News:Cyclosporine Reduces Reperfusion Injury and Infarct Size Following Acute Myocardial Infarction
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August 1, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [1]
NEJM-France: A new preliminary French study suggests the beneficial effect of cyclosporine in reducing reperfusion injury and infarct size during PCI following acute myocardial infarction.
Reperfusion injury following acute myocardial infarction can result in detrimental effects such as ventricular arrhythmias, myocardial stunning and microvascular dysfunction. The opening of mitochondrial permeability-transition pore during reperfusion results in various metabolic alterations that ultimately cause cardiac cell death. Cyclosporine is an immunosuppressive drug that is used in the setting of acute allograft rejection. This drug also has been proven to be a potent inhibitor of the mitochondrial permeability.
Piot and colleagues from CEDEX, France explored the use of this drug further in the management of patients with acute myocardial infarction in a multicenter, randomized, single blind, controlled trial. This study consisted of 58 patients who presented within 12 hours of onset of chest pain and had ST segment elevation of >0.1 mV in two contiguous leads. Patients were randomized to receive either intravenous (IV) bolus dose of cyclosporine (n=30) or normal saline (n=28) following coronary angiography. Cyclosporine was administered at a bolus dose of 2.5 mg/kg body weight.
The primary endpoint of this study consisted of infarct size measured by cardiac biomarkers (creatine kinase and troponin I). The secondary endpoint consisted of infarct size measured by the area of delayed hyperenhancement identified on cardiac magnetic resonance imaging 5 days following infarction. The serum levels of cyclosporine were measured at 1 and 20 minutes and at 3 and 12 hours following the injection of the drug.
There was no significant difference in the baseline characteristics between the treatment and placebo groups. The mean age of the study patients was 58 years and 80% of the patients were men. All patients underwent stenting of the culprit arteries and the post procedure TIMI flow grade was 2.7±0.2 in both groups. The area under the curve for serum creatine kinase following reperfusion was significantly reduced in the cyclosporine group compared with the saline group with a 40% reduction in the infarct size with cyclosporine (p=0.04). However, there was no difference in the area under the curve for troponin I release between the two groups (p=0.15).
The MRI results were available in 27 patients. The absolute mass of the area of hyperenhancement (HE) on MRI was significantly reduced in the cyclosporine group compared with the saline group [37 g vs. 46 g (20% reduction in the area of HE), p=0.04] corresponding to 26% and 36% reduction in the area under the curve for creatine kinase and troponin I. There was no significant difference in the adverse events between the two groups during the first 48 hours (p=0.11) and at 3 months (p=0.28) with no adverse events between 48 hours and 3 months. The improvement in the infarct size measured using cardiac biomarkers and MRI did not translate into improved ejection fraction measured on echocardiography at 3 months between the treatment and saline groups (50±2% vs. 47±3%, p=0.32).
Although this trial suggests beneficial effects with the administration of IV cyclosporine in reducing reperfusion injury and infarct size, it has limitations due to the small sample size. Furthermore, the potential adverse effects associated with this drug will need to be taken into consideration. While the concept of treating reperfusion injury by targeting the mitochondrial permeability is interesting and novel, the authors report that “the present data is preliminary and require confirmation in larger clinical trial”.
Sources of Funding
This study was supported by a Programme Hospitalier de Recherche Clinique 2004 grant from the French government.
Source
http://content.nejm.org/cgi/content/short/359/5/473?query=TOC
