Is erythropoietin behind maladaptive anemic heart failure?

Abstract

HEART FAILURE (HF) is a major public health problem worldwide. HF is a syndrome arising from multiple causes that will affect one in five adults in their lifetime. Despite the progress that has been made in the treatment of chronic HF, the overall morbidity and mortality remain high (8). Therefore, it is imperative that there is a continued push to more fully understand the molecular mechanisms responsible for this disease to discover and develop novel therapies. Among the multiple characteristics of chronic HF, anemia, defined by the World Health Organization criteria as a hemoglobin (Hb) concentration of Ͻ13 g/dl in adult men and Ͻ12 g/dl in adult women, is found in 30% to 40% of cases and is an independent risk factor for more severe HF (1,2,12,17).When compared with HF patients with normal Hb levels, the presence of anemia is associated with worsened clinical symptoms, more severe systolic and diastolic dysfunction, and a significant increase in mortality in patients with advanced HF (4, 6, 7, 17). Moreover, these patients have higher brain natriuretic peptide levels, increased extracellular and plasma volume, and more rapid deterioration of renal function. It has been shown that chronic untreated anemia can result in increased cardiac output that eventually can lead to ventricular dilation, increased left ventricular (LV) mass, and the development of LV hypertrophy, which represent cardiac remodeling parameters that are strong predictors of morbidity and mortality (12). Understanding how chronic anemia leads to LV remodeling and poorer outcomes in HF is essential to improve how we may treat these large number of patients with HF.Naito and colleagues (12a) report an animal model of chronic anemia that leads initially to an adaptive phase of preserved cardiac function despite LV remodeling followed over time by maladaptation and severe LV dysfunction. The compensatory phase followed by decompensation appears to correlate with the dynamic regulation of serum erythropoietin (EPO) levels and cardiac EPO signaling. This study underscores the significance of cardiac EPO-EPO receptor (EPO-R) signaling as a cardioprotective axis.EPO, a hematopoietic cytokine that is primarily synthesized in kidney peritubular cells in response to hypoxia, has long been used as a clinical treatment for conditions of low Hb. The physiological effects of EPO in hematopoietic cells are mediated through its interaction with its specific cellular receptor, EPO-R, a member of the type I superfamily of single-transmembrane cytokine receptors (3,9). Recently, data have accumulated demonstrating that the EPO-R is present in a variety of other tissues outside the blood, including cardiomyocytes, suggesting the potential roles of EPO signaling beyond hematopoiesis and the treatment of anemia (20). Recombinanthuman EPO administration has been shown to exert a broad tissue-protective effect in a variety of experimental models. In the cardiovascular system, EPO has been shown to exert marked myocardial protective effects against ischemia-reperfusio...

Recombinant Erythropoietin Mitigates Reperfusion Injury in Neonatal Rat Cardiomyocytes by Novel Multiple Signalling Pathways

“…Heart Failure (HF) is a state in which the heart cannot provide sufficient cardiac output to satisfy the metabolic needs of the body. It is a significant wellbeing issue around the world [1]. HF due to myocardial infarction (MI) or ischemia/reperfusion injury (I/R) results in cardiomyocytes loss.…”