenced by various hemodynamic conditions and that pw value is less sensitive to the changes of microvascular status than imr . suggested pathophysiology of peri - procedural myocardial injury includes embolism of atheromatous and thrombotic debris , platelet activation and thrombosis , neurohormonal activation and modulation of vascular and myocardial functions , oxidative stress and inflammation.21)22 ) atorvastatin is the most widely used 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor . in addition to beneficial lipid modulation effects , its benefits in acs begin early , suggesting its pleiotropic effects,23)24 ) such as improving or restoring endothelial function , enhancing the stability of atherosclerotic plaques , and decreasing oxidative stress and vascular inflammation.25 ) it has been demonstrated that increased myocardial crp levels are associated with endothelial toxicity and reduced cardiac microvessel density in cardiovascular disease specimens.26 ) previous studies have demonstrated that an inflammatory status with increased crp levels at the time of pci may increase subsequent clinical events or myocardial damage.27)28 ) post - pci crp levels in the high dose loading group were significantly lower than in the low dose group in our study , supporting the anti - inflammatory actions of atorvastatin seen in previous studies.29)30 ) as there was no difference in baseline clinical characteristics and crp levels between the high and low dose groups , the difference in post - pci crp levels likely result from the effects of the study drug . first , this study was not a blinded study , with a relatively small study population . second , the criterion for microcirculatory impairment used in this study was defined based on previous studies and there is no conclusive evidence on the cut - off value of microvascular impairment . however , previous studies in asymptomatic , normal control subjects have found that the normal imr is < 25.14)15)16 ) third , pre - pci measurements of imr , cfr and wedge pressure were not mandatory and the comparison of these parameters between pre- and post - pci was not available in all patients . finally , we could not assess the association between post - pci microcirculatory impairment and adverse clinical outcomes due to limited sample size . pre - treatment with high dose atorvastatin reduces microvascular dysfunction verified by post pci imr and exerts an anti - inflammatory effect during pci in patients with nste - acs . first , this study was not a blinded study , with a relatively small study population . second , the criterion for microcirculatory impairment used in this study was defined based on previous studies and there is no conclusive evidence on the cut - off value of microvascular impairment . however , previous studies in asymptomatic , normal control subjects have found that the normal imr is < 25.14)15)16 ) third , pre - pci measurements of imr , cfr and wedge pressure were not mandatory and the comparison of these parameters between pre- and post - pci was not available in all patients . finally , we could not assess the association between post - pci microcirculatory impairment and adverse clinical outcomes due to limited sample size . pre - treatment with high dose atorvastatin reduces microvascular dysfunction verified by post pci imr and exerts an anti - inflammatory effect during pci in patients with nste - acs .
background and objectivesthere is controversy surrounding whether or not high dose statin administration before percutaneous coronary intervention ( pci ) decreases peri - procedural microvascular injury . 
 we performed a prospective randomized study to investigate the mechanisms and effects of pre - treatment high dose atorvastatin on myocardial damage in patients with non - st - segment elevation acute coronary syndrome ( nste - acs ) undergoing pci.subjects and methodsseventy seven patients with nste - acs were randomly assigned to either the high dose group ( atorvastatin 80 mg loading 12 to 24 h before pci with a further 40 mg loading 2 h before pci , n=39 ) or low dose group ( atorvastatin 10 mg administration 12 to 24 h before pci , n=38 ) . 
 index of microcirculatory resistance ( imr ) was measured after stent implantation . 
 creatine kinase - myocardial band ( ck - mb ) and high sensitivity c - reactive protein ( crp ) levels were measured before and after pci.resultsthe baseline characteristics were not different between the two patient groups . 
 compared to the low dose group , the high dose group had lower post pci imr ( 14.15.0 vs. 19.29.3 u , p=0.003 ) . 
 post pci ck - mb was also lower in the high dose group ( median : 1.40 ng / ml ( interquartile range [ iqr : 0.75 to 3.45 ] vs. 4.00 [ iqr : 1.70 to 7.37 ] , p=0.002 ) as was the post - pci crp level ( 0.09 mg / dl [ iqr : 0.04 to 0.16 ] vs. 0.22 [ iqr : 0.08 to 0.60 ] , p=0.001).conclusionpre - treatment with high dose atorvastatin reduces peri - pci microvascular dysfunction verified by post - pci imr and exerts an immediate anti - inflammatory effect in patients with nste - acs .