Background Experimental evidence suggests that cyclosporine,which inhibits the opening of mitochondrial permeability-transitionpores, attenuates lethal myocardial injury that occurs at thetime of reperfusion. In this pilot trial, we sought to determinewhether the administration of cyclosporine at the time of percutaneouscoronary intervention (PCI) would limit the size of the infarctduring acute myocardial infarction.
Methods We randomly assigned 58 patients who presented withacute ST-elevation myocardial infarction to receive either anintravenous bolus of 2.5 mg of cyclosporine per kilogram ofbody weight (cyclosporine group) or normal saline (control group)immediately before undergoing PCI. Infarct size was assessedin all patients by measuring the release of creatine kinaseand troponin I and in a subgroup of 27 patients by performingmagnetic resonance imaging (MRI) on day 5 after infarction.
Results The cyclosporine and control groups were similar withrespect to ischemia time, the size of the area at risk, andthe ejection fraction before PCI. The release of creatine kinasewas significantly reduced in the cyclosporine group as comparedwith the control group (P=0.04). The release of troponin I wasnot significantly reduced (P=0.15). On day 5, the absolute massof the area of hyperenhancement (i.e., infarcted tissue) onMRI was significantly reduced in the cyclosporine group as comparedwith the control group, with a median of 37 g (interquartilerange, 21 to 51) versus 46 g (interquartile range, 20 to 65;P=0.04). No adverse effects of cyclosporine administration weredetected.
Conclusions In our small, pilot trial, administration of cyclosporineat the time of reperfusion was associated with a smaller infarctby some measures than that seen with placebo. These data arepreliminary and require confirmation in a larger clinical trial.
Myocardial infarction is a disabling disease that is commonin the United States, with more than 1.5 million new cases diagnosedeach year.1,2 Infarct size is a major determinant of mortalityin myocardial infarction.3,4 Limitation of infarct size hastherefore been an important objective of strategies to improveoutcomes. Currently, the most effective way to limit infarctsize is to reperfuse the jeopardized myocardium as soon as possiblewith the use of coronary angioplasty or thrombolysis and toprevent reocclusion of the coronary artery with the use of antiplatelettherapy.
Although reperfusion is undoubtedly beneficial, it has detrimentaleffects, including myocardial stunning, ventricular arrhythmias,and microvascular dysfunction.5,6,7 Accumulating evidence suggeststhat reperfusion may also cause irreversible myocardial injury,possibly through a form of mitochondrial dysfunction that hasbeen designated permeability transition.8,9,10,11,12 The openingof a nonspecific high-conductance channel (called the mitochondrialpermeability-transition pore) in the inner mitochondrial membraneresults in the collapse of the membrane potential, the uncouplingof the respiratory chain, the efflux of cytochrome c and otherproapoptotic factors, and the hydrolysis rather than synthesisof ATP; these metabolic alterations may lead to cardiomyocytedeath.13,14 Calcium overload and excessive production of reactiveoxygen species in the early minutes of reflow trigger the openingof the mitochondrial permeability-transition pore.10,12,14 Griffithsand Halestrap found that in the isolated rat heart, the permeability-transitionpore remains closed during ischemia but opens at the time ofreperfusion.15
In addition to its well-known immunosuppressive properties,cyclosporine is a potent inhibitor of mitochondrial permeabilitytransition, and several reports indicate that it can limit ischemia–reperfusioninjury under experimental conditions.8,15,16,17,18,19,20,21The objective of the present study was to determine whetherthe administration of cyclosporine at the onset of reperfusionreduces the infarct size in patients with ongoing acute myocardialinfarction.
Methods
Trial
This study was a prospective, multicenter, randomized, single-blind,controlled trial. The trial was designed, the data were collectedand analyzed, and the manuscript was written solely by the authors.Cyclosporine for the trial was purchased with institutionalgrant support; the manufacturer had no role in the study. Thetrial was performed in accordance with the Declaration of Helsinki(revised version, 1996), the European Guidelines for Good ClinicalPractice (version 11, July 1990), and French laws. In accordancewith French law, the study protocol was approved by the ethicscommittee of the institution of the principal investigator (Dr.Ovize) acting on behalf of all the institutions involved inthis trial. All subjects gave written informed consent beforebeing included in the study.
