What is the Role of Erythropoietin in Acute Myocardial Infarct? Bridging the Gap Between Experimental Models and Clinical Trials

Abstract

Erythropoietin (EPO) is the main hormone that regulates erythropoiesis. Beyond its well-known hematopoietic action, EPO has diverse cellular effects in non-hematopoietic tissues. It has been shown to inhibit apoptosis by activating pro-survival pathways in the myocardium, to mobilize endothelial progenitor cells and to inhibit migration of inflammatory cells. EPO has also been shown to have potent pro-angiogenic properties. Numerous experimental data support the cardioprotective effects of EPO in animal models of acute myocardial infarct (AMI). However, these findings are not supported by recent clinical trials designed to investigate the safety and efficacy of EPO in patients with AMI. In this article, we begin by providing a comprehensive review of the cardioprotective effects of EPO in experimental animal models and the molecular mechanisms underlying these effects. We then discuss the EPO data obtained through clinical trials. We compare similarities and differences between the animal and human studies as well as between the different clinical studies in terms of sample size and study design including the dose, the route and the timing of administration as well as confounding factors such as comorbidities and concomitant treatments. Finally, we question the gap between the experimental and the translational clinical data and propose further developments to address these discrepancies and clearly evaluate the role of EPO in the clinical setting of MI.

Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

“…It may have deleterious effects that can outweigh its cardioprotective effects. Therefore, the molecular mechanisms of EPO treatment require further elucidation to optimize future therapy regimens [12,13]. …”

Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial

“…In the model of permanent occlusion animals were mostly treated by a single intraperitoneal dose of 3000–5000 IU/kg of body weight erythropoietin immediately after ligation or even before [20, 21]. The best results were achieved when EPO was applied at the time of occlusion.…”

Endogenous erythropoietin, acute kidney injury, and prognosis in patients with acute coronary syndrome

“…Хотя в эксперименталь-ных работах установлена способность ЭПО уменьшать зону ИМ и улучшать функцию левого желудочка [26], к сожалению, в клинических исследованиях не удалось продемонстрировать эффективность ЭПО при лечении больных ОИМ [27], а в крупном исследовании REVEAL наблюдалось ухудшение прогноза при применении ЭПО [28].…”

“…[26] справедливо отме-чают, что разница между положительным эффектом введе-ния ЭПО в эксперименте и отсутствием эффекта от введе-ния ЭПО в клинических исследованиях зависит от многих факторов, в частности от дозы ЭПО. В одном из наших ис-следований [30], в котором мы изучали возможность ЭПО предотвращать ОПП, крысы получали дозу ЭПО, много-кратно превышающую ту, что используется в клинике.…”