Cardiac iron deficiency (ID) develops independently from systemic iron status and impairs function of the failing heart. We hypothesized that myocardial infarction (MI) alters cardiac iron homeostasis and thereby promotes the development of cardiac ID. To test this, we investigated the effect of iron injections in mice with postinfarction heart failure (HF) aiming to prevent the development of cardiac ID and improve adverse left ventricular (LV) remodeling.

Myocardial iron content in the LV was higher 4 weeks after MI, gradually decreased over time, and was significantly lower 24 weeks after MI, compared to sham-operated mice (157±15%, P<0.001 at 4 weeks, 84±5%, P=0.001 at 24 weeks vs sham). LV expression of the peptide hormone hepcidin, which down-regulates the activity of the membrane-bound iron exporter ferroportin (Fpn) by binding and inducing Fpn internalization, was enhanced 4 weeks after MI (Hepcidin/Gapdh mRNA: 445±12%, P=0.03 vs sham), and decreased after 24 weeks (19±3%, P=0.01 vs sham). Conversely, the LV expression levels of membrane-bound Fpn were lower 4 weeks after MI (Fpn protein: 79±7%, P=0.04 vs sham), and higher after 24 weeks (135±56%, P=0.001 vs sham). To assess whether hepcidin directly regulates Fpn expression in cardiomyocytes, we suppressed hepcidin expression by transfecting hepcidin targeting siRNA in cultured cardiomyocytes (NRCMs). Suppression of hepcidin expression resulted in increased membrane bound-Fpn, suggesting a direct effect of hepcidin on the function of Fpn. Hypoxia and the pro-hypertrophic endothelin-1 (ET1) suppressed hepcidin expression and raised the levels of membrane-bound Fpn in NRCMs. To prevent cardiac ID and pathological LV remodeling after MI, 15 mg/kg of ferric carboxymaltose was intravenously injected 12, 16 and 20 weeks after MI. Iron injections prevented cardiac ID, improved electron transport chain complex I expression and activity, and preserved LV function, compared to saline injected MI mice (preventive iron vs saline: LVEF 43±0.1% vs 30±0.7%, P=0.02). Notably, human failing hearts also displayed lower iron content (56±3%, P<0.0001 vs non-failing donor hearts) with suppressed hepcidin expression (Hepcidin/Gapdh mRNA: 11±3%, P=0.002 vs non-failing donor hearts) and higher membrane-bound Fpn levels (Fpn protein: 218±25%, P=0.002 vs non-failing donor hearts).

In conclusion, MI alters cardiac iron homeostasis and promotes long-term cardiac ID. The development of cardiac ID is associated with adverse LV remodeling and cardiac dysfunction, which is prevented by iron treatment. We propose a novel cardiac hepcidin-Fpn-based autocrine mechanism that may promote development of cardiac ID after MI.

Data are presented as mean ± SEM%.