Study Population
Men and women, 18 years of age or older, who presented within12 hours after the onset of chest pain, who had ST-segment elevationof more than 0.1 mV in two contiguous leads, and for whom theclinical decision was made to treat with percutaneous coronaryintervention (PCI) were eligible for enrollment. Patients wereeligible for the study whether they were undergoing primaryPCI or rescue PCI. Occlusion of the culprit coronary artery(Thrombolysis in Myocardial Infarction [TIMI] flow grade 0)at the time of admission was also a criterion for inclusion.22
Patients with cardiac arrest, ventricular fibrillation, cardiogenicshock, stent thrombosis, previous acute myocardial infarction,or angina within 48 hours before infarction were not includedin the study. Patients with occlusion of the left main or leftcircumflex coronary artery or with evidence of coronary collateralsto the region at risk on initial coronary angiography (at thetime of admission) were excluded.23 Patients with known hypersensitivityto cyclosporine, known renal failure or a serum creatinine levelof 120 µmol per liter (1.36 mg per deciliter) or moreat admission, liver failure, or uncontrolled hypertension andwomen who were pregnant or who were of childbearing age andwere not using contraception were not included. Finally, patientswho had any disorder that is associated with immunologic dysfunction(e.g., cancer, lymphoma, a positive serologic test for the humanimmunodeficiency virus, or hepatitis) more recently than 6 monthsbefore presentation were excluded.
Angiography and PCI
Left ventricular and coronary angiography was performed withthe use of standard techniques, just before revascularization.The size of the area at risk, a major determinant of infarctsize,24 was estimated for each patient by measuring the circumferentialextent of abnormally contracting segments, according to themethod of Feild et al.25 Revascularization was performed withthe use of direct stenting.26
Experimental Protocol
After coronary angiography was performed but before the stentwas implanted, patients who met the enrollment criteria wererandomly assigned to either the control group or the cyclosporinegroup. Randomization was performed with the use of a computer-generatedrandomization sequence. Numbered, sealed envelopes that containedthe study group assignment were distributed to each catheterizationlaboratory and were opened after informed consent had been obtained.
Less than 10 minutes before direct stenting, the patients inthe cyclosporine group received an intravenous bolus injectionof 2.5 mg of cyclosporine (Sandimmune, Novartis) per kilogramof body weight. Cyclosporine was dissolved in normal saline(final concentration, 25 mg per milliliter) and was injectedthrough a catheter that was positioned within an antecubitalvein. The patients in the control group received an equivalentvolume of normal saline. The dose of cyclosporine was chosenarbitrarily, based on experimental data of Argaud et al.,17,27as well as on our experience in the treatment of heart-transplantrecipients, for whom this dose would be a typical loading dose.
Infarct Size
The primary end point was the size of the infarct as assessedby measurements of cardiac biomarkers. Blood samples were obtainedat admission and repeatedly over the next 3 days. The area underthe curve (AUC) (expressed in arbitrary units) for creatinekinase and troponin I release (Beckman kit) was measured ineach patient by computerized planimetry (Image J1.32j).26,28,29
The principal secondary end point was the size of the infarctas measured by the area of delayed hyperenhancement that wasseen on cardiac magnetic resonance imaging (MRI), assessed onday 5 after infarction.30,31,32,33 Because MRI facilities wereavailable in only one of the three study centers, this estimationof infarct size could be performed in only a subgroup of patients.Imaging was performed on a 1.5-T whole-body MRI scanner (MagnetomAvanto, Siemens). For the late-enhancement analysis, 0.2 mmolof gadolinium–tetrazacyclododecanetetraacetic acid (DOTA)per kilogram was injected at a rate of 4 ml per second and wasflushed with 15 ml of saline. Delayed hyperenhancement was evaluated10 minutes after the injection of gadolinium–DOTA withthe use of a three-dimensional inversion-recovery gradient–echosequence. The images were analyzed in short-axis slices coveringthe entire left ventricle. Myocardial infarction was identifiedby delayed hyperenhancement within the myocardium, defined quantitativelyby an intensity of the myocardial postcontrast signal that wasmore than 2 SD above that in a reference region of remote, noninfarctedmyocardium within the same slice. For all slices, the absolutemass of the infarcted area was calculated according to the followingformula: infarct mass (in grams of tissue)= (hyperenhanced area[in square centimeters])xslice thickness (in centimeters)xmyocardialspecific density (1.05 g per cubic centimeter).
