Introduction: anemia in heart failure.

During the last two decades, advances in our understanding of the role of neurohormonal activation in the pathogenesis of chronic heart failure have led to rational therapies with a remarkable improvement in survival. In spite of this, the prognosis of heart failure still remains dismal. One of the factors that contribute to worse prognosis in patients with heart failure is the presence of several comorbidities. Over the last few years, anemia has come to be recognized as an important comorbidity that is common in patients with heart failure and is strongly associated with poor clinical status and worse outcomes. Therefore, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. In 2000 Silverberg and his colleagues from Israel were the first to report the effects of erythropoietin treatment on anemic patients with heart failure [1]. This landmark report was responsible for raising worldwide interest in anemia in heart failure, and the potential therapeutic implications of treating anemia. Several small-sized studies have shown beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron [2]. However, little is known about the pathophysiological basis of the remarkable association of anemia with heart failure outcomes [3]. It is unclear whether anemia is just a marker or a mediator of poor outcomes. If anemia is a mediator, there may be potential benefits of correcting anemia. However, the ideal threshold at which therapy should be initiated and the extent of correction considered safe and desirable in the individual patient with heart failure needs to be known. These issues become more important because of increasing safety concerns that recombinant erythropoietin therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease [4], and may worsen cancer in patients receiving chemotherapy to treat various types of cancer [5]. In this special issue of Heart Failure Reviews, seven international experts discuss various aspects of anemia in heart failure. In the first section, I point out that although the reasons for anemia in heart failure may be multifactorial, anemia of chronic disease appears to be the most frequent cause. Therefore, if correction of anemia is important, use of erythropoiesis stimulating agents (ESA) may be the only rational approach that works. Whether anemia worsens heart failure due to reduced LV function is not known. It is clear, however, that chronic severe anemia leads to a vasodilated state, and in patients with normal LV function can cause fluid retention and high output heart failure, through neurohormonal activation, identical to that seen in low output heart failure [6]. In patients with LV dysfunction, increased myocardial workload to compensate for reduced tissue oxygen delivery and volume overload can worsen LV remodeling and contribute to adverse outcomes. I argue, however, that because increase in hemoglobin (by any means) is associated with an elevation in the systemic vascular resistance, it is unlikely that correction of anemia will improve impaired LV function. Therefore, nonhemodynamic mechanisms may play a more important if therapy with ESA to increase hemoglobin is found to be beneficial. Roberto Latini, Michael Brines, and Fabio Fiordaliso examine this exciting area of the nonhemopoietic effects of ESAs and review the studies showing