A single dose of clinically relevant intravenous iron induces cardiac ferroptosis in cardiometabolic heart failure
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome in patients with a left ventricular ejection fraction (LVEF) =50% and evidence of diastolic dysfunction (abnormal LV filling and elevated filling pressures) causing symptoms including decreased exercise tolerance and dyspnea. Characterization of clinical phenogroups within HFpEF patients using the standards from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) identified one of three that predominantly demonstrates cardiometabolic and inflammatory phenotypes (cardiometabolic HFpEF). (1) This patient population accounts for the largest healthcare burden and has the highest mortality of all three phenogroups. While the primary goal of iron infusion is to enhance HF outcomes, it's crucial to acknowledge the potential for unintended acute myocardial injury following IV iron infusion. This realization prompted us to investigate if a single clinically relevant dose of IV iron could induce ferroptosis in the myocardium.  We identified that a single clinically relevant dose of IV iron acutely induced changes consistent with myocardial ferroptosis. This discovery highlights the urgency of determining if repeated doses of IV iron induce repetitive bouts of ferroptosis and if this adversely affects cardiac function. Further studies should evaluate if the co-administration of ferroptosis inhibitors with IV iron mitigates potential harm while providing the benefits of iron supplementation in cardiometabolic HFpEF. Overall design: Whole heart of mice fed high fta high sucrose diet or standard chow for 18 weeks given a single dose of IV iron dextran. 48 hours after administration hearts were purfused with PBS and harvested for analysis. Hearts were flash frozen and sent for sequencing.