Other End Points
The whole-blood concentration of cyclosporine was measured at1 and 20 minutes and at 3 and 12 hours after injection withthe use of a radioimmunoassay kit (DiaSorin). Blood pressureand serum concentrations of creatinine and potassium were measuredon admission and 24, 48, and 72 hours after PCI. Serum concentrationsof bilirubin, -glutamyltransferase, and alkaline phosphatase,as well as white-cell counts, were measured on admission and24 hours after PCI.
We recorded the cumulative incidence of major adverse eventsthat occurred within the first 48 hours after reperfusion, includingdeath, heart failure, acute myocardial infarction, stroke, recurrentischemia, the need for repeat revascularization, renal or hepaticinsufficiency, vascular complications, and bleeding. We alsospecifically assessed infarct-related adverse events, includingheart failure and ventricular fibrillation. In addition, 3 monthsafter acute myocardial infarction, cardiac events were recorded,and global left ventricular function was assessed by echocardiography(Vivid 7 systems; GE Vingmed).
Statistical Analysis
To calculate the target sample size for the present trial, weused the available database of the study of myocardial postconditioningby Staat et al.26 We hypothesized that cyclosporine would reducethe AUC for creatine kinase release by 30%. For a statisticalpower of 80% and a probability of a type I error of 0.05 usinga two-sided test, we calculated that the sample size shouldbe 62 subjects (31 per group).
All analyses were performed by independent experts who wereunaware of the treatment-group assignments. Between-group comparisonsof AUCs for serum creatine kinase or troponin I release, thetime of ischemia, the area at risk, and the infarct size asassessed by MRI were performed with the use of the Wilcoxonrank-sum test. We performed an analysis of covariance to testfor equality of the slopes of the regression of infarct sizeon the area at risk in the cyclosporine and control groups.A comparison of the incidence of cumulative adverse clinicalevents between the groups was performed by means of Fisher'sexact test. All values are expressed as medians and interquartileranges. All reported P values are two-sided.
Results
Characteristics of the Study Population
From July 2005 to October 2006, a total of 340 patients werehospitalized at the three study centers for management of acutemyocardial infarction; 230 of these patients underwent PCI.Among these 230 patients, 24 were not evaluated for enrollmentbecause study personnel were not available. Another 148 wereevaluated and excluded for the following reasons: onset of chestpain more than 12 hours before presentation (20 patients), preadmissionventricular fibrillation (3), cardiac arrest before PCI (14),occlusion of the left main or circumflex coronary artery (27),stent thrombosis (16), previous myocardial infarction in thesame territory (12), TIMI flow grade of more than 0 at admission(49), or evidence of coronary collaterals on initial angiography(7). Data are thus presented for 58 patients (28 in the controlgroup and 30 in the cyclosporine group).
There was no significant difference between the two groups withrespect to baseline characteristics (Table 1). The mean ageof the trial participants was 58 years, and almost 80% weremen. The two study groups were similar with respect to ischemiatime, the size of the area at risk, and the ejection fractionbefore PCI. Thrombolytic therapy before PCI failed in 13 patients(8 in the control group and 5 in the cyclosporine group).
Table 1. Baseline Characteristics of the Study Population.
Stenting of the culprit lesion was performed in all patients(Table 1). No patient underwent PCI on arteries other than theinfarct-related artery. In four patients, TIMI 2 flow was notachieved after PCI.
