Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches (original) (raw)
Anand, I. S. Anemia and chronic heart failure implications and treatment options. J. Am. Coll. Cardiol.52, 501–511 (2008). PubMed Google Scholar
Groenveld, H. et al. Anemia and mortality in heart failure patients: a systematic review and meta-analysis. J. Am. Coll. Cardiol.52, 818–827 (2008). PubMed Google Scholar
Tang, Y. D. & Katz, S. D. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment options. Circulation113, 2454–2461 (2006). PubMed Google Scholar
Go, A. S. et al. Hemoglobin level, chronic kidney disease, and the risk of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure Outcomes and Resource Utilization (ANCHOR) Study. Circulation113, 2713–2723 (2006). CASPubMed Google Scholar
Ezekowitz, J. A., McAlister, F. A. & Armstrong, P. W. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new-onset heart failure. Circulation107, 986–994 (2003). Google Scholar
Vrtovec, B. et al. Significance of anemia in patients with advanced heart failure receiving long-term mechanical circulatory support. Eur. J. Heart Fail.11, 1000–1004 (2009). PubMed Google Scholar
Schroten, N. F. et al. High cumulative incidence of cancer in patients with cardio-renal-anaemia syndrome. Eur. J. Heart Fail.12, 855–860 (2010). CASPubMed Google Scholar
Kalra, P. R. et al. Effect of anemia on exercise tolerance in chronic heart failure in men. Am. J. Cardiol.91, 888–891 (2003). PubMed Google Scholar
O'Meara, E. et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation21, 986–994 (2006). Google Scholar
Hogenhuis, J. et al. Anaemia and renal dysfunction are independently associated with BNP and NT-proBNP levels in patients with heart failure. Eur. J. Heart Fail.9, 787–794 (2007). CASPubMed Google Scholar
Sharma, R. et al. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE Trial. Eur. Heart J.25, 1021–1028 (2004). CASPubMed Google Scholar
Mozaffarian, D., Nye, R. & levy, W. C. Anemia predicts mortality in severe heart failure. The Prospective Randomized Amlodipine survival Evaluation. J. Am. Coll. Cardiol.41, 1933–1939 (2003). PubMed Google Scholar
Okonko, D. O. & Anker, S. D. Anemia in chronic heart failure: pathogenetic mechanisms. J. Card. Fail.10, S5–S9 (2004). CASPubMed Google Scholar
McClellan, W. M., Flanders, W. D., Langston, R. D., Jurkovitz, C. & Presley, R. Anemia and renal insufficiency are independent risk factors death among patients with congestive heart failure admitted to community hospitals: a population-based study. J. Am. Soc. Nephrol.13, 1928–1936 (2002). PubMed Google Scholar
Anand, I. S. et al. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive heart failure. Circulation80, 299–305 (1989). CASPubMed Google Scholar
Westenbrink, B. D. et al. Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well. Eur. Heart J.28, 166–171 (2007). CASPubMed Google Scholar
Androne, A. S. et al. Hemodilution is common in patients with advanced heart failure. Circulation107, 226–229 (2003). PubMed Google Scholar
Van der Meer, P. et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline partially explain the occurrence of anemia in heart failure. Circulation112, 1743–1747 (2005). CASPubMed Google Scholar
Anand, I. S. et al. Anemia and change in haemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from Val-HeFT Circulation112, 1121–1127 (2005). CASPubMed Google Scholar
Komajda, M. et al. The impact of new onset anemia on morbidity and mortality in chronic heart failure: results from COMET. Eur. Heart J.27, 1440–1446 (2006). PubMed Google Scholar
Von Haehling, S. et al. Anaemia among patients with heart failure and preserved or reduced ejection fraction: results from the SENIORS Study. Eur. J. Heart Fail.13, 656–663 (2011). PubMed Google Scholar
Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med.352, 1011–1023 (2005). CASPubMed Google Scholar
Westenbrink, B. D. et al. Bone marrow dysfunction in chronic heart failure patients. Eur. J. Heart Fail.12, 676–684 (2010). CASPubMed Google Scholar
