Congestive heart failure (CHF) is a rapidly growing public health problem, affecting nearly five million people in the US alone, with nearly half a million new cases annually.The prevalence of CHF is highest in the elderly; ten out of every 1,000 persons over age 65 are affected. Anemia has been considered a modifiable comorbidity in heart failure. Utilizing the World Health Organization (WHO) definition for anemia (hemoglobin <13g/dl in men and <12g/dl in women), the prevalence of anemia in CHF patients has been estimated up to 55% in all cases, and as high as 79% in those with advanced, New York Heart Association (NYHA) class IV CHF. Anemia can be associated with adverse consequences such as left ventricular hypertrophy and dilation, as well as worsening heart failure.
Likewise, renal insufficiency is common in CHF, with as many as 50% of heart failure patients with renal dysfunction. Progressive renal failure leads to a decrease in circulating erythropoietin, which in turn leads to a decrease in bone marrow erythrocyte production and hemoglobin levels. The complex interrelation between CHF, renal insufficiency, and anemia has been termed the cardio-renal-anemia syndrome and will be discussed in this review.
Erythropoietin (EPO), a glycoprotein with a molecular weight of 34,000Da, is produced by the peritubular interstitium of the kidney. By protecting erythroid progenitor cells from apoptosis, EPO enables these stem cell to proliferate and to differentiate into functional erythrocytes. In response to hypoxemia or to a reduction in hematocrit, EPO production is increased. With severe hypoxia, the liver also generates as much as one-third of total EPO body production. Conversely, with inflammatory anemia, EPO gene expression and EPO production are inhibited. The mechanism for this inhibition was recently elucidated; inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor-alfa (TNF-α) inhibit EPO gene expression.
The EPO gene has been mapped to human chromosome 7 (7q21). Recombinant EPO was first used therapeutically in 1987 in patients with anemia secondary to chronic renal insufficiency.
Congestive Heart Failure and Chronic Kidney Disease-associated Anemia
Despite its high prevalence and attendant adverse consequences, CHF-associated anemia may be under-appreciated. Twenty-two per cent of patients in the large Studies of Left Ventricular Dysfunction (SOLVD) trial were anemic; anemia severity was linearly associated with increased mortality.
Similarly, in another prospective trial, Outcome of Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF), hemoglobin levels were independently associated with up to a 12% increased risk of death or hospitalization for every 1g/dl hemoglobin decrement. In addition, anemia was also associated with patient age, renal function, and reduced peak oxygen consumption, even when corrected for ejection fraction.
CHF-associated anemia has a multitude of causes. CHF is a chronic inflammatory disorder with marked elevations of cytokines such as interleukins and TNF-α. These inflammatory cytokines interfere with the production and activity of EPO; furthermore, they may inhibit release of iron from tissue stores. Moreover, volume expansion from the failing heart and its accompanying renal insufficiency can result in hemodilution.
Anemia in CHF may also result from the pharmacological agents used to treat heart failure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the cornerstones of current management. These agents may interfere with erythropoeisis via direct myelosuppression or by EPO receptor-mediated blunting. In hypertensive patients, the use of ACE-I or ARB treatment can result in a hemoglobin decrease as much as 0.3mg/dl. Other potential contributors include blood loss from the gastrointestinal tract as a result of chronic aspirin use and diminished absorption of iron and other nutrients as a result of bowel edema. Finally, decreased EPO production accompanying chronic kidney disease may also contribute to anemia.
Regarding renal insufficiency, sub-optimally controlled CHF results in deterioration in kidney function of about one milliliter per minute per month in glomerular filtration rate (GFR). Activation of both the renin-angiotensin-aldosterone system as well as the sympathetic nervous system in the failing heart seem to play a role in renal function decline. As a result of reduced renal blood flow, the activated neurohumoral cascade is complicated by further vasoconstriction of the renal vasculature with resultant renal ischemia and a decrement in GFR.
