Author + information
- Terrence X. O'Brien, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Terrence X. O'Brien, Medical University of South Carolina, Medicine/Cardiology, 25 Courtenay Drive, ART 7063, Charleston, South Carolina 29425-0592
“When the heart is diseased, its work is imperfectly performed; the vessels proceeding from the heart become inactive so that you cannot feel them.” So goes one of the cardiac glosses of the Ebers papyrus, written about 1600 bc (1). This description is compatible with heart failure, and this ancient author illustrates that careful clinical observation has long been a required predecessor to understanding disease. So too has it been in recent years with the study of anemia and iron metabolism in heart failure. Clinical observations and basic mechanistic experiments have led to clinical trials, which in turn have led to new observational studies such as that by Okonko et al. (2) in this issue of the Journal.
Iron is essential to life because it facilitates reversible oxidation-reduction reactions. The most important of these is the heme reaction, but iron is also a catalyst in many enzymatic systems active in the heart, including cytochromes, metalloproteinases, and so on (3). In its simplest form, iron metabolism involves a continuous loop whereby dietary, stored, or macrophage-recycled iron is transported via transferrin to transferrin receptors and stored as ferritin, in the marrow or in other organs. Abnormal iron absorption can occur in both ischemic and nonischemic systolic heart failure and can lead to clinical anemia (4). This is a continuum, and there may be iron depletion without anemia or even normal iron homeostasis with heart failure. When iron deficiency is present, the classic laboratory findings include low ferritin, normal or high total iron-binding capacity (TIBC), and low transferrin saturation (TSAT) (3). Alternatively, with anemia of chronic disease, there is inadequate iron delivery despite adequate reserves (i.e., low TSAT, high TIBC, and high or normal ferritin), common in disorders with proinflammatory cytokines, such as heart failure (4). There can be significant overlap, and other tools for determining iron homeostasis include peripheral indexes, marrow analysis, direct iron levels, and circulating transferring receptor levels. Of course, patients with heart failure may also have other causes of anemia, such as bleeding, vitamin deficiency, hemolysis, drug reaction, malignancy, other chronic inflammatory conditions, and so on.
Reports on the incidence of anemia in heart failure populations vary. A meta-analysis of 34 studies found the average prevalence to be 37% (5). There are several theories for why iron metabolism may be abnormal in heart failure. Neurohormonal activation likely contributes. There may be abnormal hepcidin-mediated gastrointestinal iron absorption, diversion of iron stores, decreased erythropoietin response, hemodilution, or inflammatory cytokine activity (4,6). For example, Nanas et al. (7) found anemia of chronic disease in 73% of their patients with heart failure in terms of depleted bone marrow stores despite normal iron, ferritin, and erythropoietin levels. Unfortunately, our knowledge of the pathophysiology of iron metabolism in heart failure is incomplete, particularly in terms of always being able to determine the etiology of anemia. What is clearer is that worsening anemia in heart failure is an independent predictor of mortality (8).
In this issue of the Journal, Okonko et al. (2) report their study of 157 patients with chronic systolic heart failure (left ventricular ejection fraction <45%), both ischemic and nonischemic, in whom they categorized iron homeostasis using standard peripheral laboratory measurements and correlated these with known cardiac risk factors and outcomes over a median follow-up period of over 2 years. The investigators classified anemia as hemoglobin <13 g/dl for men and <12 g/dl for women, with iron deficiency defined as TSAT <20%, TIBC >45 μmol/l, and ferritin <30 μg/l. Low ferritin levels signified inadequate iron reserves and were correlated with higher New York Heart Association functional class. Anemia of chronic disease included ferritin >30 μg/l (also analyzed at >100 μg/l). Patients with both anemia of chronic disease and iron-deficiency anemia were defined as having TSAT <20% and ferritin <30 μg/l. Serum transferrin receptor measurements were made in a cohort to confirm findings.
The investigators found that 39% of their patients with heart failure were anemic. Whether anemic or not, iron deficiency (i.e., low TSAT in the face of adequate iron stores (normal or high ferritin) was found in 43% of patients and was correlated with lower hemoglobin values and higher New York Heart Association functional class. Interestingly, 30% of nonanemic patients with heart failure had iron deficiency, presumably identified before the development of anemia. Among the patients with anemia, anemia of chronic disease was found in 26%, iron-deficiency anemia was present in 16%, and 17% had both concomitantly. The investigators found that iron deficiency was correlated independently with heart failure severity (whether anemia was present or not), exercise intolerance, and higher risk for death. Indeed, in patients with iron deficiency, those who were anemic had twice the death rate of nonanemic patients and 4 times the death rate of non–iron-deficient patients, whether they were anemic or not. This study remains an important refinement in understanding clinical iron homeostasis independent of anemia in heart failure. The diagnostic distinction in iron-deficient patients between iron-deficiency anemia, anemia of chronic disease, and, in particular, both concomitantly was shown to provide important prognostic information determined with readily available clinical indexes (i.e., TSAT, hemoglobin, TIBC, and ferritin).
Many of the advances in the heart failure field have taken advantage of information gleaned from novel biomarkers. However important, new biomarkers have limitations: they may not be readily available, they may overlap with other noncardiac diseases, clinicians may not be used to ordering or interpreting them, data may be based on surrogate endpoints, and in many cases they may not provide information independent of traditional risk factors. This study, and others, emphasizes the prognostic role of iron metabolism measurements, which may have just as useful a role and are already widely available.
Left unanswered in an observational study is whether treatment affects outcomes. There is evidence that improvements in anemia may decrease symptoms and enhance left ventricular function (8). For example, the recent FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial (9) examined therapy with intravenous iron in patients with heart failure with iron deficiency (thereby bypassing any abnormal gastrointestinal absorption) and found significant favorable responses in symptoms and quality-of-life assessments. However, how, if, or when treatment of anemia and/or iron deficiency in heart failure should be done remains unclear in most clinical situations. Ongoing trials with darbepoetin alfa and other therapies are eagerly awaited (10). Until then, without clear mortality data, the American College of Cardiology and American Heart Foundation 2009 focused heart failure guidelines update emphasizes that although anemia may be associated with worsening heart failure, its correction has not been established as therapy independent of other established indications (11).
So how does this study by Okonko et al. (2) improve our management of heart failure? Whether written on papyrus or in the Journal, careful observational studies are crucial to advancement. The improved diagnostic accuracy demonstrated is an argument for more patients with heart failure to have their iron metabolism measured, especially as part of research trials. This could better focus treatment results to the type of iron dysregulation present. The hope is that one day not too far off, abnormal iron homeostasis may become one of the treatable aberrant metabolic pathways in the heart failure syndrome.
Dr. O’Brien has reported that he has no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Okonko D.O.,
- Mandal A.K.J.,
- Missouris C.G.,
- Poole-Wilson P.A.
- Beutler E.
- Groenveld H.F.,
- Januzzi J.L.,
- Damman K.,
- et al.
- Nanas J.N.,
- Matsouka C.,
- Karageorgopoulos D.,
- et al.
- Hunt S.A.,
- Abraham W.T.,
- Chin M.H.,
- et al.