Kissel, C. K. et al. Selective functional exhaustion of haematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J. Am. Coll. Cardiol.49, 2341–2349 (2007). PubMed Google Scholar
Okonko, D. O. et al. Association of deranged adrenal steroid metabolism with anemia in chronic heart failure. Am. J. Cardiol.96, 101–103 (2005). CASPubMed Google Scholar
Van der Meer, P. et al. Adequacy of endogenous erythropoietin levels and mortality in anemic heart failure patients. Eur. Heart J.29, 1510–1515 (2008). CASPubMed Google Scholar
Opasich, C. et al. Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anemia in patients with chronic heart failure. Eur. Heart J.26, 2232–2237 (2005). CASPubMed Google Scholar
Witte, K. K. et al. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am. Heart J.147, 924–930 (2004). PubMed Google Scholar
Wong, L. S. et al. Anaemia is associated with shorter telomere length in patients with chronic heart failure. Eur. J. Heart Fail.12, 348–353 (2010). CASPubMed Google Scholar
de Silva, R. et al. Anemia, renal dysfunction, and their interaction in patients with chronic heart failure. Am. J. Cardiol.98, 391–398 (2006). PubMed Google Scholar
Nanas, J. N. et al. Etiology of anemia in patients with advanced heart failure. J. Am. Coll. Cardiol.48, 2485–2489 (2006). PubMed Google Scholar
Anker, S. D. et al. Rationale and design of Ferinject Assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. Eur. J. Heart Fail.11, 1084–1091 (2009). CASPubMedPubMed Central Google Scholar
Anker, S. D. et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N. Engl. J. Med.361, 2436–2448 (2009). CASPubMed Google Scholar
González-Costello, J. & Comín-Colet, J. Iron deficiency and anemia in heart failure: understanding the FAIR-HF trial. Eur. J. Heart Fail.12, 1159–1162 (2010). PubMed Google Scholar
Jankowska, E. A. et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur. Heart J.31, 1872–1880 (2010). CASPubMed Google Scholar
Cavill, I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol. Dial. Transplant.18(Suppl 8), viii24–viii28 (2003). CASPubMed Google Scholar
Silverberg, D. S, Iaina, A., Schwartz, D. & Wexler, D. Intravenous iron in heart failure: beyond targeting anemia. Curr. Heart Fail. Rep.8, 14–21 (2011). CASPubMed Google Scholar
Van der Meer, P. et al. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure. J. Am. Coll. Cardiol.44, 63–67 (2004). CASPubMed Google Scholar
Belonje, A. M., Voors, A. A., Van der Meer, P., Van Gilst. W. H. & Van Veldhuisen, D. J. Endogenous erythropoietin and outcome in heart failure. Circulation121, 245–251 (2010). CASPubMed Google Scholar
Macdougall, I. C. & Eckardt, K. U. Novel strategies for stimulating erythropoiesis and potential new treatments for anaemia. Lancet368, 947–953 (2006). CASPubMed Google Scholar
Silverberg, D. S. et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J. Am. Coll. Cardiol.35, 1737–1744 (2000). CASPubMed Google Scholar
Silverberg, D. S. et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J. Am. Coll. Cardiol.37, 1775–1780 (2001). CASPubMed Google Scholar
Mancini, D. M. et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe heart chronic failure. Circulation107, 294–299 (2003). CASPubMed Google Scholar
Palazzuoli, A. et al. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am. Heart J.152, 1096–1015 (2006). PubMed Google Scholar
Parassis, J. T. et al. Effects of darbepoetin alfa on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. Heart J.155, 751–757 (2008). Google Scholar
Ponikowski, P. et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J. Am. Coll. Cardiol.49, 753–762 (2007). CASPubMed Google Scholar
Van Veldhuisen, D. J. et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur. Heart J.18, 2208–2216 (2007). Google Scholar
Ghali, J. K. et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation117, 526–535 (2008). CASPubMed Google Scholar