Infarct Size
The AUC for serum creatine kinase release after reperfusionwas significantly reduced in the cyclosporine group as comparedwith the control group, with a median of 138,053 arbitrary units(interquartile range, 114,008 to 283,461) in the cyclosporinegroup versus 247,930 (interquartile range, 145,639 to 404,349)in the control group (P=0.04 for the difference), which representsa reduction in infarct size of approximately 40% (Figure 1A).The median AUC for troponin I release was 112,312 arbitraryunits (interquartile range, 48,680 to 153,956) in the cyclosporinegroup and 129,320 arbitrary units (interquartile range, 65,019to 224,116) in the control group. This difference was not significant(P=0.15) (Figure 1B).
Figure 1. Assessment of Infarct Size by Biomarker Measurement.
Serum creatine kinase was measured every 4 hours on day 1 and every 6 hours on days 2 and 3 after coronary reperfusion. Curves for the control and cyclosporine groups are shown in Panel A. Cyclosporine administration (Adm.) resulted in a significant reduction in infarct size of approximately 40% as measured by creatine kinase release. Serum troponin I was measured every 4 hours on day 1 and every 6 hours on days 2 and 3 after coronary reperfusion. Curves for the control and cyclosporine groups are shown in Panel B. Cyclosporine administration did not result in a significant reduction in infarct size as measured by troponin I release. T bars denote standard errors.
In the control group, there was a significant correlation betweenthe AUC for serum creatine kinase release and the original areaat risk (as defined by the circumferential extent of abnormallycontracting segments on initial left ventricular angiography).As shown in Figure 2A, the regression line for the cyclosporinegroup had a smaller slope than the regression line for the controlgroup, indicating that for any given size of area at risk, smallerinfarcts developed in the cyclosporine-treated patients. Thisdifference in the slope was significant by analysis of covariance(P=0.006). An analysis of the data for troponin I provided similarresults, including a significant correlation between the AUCfor troponin I release and the area at risk, with a smallerslope of the regression line for the cyclosporine group thanfor the control group (P=0.002 by analysis of covariance) (Figure 2B).
Figure 2. Infarct Size as a Function of the Area at Risk.
The area under the curve (AUC) for serum creatine kinase release was expressed as a function of the circumferential extent of abnormally contracting segments (ACS), an estimate of the area at risk, as shown in Panel A. There was a significant correlation between the two variables in the control group (r2=0.60). Data points for the cyclosporine group (r2=0.34) lie below the regression line for the control group. These data indicate that, for any given area at risk, cyclosporine administration was associated with a reduction in the resulting infarct size as measured by creatine kinase release. This difference was significant by analysis of covariance (P=0.006). There was also a significant correlation between the AUC for troponin I release and the area at risk in the control group (r2=0.54), as shown in Panel B. Data points for the cyclosporine group (r2=0.26) lie below the regression line for the control group. These data indicate that, for any given area at risk, cyclosporine administration was associated with a reduction in the resulting infarct size as measured by troponin I release. This difference was confirmed to be significant by analysis of covariance (P=0.002).
In a subgroup of 27 patients, the absolute mass of the areaof hyperenhancement on MRI was significantly reduced in thecyclosporine group as compared with the control group, witha median of 37 g (interquartile range, 21 to 51) versus 46 g(interquartile range, 20 to 65; P=0.04) (Figure 3). This 20%reduction in the area of hyperenhancement on MRI correspondedto the 26% and 36% reductions in AUCs for creatine kinase andtroponin I release, respectively, that were observed in thissubgroup of patients (baseline characteristics of the subgroupcan be found in the Supplementary Appendix, available with thefull text of this article at www.nejm.org).
Figure 3. Assessment of Infarct Size by Magnetic Resonance Imaging (MRI).
