Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction

Abstract

Aims Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of preemptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. Methods and results MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localised ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. Conclusion We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long-term after MI. Preemptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in postinfarction LV remodelling and HF.

Elevated SLC40A1 impairs cardiac function and exacerbates mitochondrial dysfunction, oxidative stress, and apoptosis in ischemic myocardia

“…Furthermore, it is important to differentiate ischemia and I/R injury as distinct pathological processes. A recent study provided evidence supporting the beneficial effects of iron supplementation after MI [52]. In our study, we found that SLC40A1 and Steap4 were upregulated in the ischemic areas during the initial phase of MI.…”

Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction

“…Additionally, the interaction between ROS, iron balance, and lipid peroxidation in the myocardium opens the way for new therapeutic targets in the management of ischemic heart diseases. For example, the investigation of molecules and pathways of ferroptosis, including ferroportin [ 71 ], FOXO1 [ 72 ], and others, may provide useful insights into the causal relationships between iron metabolism, ROS, and myocardial viability following ischemia.…”

Critical re‐evaluation of the identification of iron deficiency states and effective iron repletion strategies in patients with chronic heart failure

“…58,[111][112][113] Clinically, patients with iron deficiency have increased cardiac TfR1 expression and impaired cardiac energetics. 114,115 Yet, independently of systemic iron, failing hearts have decreased myocardial iron content and reduced mitochondrial activity, as well as decreased hepcidin, increased ferroportin and decreased sTfR 110,116,117 ; the latter findings suggests diminished entry into and enhanced egress of iron from cardiomyocytes. Furthermore, experimental chronic sympathetic stimulation causes intracellular iron deficiency and mitochondrial dysfunction in cardiomyocytes, 118 and increased plasma norepinephrine is associated with cardiac iron depletion, low sTfR and low TSAT in patients with heart failure.…”

“…[121][122][123][124][125] Functional iron deficiency explains why patients with heart failure do not respond favourably to oral iron, whose slow pharmacokinetics allow for trapping in macrophages and hepatocytes. 126 With the progression of heart failure, serum levels of both hepcidin and ferritin may be affected by occult gastrointestinal bleeding, 125 by changes in hepatic function related to congestion inflammation, 82,83,127 by changes in intracellular expression of both proteins in response to stress or injury, 110,116,117 or by the use of certain foundational drugs for heart failure, which can reduce serum levels of both hepcidin and ferritin. 124,128 For all these reasons, neither serum ferritin nor hepcidin levels can be used to reliably identify iron-deficient patients with heart failure.…”