Van der Meer, P., Groenveld, H. F., Januzzi, J. L. & Van Veldhuisen, D. J. Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart95, 1309–1314 (2009). CASPubMed Google Scholar
McMurray, J. J. et al. Design of the Reduction of Events with darbepoetin alfa in Heart Failure (RED-HF): a phase III, anaemia correction, morbidity-mortality trial. Eur. J. Heart Fail.11, 795–801 (2009). CASPubMed Google Scholar
Singh, A. K. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med.355, 2085–2098 (2006). CASPubMed Google Scholar
Drueke, T. B. et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N. Engl. J. Med.355, 2071–2084 (2006). CASPubMed Google Scholar
Van Veldhuisen, D. J. & McMurray, J. J. Are erythropoietin stimulating proteins safe and efficacious in heart failure? Why we need an adequately powered randomised outcome trial. Eur. J. Heart Fail.9, 110–112 (2007). CASPubMed Google Scholar
Pfeffer, M. A. et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med.361, 2019–2032 (2009). PubMed Google Scholar
Desai, A., Lewis, E., Solomon, S., McMurray, J. J. & Pfeffer, M. Impact of erythropoiesis-stimulating agents on morbidity and mortality in patients with heart failure: an updated, post-TREAT meta-analysis. Eur. J. Heart Fail.12, 936–942 (2010). PubMed Google Scholar
Szczech, L. A. et al. A secondary analysis of the CHOIR trial shows that comorbid conditions differentially affect outcomes during anemia treatment. Kidney Int.77, 239–246 (2010). CASPubMed Google Scholar
Westenbrink, B. D. et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur. Heart J.28, 2018–2027 (2007). CASPubMed Google Scholar
De Boer, R. A., Pinto, Y. M., Van Veldhuisen, D. J. The imbalance between oxygen demand and supply as a potential mechanism in the pathophysiology of heart failure: the role of microvascular growth and abnormalities. Mircocirculation10, 113–126 (2003). Google Scholar
Lipsic, E. et al. Protective effects of erythropoietin in cardiac ischemia: from bench to bedside. J. Am. Coll. Cardiol.48, 2161–2167 (2006). CASPubMed Google Scholar
Voors, A. A. et al. A single dose of erythropoietin in ST-elevation myocardial infarction. Eur. Heart J.31, 2593–2600 (2010). CASPubMed Google Scholar
Binbrek, A. S., Rao, N. S., Al Khaja, N., Asseqqaf, J. & Sobel, B. E. Erythropoietin to augment myocardial salvage induced by coronary thrombolysis in patients with ST-elevation acute myocardial infarction. Am. J. Cardiol.104, 1035–1040 (2009). CASPubMed Google Scholar
Ehrenreich, H. et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med.8, 495–505 (2002). CASPubMedPubMed Central Google Scholar
Ehrenreich, H. et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke40, e647–e656 (2009). CASPubMed Google Scholar
Van der Meer, P. et al. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur. J. Heart Fail.6, 853–859 (2004). CASPubMed Google Scholar
Koury, M. J. & Bondurant, M. C. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science248, 378–381 (1990). CASPubMed Google Scholar
Lipsic, E. et al. Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit. Eur. J. Heart Fail.10, 22–29 (2008). CASPubMed Google Scholar
Moon, C. et al. Erythropoietin, modified to not stimulate red blood cell production, retains its cardioprotective properties. J. Pharmacol. Exp. Ther.316, 999–1005 (2006). CASPubMed Google Scholar
Ogino, A. et al. Erythropoietin receptor signalling mitigates renal dysfunction-associated heart failure by mechanisms unrelated to relief of anemia. J. Am. Coll. Cardiol.56, 1949–1958 (2010). CASPubMed Google Scholar
Klapholz, M. et al. The safety and tolerability of darbepoetin alfa in patients with anaemia and heart failure. Eur. J. Heart Fail.11, 1071–1077 (2009). CASPubMed Google Scholar
Kazory, A. & Ross, E. A. Anemia: the point of convergence or divergence for kidney disease and heart failure. J. Am. Coll. Cardiol.53, 639–647 (2009). PubMed Google Scholar
