Reduction of myocardial damage during acute ischemia

National Institute On Aging

Investigators

Abstract

The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia to elucidate the mechanisms of cellular death in the myocardium and development of the subsequent CHF and to evaluate the potential of different therapeutic modalities. The ultimate goal is to limit the extent of myocardial damage and to prevent or attenuate the development of CHF.[unreadable] Erythropoietin reduses the myocardial ischemic damage.[unreadable] Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic factor with neuroprotective properties. We have demonstrated that the antiapoptotic effects of EPO also resulted in cardioprotection. In experiments in rats we showed that single systemic administration of recombinant human EPO (3000 IU/kg) immediately after permanent ligation of a coronary artery results in 75% reduction of the size of myocardial infarction eight weeks later. During eight weeks after induction of myocardial infarction, left ventricular remodeling and function decline in EPO treated rats was significantly attenuated and statistically was not different from that in sham operated animals. Twenty four hours after ligation of coronary artery the amount of apoptotic myocytes measured in the myocardial risk area (area immediately adjacent to the infarct site) was reduced in half in the EPO treated rats in comparison to untreated animals. In subsequent experiments we established that single intravenous dose of 3000 IU/kg is cardioprotective up to 12 hrs after coronary ligation, but it is losing its cardioprotective properties after 24 hrs. If animals are treated with EPO immediately after coronary ligation, the treatment dose can be reduced up to 150 IU/kg (usual, FDA approved dose for the treatment of anemia) without the lose of effectiveness, however, the therapeutic window in this case is also reduced to 4 hrs. In additional experiments we showed that repeated daily EPO injection do not have any added benefits comparing with a single injection immediately after coronaty ligation.