Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

Pharmacological approaches to reperfusion therapy.

Despite the fact that numerous clinical trials investigating infarct size have been completed over the last two to three decades, the methods for treating lethal reperfusion injury efficiently have only become established very recently. After several years of accumulating evidence in experimental preparations that lethal reperfusion injury might exist, the description of the phenomenon of ischaemic post-conditioning in animal models has fully convinced us of the existence and importance of irreversible myocardial damage occurring after reflow. Transfer to the clinics was possible in small phase II trials, provided care was taken to assess the determinants of infarct size and, most importantly, to consider the timing of drug administration with respect to the time of reflow. Technical questions remain to be resolved regarding the assessment of the area at risk in the difficult setting of emergency care for reperfusion therapy. Nevertheless, convincing pharmacological trials are being performed that mark the start of a new era that will, in the future, improve the prognosis of patients with ST-segment elevation myocardial infarction through the prevention of lethal myocardial reperfusion injury. At present, while erythropoietin and adenosine have not proved efficient for alleviation of lethal reperfusion injury, a significant benefit has been reported for cyclosporin and exenatide. New pharmacological agents need to be identified and tested in phase II trials. In the meantime, clinical outcome studies are currently being conducted for cyclosporin.

Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: This study aimed to determine whether post-conditioning at the time of percutaneous coronary intervention could reduce reperfusion-induced myocardial edema in patients with acute ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Myocardial edema is a reperfusion injury with potentially severe consequences. Post-conditioning is a cardioprotective therapy that reduces infarct size after reperfusion, but no previous studies have analyzed the impact of this strategy on reperfusion-induced myocardial edema in humans. METHODS: Fifty patients with STEMI were randomly assigned to either a control or post-conditioned group. Cardiac magnetic resonance imaging was performed within 48 to 72 h after admission. Myocardial edema was measured by T2-weighted sequences, and infarct size was determined by late gadolinium enhancement sequences and creatine kinase release. RESULTS: The post-conditioned and control groups were similar with respect to ischemia time, the size of the area at risk, and the ejection fraction before percutaneous coronary intervention. As expected, post-conditioning was associated with smaller infarct size (13 ± 7 g/m(2) vs. 21 ± 14 g/m(2); p = 0.01) and creatine kinase peak serum level (median [interquartile range]: 1,695 [1,118 to 3,692] IU/l vs. 3,505 [2,307 to 4,929] IU/l; p = 0.003). At reperfusion, the extent of myocardial edema was significantly reduced in the post-conditioned group as compared with the control group (23 ± 16 g/m(2) vs. 34 ± 18 g/m(2); p = 0.03); the relative increase in T2W signal intensity was also significantly lower (p = 0.02). This protective effect was confirmed after adjustment for the size of the area at risk. CONCLUSIONS: This randomized study demonstrated that post-conditioning reduced infarct size and edema in patients with reperfused STEMI.

Infarct size reduction in patients with STEMI: why we can do it!

Major progress has been made over the last three decades for the treatment of patients with ST elevation myocardial infarction (STEMI). The major objective of this treatment is to reduce infarct size, which is the major prognostic factor in this population. Most of the efforts have been focused on improving reperfusion therapy in order to open as quickly as possible, and to prevent reocclusion, of the culprit coronary artery. During the past years, preclinical research has allowed researchers to well-characterize animal models of acute MI and precisely describe the major determinants of infarct size, that is area at risk, collateral flow, duration of ischemia, and timing of the protective intervention with respect to reflow. Recent reports have clearly demonstrated that lethal reperfusion injury exists, that it is of significant importance, and that it can be prevented by protective interventions applied immediately before reflow. Time has come to, on top of reperfusion therapy, better protect the muscle against lethal reperfusion injury. Although many past infarct size reduction studies have been negative, recent proof-of-concept studies have shown that infarct size reduction is possible in patients with STEMI, at least in part because the major determinants of infarct size have been taken into account. Accumulated knowledge from animal models together with encouraging results obtained in phase II infarct size reduction clinical trials should help us improve the design of future studies aimed at reducing infarct size in patients with STEMI.

Inhibition of mitochondrial permeability transition pore opening: translation to patients.

A large body of experimental evidence indicates that during an acute myocardial infarction (AMI), tissue injury occurring after reperfusion represents a significant amount of the whole, irreversible damage. It is now recognized that mitochondrial permeability transition pore opening plays a crucial role in this specific component of myocardial infarction. Ischaemic postconditioning and cyclosporine A (CsA) have been shown to dramatically reduce infarct size in many animal species. Recent proof-of-concept clinical trials support the idea that lethal myocardial reperfusion injury is also of significant importance in patients with ongoing AMI, and that targeting mitochondrial permeability transition by either percutaneous coronary intervention postconditioning or CsA can reduce infarct size and improve the recovery of contractile function after reperfusion. Large-scale trials are ongoing to address whether these new treatments may improve clinical outcome in reperfused AMI patients.