Iron Metabolism, Incident Heart Failure Phenotypes and Cardiac Dysfunction in Late Life

Abstract

Iron contributes to a variety of biological processes, such as oxygen transport, mitochondrial respiration, and free radical protection with particular importance in cells with high energy requirements, such as cardiomyocytes. People with iron deficiency suffer from a range of symptoms, including fatigue, dizziness, pallor, restless leg syndrome, and even pica, among many others. Iron deficiency is the most common nutritional disorder worldwide and affects many children and young women in low and middle-income countries. Iron deficiency also affects many older adults, in whom gastrointestinal blood loss, and decreased iron absorption account for most cases. In late life, reduced iron stores are associated with a higher risk of impaired physical and cognitive capacity and mortality. Iron deficiency can be diagnosed using readily available blood biomarkers and can be treated using oral supplements and intravenous iron products. Given the widespread prevalence of iron deficiency and the ability to identify and manage iron deficiency cases, studying the effects of iron deficiency may have important public health implications. Iron metabolism plays an important role in cardiomyocyte function given the high energy requirements of this cell type. In patients with chronic heart failure, iron deficiency is associated with impaired functional capacity and higher risks of heart failure hospitalization and death independent of anemia. Like heart failure, the prevalence of iron deficiency increases with older age. Nevertheless, the role of iron deficiency in the development of subclinical cardiac dysfunction and its progression to incident heart failure in late life remains unknown. While the gold standard method for iron deficiency diagnosis is the assessment of iron in bone marrow biopsy, blood biomarkers are routinely used in clinical practice. Circulating ferritin levels are used to diagnose total body iron stores. Hepcidin regulates plasma and tissue iron levels by degrading and blocking iron binding to the iron exporter ferroportin. Ferritin may provide insight into absolute iron deficiency, whereas hepcidin may allow assessment of functional iron deficiency. I sought to assess the relationships between plasma ferritin and hepcidin with incident heart failure (manuscript 1) and subclinical cardiac dysfunction (manuscript 2) and among older adults in the Atherosclerosis Risk in Communities (ARIC) study, an ongoing, longitudinal, observational cohort study of adults in four communities across the United States. In Study 1, we evaluated the association of lower ferritin and hepcidin levels with incident heart failure. We detected an association of lower levels of ferritin and hepcidin with higher risks of incident heart failure overall and incident heart failure with preserved ejection fraction, but not heart failure with reduced ejection fraction. In Study 2, we observed cross-sectional associations of lower ferritin and hepcidin levels with measures of LV diastolic dysfunction and higher LV filling pressure. The associations were consistent across gender categories and independent of several potential confounders. The results highlight the potential contributions of iron deficiency to cardiac dysfunction independent of concomitant anemia. The results of the two studies build up and show that lower iron stores were not only associated with the intermediate phenotype of cardiac dysfunction but also with the clinical outcome of incident HF.