The size of the area of late hyperenhancement on MRI is presented for 11 patients in the control group (black circles) and 16 patients in the cyclosporine group (white circles). The mean infarct size as assessed by MRI was significantly greater in the control group (black square) than in the cyclosporine group (white square). The size of the area of late hyperenhancement was calculated with the use of the following formula: infarct mass (in grams of tissue)= (hyperenhanced area [in square centimeters])xslice thickness (in centimeters)xmyocardial specific density (1.05 g per cubic centimeter). P=0.04 for the comparison with the control group.
Other End Points
The whole-blood concentration of cyclosporine reached a peaklevel (mean ±SE, 6272±714 ng per milliliter) 1minute after injection (Figure 4). None of the treated patientshad any clinical symptoms after the administration of cyclosporine.There were no significant changes in blood pressure; in serumconcentrations of creatinine, potassium, bilirubin, -glutamyl-transpeptidase,or alkaline phosphatase; or in the white-cell count.
Figure 4. Blood Concentration of Cyclosporine during Reperfusion.
The whole-blood concentration of cyclosporine is shown at various times during early reperfusion. T bars denote standard errors.
During the first 48 hours after reperfusion, seven adverse clinicalevents were recorded in the control group: one episode of ventricularfibrillation and six episodes of heart failure. There were threeadverse clinical events in the cyclosporine group: one episodeof ventricular fibrillation, one episode of heart failure, andone episode of recurrent ischemia (P=0.11). When only infarct-relatedevents were considered (i.e., ventricular fibrillation and heartfailure), seven events were observed in the control group versustwo in the cyclosporine group (P=0.05).
Three months after infarction, three patients in the controlgroup and one in the cyclosporine group required rehospitalizationfor heart failure (P=0.28). These four patients were among thosewho had had heart failure within the first 2 days after acutemyocardial infarction. There were no other adverse events duringthe interval from 48 hours to 3 months. At 3 months, the meanleft ventricular ejection fraction as measured by echocardiographywas 47±3% in the control group and 50±2% in thecyclosporine group (P=0.32).
Discussion
In our small, proof-of-concept trial, the administration ofcyclosporine in patients with acute myocardial infarction atthe time of reperfusion was associated with a smaller infarctsize, as assessed by some measures, than that seen with placebo.Infarct size was assessed both by measuring the release of thecardiac biomarkers creatine kinase and troponin I and by measuringthe area of late hyperenhancement of the reperfused myocardiumon MRI on day 5. The AUC for the creatine kinase concentrationsuggests that the administration of cyclosporine was associatedwith a reduction in infarct size of approximately 40%. Thisfinding was confirmed by a significant reduction in the areaof late hyperenhancement on MRI in the cyclosporine-treatedpatients. However, the AUC for the troponin I concentrationdid not differ significantly between the two groups.
We investigated these observations further by comparing theinfarct size, as measured by the release of cardiac biomarkers,with the size of the area at risk, as determined by left ventricularangiography. The slope of this relationship was not as steepin the cyclosporine group as in the control group, regardlessof whether measurements of creatine kinase or of troponin Iwere used to assess infarct size.
The fact that cyclosporine reduced the infarct size, as estimatedby the release of creatine kinase, when administered at thetime of reperfusion suggests that lethal reperfusion injuryoccurs in humans.23,34,35 This observation supports the argumentthat reperfusion necrosis is a major component of infarct sizeafter prolonged ischemia and reperfusion and raises the possibilitythat lethal reperfusion injury may be an important new pharmacologictarget for the treatment of patients with ongoing acute myocardialinfarction.26,34
The rationale for evaluating the ability of cyclosporine toreduce infarct size in patients with ongoing acute myocardialinfarction was based on experimental evidence that indicateda crucial role of the opening of the mitochondrial permeability-transitionpore in lethal reperfusion injury.9,10,14,17,18,19,20 Underphysiologic conditions, the inner mitochondrial membrane isimpermeable to almost all metabolites and ions, and the permeability-transitionpore is in a closed conformation.9,10,12,36,37 At the time ofreperfusion after prolonged ischemia, abrupt matrix accumulationof calcium and overproduction of reactive oxygen species triggerthe opening of the pore.14,15,38 The resulting collapse of themembrane potential, uncoupling of the respiratory chain, effluxof proapoptotic factors, and hydrolysis of ATP may ultimatelycause irreversible damage.