Phrommintikul, A., Haas, S. J., Elsik, M. & Krum, H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet369, 381–388 (2007). CASPubMed Google Scholar
Macdougall, I. C. & Cooper, A. C. Hyporesponsiveness to erythropoietic therapy due to chronic inflammation. Eur. J. Clin. Invest.35 (Suppl 3), 32–35 (2005). CASPubMed Google Scholar
Regidor, D. L. et al. Associations between changes in haemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J. Am. Soc. Nephrol.17, 1181–1191 (2006). CASPubMed Google Scholar
Solomon, S. D. et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N. Engl. J. Med.363, 1146–1155 (2010). CASPubMed Google Scholar
Abraham, W. T. et al. Treatment of anemia with darbepoetin alfa in heart failure. Congest. Heart Fail.16, 87–95 (2010). CASPubMed Google Scholar
Rossert, J., Gassmann-Mayer, C., Frei, D. & McClellan, W. Prevalence and predictors of epoetin hyporeponsiveness in chronic kidney disease patients. Nephrol. Dial. Transplant.22, 794–800 (2007). PubMed Google Scholar
Van der Putten, K. et al. Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients. Eur. J. Heart Fail.12, 943–950 (2010). CASPubMed Google Scholar
Dallalio, G., Law, E. & Means, R. T. Jr. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood107, 2702–2704 (2006). CASPubMedPubMed Central Google Scholar
Streja, E. et al. Erythropoietin, iron depletion, and relative thrombocytosis: a possible explanation for hemoglobin-survival paradox in hemodialysis. Am. J. Kidney Dis.52, 727–736 (2008). CASPubMedPubMed Central Google Scholar
Dahl, N. V., Henry, D. H. & Coyne, D. W. Thrombosis with erythropoietic stimulating agents- Does iron deficient erythropoiesis play a role? Semin. Dial.21, 210–211 (2008). PubMed Google Scholar
Fairbanks, V. & Beutler, E. in Williams Hematology 6th edn (ed Beutler, E.) 295–304, 447–440 (McGraw-Hill, New York, 2001). Google Scholar
Dunn, L. L., Rahmanto, Y. S. & Richardson, D. R. Iron uptake and metabolism in the new millennium. Trends Cell Biol.17, 93–100 (2007). CASPubMed Google Scholar
Anderson, G. J. & Vulpe, C. D. Mammalian iron transport. Cell. Mol. Life Sci.66, 3241–3261 (2009). CASPubMed Google Scholar
Cairo, G., Bernuzzi, F. & Recalcati, S. A precious metal: iron, an essential nutrient for all cells. Genes Nutr.1, 25–39 (2006). CASPubMedPubMed Central Google Scholar
Andrews, N. C. Disorders of iron metabolism. N. Engl. J. Med.341, 1986–1995 (1999). CASPubMed Google Scholar
Sutak, R., Lesuisse, E., Tachezy, J. & Richardson, D. R. Crusade for iron: iron uptake in unicellular eukaryocytes and its significance for virulence. Trends Microbiol.16, 261–268 (2008). CASPubMed Google Scholar
Wilson, M. T. & Reeder, B. J. Oxygen-binding haem proteins. Exp. Physiol.93, 128–132 (2008). CASPubMed Google Scholar
Zimmerman, M. B. & Hurrell, R. F. Nutritional iron deficiency. Lancet370, 511–520 (2007). Google Scholar
Anker, S. D. & Sharma, R. The syndrome of cardiac cachexia. Int. J. Cardiol.85, 51–66 (2002). PubMed Google Scholar
Weiss, G. Iron metabolism in the anemia of chronic disease. Biochim. Biophys. Acta1790, 682–693 (2009). CASPubMed Google Scholar
Gisbert, J. P. & Gomollon, F. An update on iron physiology. World J. Gastroenterol.15, 4659–4665 (2009). PubMedPubMed Central Google Scholar
Dong, F. et al. Dietary iron deficiency induce ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthese and protein tyrosine nitration. Clin. Sci. (Lond.)109, 277–286 (2005). CAS Google Scholar
Brownlie, T., Utermohlen, V., Hinton, P. S. & Haas, J. D. Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. Am. J. Clin. Nutr.79, 437–443 (2004). CASPubMed Google Scholar
Haas, J. D. & Brownlie, T. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J. Nutr.131, 676S–690S (2001). CASPubMed Google Scholar
Handelman, G. J. & Levin, N. W. Iron anemia in human biology. A review of mechanisms. Heart Fail. Rev.13, 393–404 (2008). PubMed Google Scholar
Merck Research Laboratories, Merck & Co Inc. The Merck Manual of Diagnosis and Therapy 16th edn 1144 (Merck & Co Inc., Rahway, 1992).
