JACC: Iron depletion linked to HF progression

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Patients with heart failure (HF) often have the presence of iron depletion, suggesting a potential link between anemia and adverse prognosis in HF, according to a study published in the July 26 issue of the Journal of the American College of Cardiology. However, editorialists questioned whether the study was powered to draw that conclusion.

Anemia is a common comorbidity with HF, and the presence of anemia in this patient population is associated with greater functional impairment, worse New York Heart Association functional class and other adverse outcomes. These associations have prompted researchers to examine the inverse relationship between anemia and survival, leading to several evaluations of the effectiveness of erythropoietin and other erythropoiesis-stimulating agents to raise hemoglobin (Hb) levels and thus potentially improve survival in HF patients.

The cause for anemia in the HF population is unclear, according to the study authors, and the mechanism linking anemia and more severe HF remains unknown. Researchers have questioned whether anemia per se is a contributor to an adverse prognosis, a contributing factor or a biomarker for advanced HF.

In the study, researchers focused on iron deficiency and its potential role in HF. They hypothesized that depletion of myocardial iron content may provide the biological link for the association between anemia and adverse prognosis in HF.

Micha T. Maeder, MD, of the Heart Centre at Alfred Hospital in Melbourne, Australia, and colleagues conducted clinical and basic studies in nine healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 percent) to obtain hemodynamic, biochemical and echocardiographic data. “In the present study, we aimed to test the hypothesis that the association between anemia and HF severity, and outcome might rather be explained by an underlying depletion of iron stores, particularly at the myocardial level,” the authors wrote. “In the context of HF, systemic and myocardial iron deficiency could thus contribute both to anemia and HF progression.”

To address this question, the researchers performed a series of complementary studies in controls and HF patients, including biochemical and hemodynamic assessments and transcardiac blood sampling. These studies were complemented by determining tissue iron content and transferrin receptor expression in human heart samples, and by investigating the regulation of the transferrin receptor in cardiomyocyte cell culture.
 
Researchers reported that patients with advanced HF had lower Hb and biochemical indices of iron deficiency as measured by lower serum iron and transferrin saturation (TFS). HF patients with anemia exhibited a greater degree of iron deficiency, with TFS lower in anemic compared with nonanemic HF patients. The authors noted that TFS measures in nonanemic patients indicated intermediate iron deficiency.

“[I]t is possible that anemia only becomes apparent in HF when total-body iron stores are sufficiently depleted, a concept that is supported by our demonstration of a strong relationship between TFS and Hb,” the authors proposed.

In another analysis, they evaluated whether a reduction in myocardial iron content occurs in HF. They found that myocardial iron content was reduced in HF versus non-HF samples (0.49 ug/g vs. 0.58 ug/g).

“To the best of our knowledge, we showed for the first time that the iron content of the failing human heart is reduced compared with nonfailing hearts,” they wrote.

In an accompanying editorial, John J. V. McMurray, MD, of the University of Glasgow in Scotland, and Piotr Ponikowski, MD, PhD, of the Military Hospital in Wroclaw, Poland, categorized  key study findings as “pathophysiologically plausible, given the crucial role that iron plays in cellular function in general and oxidative metabolism in particular, especially in metabolically active tissue. Although attractive, this hypothesis needs further testing.”
 
The editorialists cautioned that the study sample was small; study subjects were atypical; and the comparison of healthy heart tissue with tissue from patients with end-stage heart failure undergoing transplantation was extreme. They called for additional studies and in their conclusion, Maeder et al also called for further studies.