Cyclosporine probably inhibits the mitochondrial permeabilitytransition by preventing the calcium-induced interaction ofcyclophilin D with a pore component.14,39 Whether the reductionin infarct size that we observed by some measures in the presentstudy is related to this mechanism is uncertain, since cyclosporineis not specific for mitochondrial cyclophilin D but has otherintracellular effects as well.40,41,42 However, data from invivo studies further support the hypothesis that specific inhibitionof the opening of the permeability-transition pore may reduceinfarct size. NIM811, a nonimmunosuppressive derivative of cyclosporinethat also binds to the matrix cyclophilin D, significantly reducedinfarct size when administered at the time of reperfusion ina rabbit model.43 Moreover, mice that lack cyclophilin D havean enhanced capacity to retain mitochondrial calcium and a delayedopening of the transition pore when calcium overload is present,and they have smaller infarcts after prolonged ischemia andreperfusion.44,45 The reduction in infarct size that was observedin the present study was similar to that seen with the use ofischemic postconditioning by means of angioplasty in patientswith ongoing acute myocardial infarction, as described by Staatet al.26 Postconditioning, in which an angioplasty balloon isinflated repeatedly in the infarct-related artery after reperfusionhas been achieved, is also believed to reduce the extent ofreperfusion injury by inhibiting the opening of the permeability-transitionpore.16,17
Cyclosporine is widely used as an immunosuppressive agent forthe prevention of acute allograft rejection. Long-term use ofcyclosporine has several potentially detrimental effects, includingrenal and hepatic toxicity and increased susceptibility to infectionsand cancers. In the present study, cyclosporine was administeredas a single intravenous bolus. Although we cannot exclude thepossibility of delayed toxicity, there was no evidence of acuterenal or hepatic injury, hypertension, or other short-term adverseeffects.
In summary, we evaluated the effect of cyclosporine in a smallpilot study of patients with acute myocardial infarction whowere undergoing PCI. The administration of cyclosporine at thetime of reperfusion was associated with a reduction in infarctsize as measured by the release of creatine kinase and delayedhyperenhancement on MRI. Release of troponin I, however, wasnot significantly reduced by the administration of cyclosporine.These data are preliminary and require confirmation in a largerclinical trial.
Supported by a Programme Hospitalier de Recherche Clinique 2004grant from the French government.
Dr. Ovize reports serving as a consultant to Novartis. No otherpotential conflict of interest relevant to this article wasreported.
We thank Valerie Prost and Alice Dubois for their excellenttechnical assistance in data monitoring.
Source Information
From Hôpital Arnaud de Villeneuve, Montpellier (C.P., T.T.C., C.M., F.R., C.S., G.G.); Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon (P.C., P.S., H.T., G.R., N.M., E.B., D.A., G.F., X.A.-F., D.R., G.K., G.D., M.O.); Service de Cardiologie, Mulhouse (R.E., J.-P.M.); and INSERM Unité 886, Lyon (H.T., G.R., D.A., G.F., G.D., M.O.) — all in France.
Address reprint requests to Dr. Ovize at Hôpital L. Pradel, Hospices Civils de Lyon, 59, Blvd. Pinel, 69394 Lyon CEDEX 03, France, or at ovize{at}sante.univ-lyon1.fr.
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Cyclosporine in Acute Myocardial Infarction
Theruvath T. P., Lemasters J. J., Rossi J. S., Simpson R. J. Jr., Hoffman I., Ibanez B., Badimon J. J., Ryding A. D., Piot C., Bonnefoy-Cudraz E., Ovize M.
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N Engl J Med 2008;
359:2286-2289, Nov 20, 2008.
Correspondence
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(hyperenhanced area [in square centimeters])xslice thickness (in centimeters)xmyocardial specific density (1.05 g per cubic centimeter). 
-glutamyltransferase, and alkaline phosphatase, as well as white-cell counts, were measured on admission and 24 hours after PCI. 
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