Myocardial Iron Deficiency and Mitochondrial Dysfunction in Advanced Heart Failure in Humans

Abstract

Background Myocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non‐invasively in human explanted hearts. Methods and Results Biventricular tissue iron levels were measured in both failing (n=138) and non‐failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1–150.3] versus 137.4 [109.2–165.9] μg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 μg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF‐MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF‐MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron‐deficient hearts. Mechanistically, iron uptake pathways were impeded in HF‐MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts. Conclusions MID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non‐invasively monitor MID.

Clinical and Molecular Aspects of Iron Metabolism in Failing Myocytes

“…These suggest that iron deficiency in the heart is additionally related to a higher export and/or a lower import of iron in the cells. These assumptions about reduced DMT-1 and TfR-1 with no changes in FPN concentration were also confirmed by Zhang et al in the failing human heart [ 104 ]. Changes in the expression of iron-metabolism proteins in HF are associated with the modification of iron-regulatory factors.…”

Iron Deficiency in Heart Failure: What Do We Know So Far?

“…Contrarily, functional ID denotes a mismatch between tissue supply and demand for iron, mainly as a result of iron maldistribution and iron use [6]. ID causes mitochondrial dysfunction and increases the oxidative load in the myocardial cells [8], leading to impairment of the The figure is created by the author Julius Lenaerts. Adapted from Loncar et al [10].…”

“…Contrarily, functional ID denotes a mismatch between tissue supply and demand for iron, mainly as a result of iron maldistribution and iron use [ 6 ]. ID causes mitochondrial dysfunction and increases the oxidative load in the myocardial cells [ 8 ], leading to impairment of the myocardial energetics and function [ 9 ] (Figure 2 ). In this article, the authors demonstrate the latest available literature on ID in heart failure (HF) patients to improve the management of this vulnerable group.…”

Iron Deficiency and Deranged Myocardial Energetics in Heart Failure

“…Of note, it has been demonstrated that intravenous iron therapy with ferric carboxymaltose (FCM) administered after an episode of acute HF in patients with systemic ID (evaluated based on circulating iron parameters) can prevent recurrent HF hospitalizations [ 14 ]. The intriguing, hypothetical concept of affecting/improving myocardial energy metabolism using particular substances given orally or intravenously (such as iron formulations) requires further translational research, in particular because myocardial iron status (strictly in the heart) is not comprehensively studied [ 15 ]. It is worth mentioning that we have limited data suggesting possible improvement of skeletal muscle energetics due to iron therapy in HF patients with ID [ 16 ].…”