Conversely, an elevated serum creatinine is a major independent risk factor for death in heart failure. Uremia is associated with an increased atherosclerotic plaque burden and a consequent high frequency of coronary lesions and coronary events. In fact, the leading cause of mortality in end-stage renal disease (ESRD) patients is from cardiovascular events. The anemia of chronic kidney disease (CKD) will further decompensate the already failing heart.
Anemia is an independent risk factor for worsening renal function, and progressive decline in renal function results in worsening anemia. Circulating EPO levels decrease as renal function declines.
What has been depicted above is a conceptual and clinical model, referred to as the cardio-renal-anemia syndrome. This vicious cycle (see Figure 1) introduced by Silverberg et al. (2002) appears to be a common clinical syndrome. Early recognition and correction of anemia may have favorable consequences and improved outcomes both in CHF and CKD. Untreated anemia, on the other hand, could be the cause of refractory CHF and rapid progression of CKD, regardless of current aggressive interventions.
Role of Growth Factors in the Treatment of CHF-associated Anemia
The introduction of EPO has made a significant impact in anemia treatment. EPO was initially used for the treatment of anemia in patients with ESRD. Subsequently, attention has shifted to its use in CHF-related anemia. Current CHF treatments emphasizing neuro-hormonal blockade have resulted in significant declines in morbidity and mortality. However, correction of CHF-associated anemia may yield additional benefits.
In anemic patients with chronic renal insufficiency treated with EPO, echocardiograms demonstrated regression of left ventricular (LV) mass, and decreases in LV dilatation. In a study of anemic patients with advanced CHF treated with EPO and intravenous (IV) iron (Silverberg et al, 2002), an improvement in hemoglobin (Hb) level was associated with improved left ventricular ejection function (LVEF), amelioration in functional class, and a decreased frequency of hospitalizations. In another single-blind, prospective study (Mancini et al., 2003) correcting anemia with EPO and oral ferrous gluconate, exercise parameters were improved, as reflected by an increase in peak oxygen consumption levels (VO2).
Besides improving anemia, EPO has additional non-erythropoietic benefits. It decreases apoptotic cell death of cardiomyocytes. By recruiting endothelial progenitor cells, it enhances angiogenesis, and hence neovascularization. CHF patients may benefit from the latter because of improvement in coronary and cerebrovascular atherosclerosis-associated ischemia.
EPO may exert anti-inflammatory effects, perhaps by decreasing levels of interleukins and other cytokines. Thus,EPO may prevent the myocardium from accruing additional damage during myocardial infarction (MI). Similarly, EPO receptors have been identified in neuronal tissues and the retina. As shown in animal models, EPO may have protective effects in acute ischemic injury of the central nervous system (CNS) and kidneys.
Similar outcomes have been reported using darbepoietin in the treatment of anemic CHF patients. Preliminary data reported from a randomized, double-blind multicenter study showed darbepoietin alfa-induced Hb increments were associated with an improved quality of life (van Veldhuisen et al., 2006).
Growth Factors Versus Blood Transfusion
Transfusion of red blood cells has become common practice, especially in the treatment of symptomatic anemia or anemia in the face of acute coronary syndromes (ACS).However, transfusions have associated risks including volume expansion, potential infection transmission, transfusion reactions and others. Moreover, transfused blood may be a poor conveyor of oxygen; longer storage periods produce low levels of 2,3 diphospho-glycerate (2,3 DPG), a substance necessary for tissue oxygen extraction.
Conclusion and Future Directions
Even with optimal pharmacologic intervention, CHF continues to be an enormous public health problem. CHF-associated anemia is an important comorbidity that, when treated, may further ameliorate the failing heart; with the use of growth factors, resultant increments in hemoglobin have been associated with improved outcomes in patients with advanced heart failure. Collaboration among primary care physicians, nephrologists and cardiologists may be necessary to properly recognize and to modify this disease. The cost-effectiveness of EPO and darbepoietin, and the role of growth factors in impacting morbidity and mortality, however, remain to be further explored with larger, randomized, double-blind, placebo-controlled studies. In addition, the optimal target levels for Hb have yet to be established.
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