Faculty Bibliography

Background- Iron deficiency has been proposed as a potential therapeutic target in heart failure, but its prevalence and association with anemia and clinical outcomes in community-dwelling adults with heart failure have not been well characterized. Methods and Results- Using data from the Third National Health and Nutrition Examination Survey, we evaluated the associations between iron deficiency, hemoglobin, C-reactive protein (CRP), and all-cause and cardiovascular mortality in 574 adults with self-reported heart failure. Iron deficiency was defined in both absolute and functional terms as a ferritin level <100 mug/L or between 100 and 299 mug/L if the transferrin saturation was <20%. Iron deficiency was present in 61.3% of participants and was associated with reduced mean hemoglobin (13.6 versus 14.2 g/dL, P=0.007) and increased mean CRP (0.95 versus 0.63 mg/dL, P=0.04). Over a median of 6.7 years of follow-up, there were 300 all-cause deaths, 193 of which were from cardiovascular causes. In age- and sex-adjusted Cox proportional hazards models, hemoglobin, CRP, and transferrin saturation but not iron deficiency were significantly associated with all-cause and cardiovascular mortality. In multivariate models, hemoglobin remained an independent predictor of cardiovascular mortality, whereas CRP remained an independent predictor of both all-cause and cardiovascular mortality. Conclusions- Iron deficiency is common in heart failure and is associated with decreased hemoglobin and increased CRP. In multivariate analysis, hemoglobin was associated with cardiovascular mortality while CRP was associated with both all-cause and cardiovascular mortality. Iron deficiency was not associated with all-cause or cardiovascular mortality in this cohort

BACKGROUND: Hemoconcentration has been proposed as a putative biomarker of effective decongestion therapy in heart failure patients. The prevalence and clinical correlates of hemoconcentration in hospitalized patients with acute decompensated heart failure (ADHF) have not been previously described. METHODS AND RESULTS: We retrospectively reviewed paired values of hemoglobin at admission and discharge to identify evidence of hemoconcentration in 295 subjects hospitalized with ADHF and determined the association between hemoconcentration and risk of worsening renal function and survival. Subjects with hemoconcentration (n = 75) received higher diuretic doses and demonstrated greater weight loss during hospitalization when compared with subjects without hemoconcentration (median [IQR] loop diuretic dose 180 (120) versus 160 (150) mg, P = .014; mean +/- SD weight loss 4.0 +/- 3.1 versus 2.2 +/- 3.1 kg, P < .001). In univariate analysis, hemoconcentration was associated with increased risk of worsening renal function (odds ratio 2.34, 95% CI 1.27-4.30, P = .006), but decreased risk of all-cause mortality (hazard ratio 0.53, 95% CI 0.29-0.96, P = .035). In multivariate analysis, hemoconcentration remained independently associated with worsening renal function, but not mortality. CONCLUSIONS: Hemoconcentration is significantly associated with increased diuretic dose, greater weight loss, and increased risk of worsening renal function during hospitalization. Hemoconcentration was significantly associated with mortality in univariate analysis, but not in multivariate analysis

Iron deficiency is a common cause of anemia in otherwise healthy individuals and plays an important role in the development of anemia within the heart failure patient population. Iron-deficient heart failure patients experience worse symptoms and are less exercise tolerant than those without iron deficiency. These symptoms may occur even before clinical anemia is evident. This article reviews studies of the benefits of the use of intravenous iron to treat iron deficiency in anemic and nonanemic heart failure patients and an overview of the physiology and pathophysiology of iron metabolism in chronic heart failure

Iron-deficiency anemia is common in patients with heart failure (HF), but the optimum diagnostic tests to detect iron deficiency and the treatment options to replete iron have not been fully characterized. Recent studies in patients with HF indicate that intravenous iron can rapidly replenish iron stores in patients having iron-deficiency anemia, with resultant increased hemoglobin levels and improved functional capacity. Preliminary data from a subgroup analysis also suggest that supplemental intravenous iron therapy can improve functional capacity even in those subjects without anemia. The mechanisms responsible for this observation are not fully characterized, but may be related to beneficial effects of iron supplementation on mitochondrial respiration in skeletal muscle. The long-term safety of using intravenous iron supplementation in HF populations is not known. Iron is a known pro-oxidant factor that can inhibit nitric oxide signaling and irreversibly injury cells. Increased iron stores are associated with vascular endothelial dysfunction and increased risk of coronary heart disease events. Additional clinical trials are needed to more fully characterize the therapeutic potential and safety of intravenous iron in HF patients

BACKGROUND:Erythropoietin mitigates myocardial damage and improves ventricular performance after experimental ischemic injury. This study assessed safety and efficacy markers relevant to the biological activity of recombinant human erythropoietin (rHuEpo) in patients with acute myocardial infarction (MI). METHODS:We conducted a prospective, placebo-controlled, randomized, double-blind trial to determine the effects of intravenous rHuEpo (200 U/kg daily for 3 consecutive days) on measures of platelet and endothelial cell activation, soluble Fas ligand, and peripheral blood mononuclear cell (PBMC) expression of angiogenesis signaling proteins in 44 subjects with acute MI treated with aspirin and clopidogrel after successful percutaneous coronary intervention. RESULTS:Recombinant human erythropoietin did not alter bleeding time, platelet function assay closure time, von Willebrand factor levels, soluble P-selectin, or soluble Fas ligand levels when compared with placebo. By contrast, rHuEpo significantly increased expression of erythropoietin receptor, vascular endothelial growth factor receptor Flt-1, and phosphorylated phosphatidylinositol 3-kinase in PBMCs when compared with placebo (all Ps < .05). CONCLUSIONS:In acute MI patients treated with aspirin and clopidogrel, short-term administration of rHuEpo did not alter markers of platelet and endothelial cell activation associated with thrombosis, yet did increase expression of angiogenesis signaling proteins in PBMCs when compared with placebo. These data provide preliminary evidence of safety and biologic activity of rHuEpo at this dosing and support continued enrollment in ongoing efficacy trials.