Session Speaker

Thrombopoietin is a Novel Cardioprotective Agent: Proof of Concept Studies in Animal and Human Hearts
John E. Baker
USA

Ischemic heart disease is the principle underlying cause of most acute myocardial infarctions, congestive heart failure, arrhythmias, and sudden cardiac death. Protection of the heart against injury from ischemia/reperfusion remains a challenge and a high priority for the cardiologist and cardiac surgeon. There are no current therapies that have been proven to directly protect the heart against the deleterious effects of ischemia and reperfusion in humans. Recent studies have shown that erythropoietin, a cytokine used to stimulate red blood cell production, protects the heart against ischemia/reperfusion injury by a mechanism that involves activation of pro-survival kinases and ATP-dependent potassium channels. Thrombopoietin (TPO), another cytokine, is the primary physiological regulator of megakaryocyte and platelet development exerting its action through the TPO receptor, c-mpl. However, it is currently unknown whether TPO plays a physiological function in the myocardium. We hypothesized that TPO would protect the heart against injury caused by ischemia/reperfusion by decreasing infarct size and enhancing recovery of ventricular function after ischemia. Our objective was to demonstrate the cardioprotective properties of human TPO in human and rat cardiac myocyte models of ischemia/reperfusion.

In human studies of ischemia/reperfusion, TPO decreased necrosis and apoptosis in isolated human cardiomyocytes maintained in culture media when treated with TPO (1-2 ng/ml) for 30 minutes prior to 4 hours hypoxia and 30 minutes reoxygenation. Protection by TPO was blocked by the ATP-dependent potassium channel antagonist glibenclamide.

In rat studies of preservation of the donor heart for transplantation, TPO (0.05 μg/kg i.v.) reduced infarct size and enzyme leakage, and increased developed pressure and coronary flow rate during reperfusion in hearts treated with TPO for 30, 45 and 60 minutes before heart excision and 18 hours cold storage with University of Wisconsin organ preservation solution. In addition, a TPO mimetic (14-amino acid peptide IEGPTLRQWLAARA) decreased post-ischemic infarct size in a “U”-shaped dose-response manner in a rat model of 30 minutes regional ischemia/2 hours reperfusion. The dose of the TPO mimetic that resulted in the maximal reduction in infarct size was 0.05 μg/kg i.v.

We conclude that a single treatment with TPO exerts an immediate protective effect against injury from myocardial ischemia/reperfusion in human and rat as manifested by a reduction in necrosis and apoptosis. TPO may have utility as a novel cardioprotective agent.