Erythropoietin in heart failure and other cardiovascular diseases: hematopoietic and pleiotropic effects.

Erythropoietin is a hypoxia-induced hormone that is a major regulator of normal erythropoiesis. Over the last decade, the production of recombinant human erythropoietin has revolutionized the treatment of anemia associated with chronic renal failure, and has led to a greater understanding of anemia pathophysiology and to the elucidation of the interactions of erythropoietin, iron, and erythropoiesis. Anemia has been shown to be independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia have expanded considerably the indications of erythropoietin use in various patient populations and are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia. The results of such treatment are promising in a variety of new clinical settings, including anemia associated with congestive heart failure. Furthermore, the erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes and preclinical studies have established erythropoietin to be a pleiotropic cytokine with anti-apoptotic activity and tissue-protective actions in the cardiovascular system, beyond correction of hemoglobin levels. Despite some potential adverse effects, such as hypertension, and the occurrence of erythropoietin resistance, early studies in heart failure patients with anemia suggest that erythropoietin therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Anemia is found in about one-third of all cases of congestive heart failure (CHF). The most likely common cause is chronic renal insufficiency, which is present in about half of all CHF cases. However, anemia can occur in CHF without renal insufficiency and is likely to be due to excessive cytokine production. The anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Long-standing anemia of any cause can cause left ventricular hypertrophy, which can lead to cardiac cell death through apoptosis and worsen CHF. Therefore, a vicious circle, cardio-renal anemia syndrome, is set up wherein CHF causes anemia, and the anemia causes more CHF and both damage the kidneys worsening the anemia and the CHF further and increasing mortality. There is now evidence that early correction of the CHF anemia with subcutaneous erythropoietin and intravenous iron improves shortness of breath and fatigue, cardiac function, renal function and exercise capacity, reducing the need for hospitalization and improving quality of life. In the present review we discuss the data on current clinical use of erythropoietin in cardiovascular disease, with the main focus on the treatment of congestive heart failure, and summarize the advances and progress made in the understanding of the hematopoietic and pleiotropic effects of erythropoietin in the cardiovascular system.