Demystifying Cardiac Iron Deficiency in End‐stage Heart Failure

Abstract

BackgroundCardiac iron depletion (CID) in heart failure (HF) remains largely unexplored regarding its prevalence, pathogenesis, and impact on the failing hearts. Hypotheses: We anticipate that iron‐deficient failing hearts will demonstrate defective iron regulatory pathways, whereby the HF progression is markedly aggravated by the mitochondrial redox imbalance.PurposeWe aim to establish CID’s defining criterion, recapitulate its pathophysiological role, and evaluate the applicability of monitoring it non‐invasively in HF.MethodsBiventricular myocardial 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 metabolism, respiration, and oxidative stress. Heart iron status was further investigated by cardiac magnetic resonance (CMR) imaging.ResultsTissue iron content in the left ventricle (LV) was significantly lower in HF versus NFC [121.4 (88.1‐150.3) vs. 137.4 (109.2‐165.9) μg/g dry weight], which was absent in the right ventricle (RV). With a priori cutoff of 86.1 μg/g d.w. in LV, we identified 23% of HF patients with CID (HF‐CID) associated with higher NYHA class and worsened LV function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF‐CID 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‐CID, while transmembrane fraction of ferroportin positively correlated with CID. CMR with T2* effectively captured myocardial iron levels in failing hearts.ConclusionsCID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the LV. CMR demonstrates clinical potential to non‐invasively monitor CID.