Mann, D. L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res.91, 988–998 (2002). CASPubMed Google Scholar
Heymans, S. et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail.11, 119–129 (2009). CASPubMedPubMed Central Google Scholar
Naito, Y. et al. Impaired expression of duodenal iron transporters in Dahl salt-sensitive heart failure rats. J. Hypertens.29, 741–748 (2011). CASPubMed Google Scholar
Merle, U., Fein, E., Gehrke, S. G., Stremmel, W. & Kulaksiz, H. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology148, 2663–2668 (2007). CASPubMed Google Scholar
Matsumoto, M. et al. Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia. Circ. J.74, 301–306 (2010). CASPubMed Google Scholar
Nicholas, G. et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc. Natl. Acad. Sci. U. S. A.99, 4596–4601 (2002). Google Scholar
Ganz, T. & Nemeth, E. Hepcidin and disorders of iron metabolism. Annu. Rev. Med.62, 347–360 (2011). CASPubMed Google Scholar
Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science306, 2090–2093 (2004). CASPubMed Google Scholar
Sunder-Plassmann, G. & Höri, W. H. Iron metabolism and iron substitution during erythropoietin therapy. Clin. Invest.72, S11–S15 (1994). CAS Google Scholar
Macdougall, I. C. et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int.50, 1694–1699 (1996). CASPubMed Google Scholar
Van Wyck, D. B., Roppolo, M., Martinez, C. O., Mazey, R. M. & McMurray, S, for the United States Iron Sucrose (Venefor) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int.68, 2846–2856 (2005). CASPubMed Google Scholar
Besarab, A., Hörl, W. H. & Silverberg, D. Iron metabolism, iron deficiency, thrombocytosis, and the cardiorenal anemia syndrome. The Oncologist14 (Suppl 1), 22–33 (2009). CASPubMed Google Scholar
Weinberg, E. D. The hazards of iron loading. Metallomics2, 732–740 (2010). CASPubMed Google Scholar
Sullivan, J. L. Long-term risk of increased use of intravenous iron. Lancet370, 481–482 (2007). PubMed Google Scholar
Cooper, C. E. Nitric oxide and iron proteins. Biochim. Biophys. Acta1411, 290–309 (1999). CASPubMed Google Scholar
Comín-Colet, J. et al. A pilot evaluation of the long-term effect of combined therapy with intravenous iron sucrose and erythropoietin in elderly patients with advanced chronic heart failure and cardio-renal anemia syndrome: influence on neurohormonal activation and clinical outcomes. J. Card. Fail.15, 727–735 (2009). PubMed Google Scholar
Bolger, A. P. et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J. Am. Coll. Cardiol.48, 1225–1227 (2006). CASPubMed Google Scholar
Usmanov, R. I., Zueva, E. B., Silverberg, D. S. & Shaked, M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J. Nephrol.21, 236–242 (2008). CASPubMed Google Scholar
Toblli, J. E., Lombraña, A., Duarte, P. & Di Genarro, F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemia patients with chronic heart failure and renal insufficiency. J. Am. Coll. Cardiol.50, 1657–1665 (2007). CASPubMed Google Scholar
Okonko, D. O. et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with chronic heart failure and iron deficiency. FERRIC-HF: a randomized, controlled, observer-blinded trial. J. Am. Coll. Cardiol.51, 103–112 (2008). CASPubMed Google Scholar