Iron deficiency in myocardial ischaemia: molecular mechanisms and therapeutic perspectives

Abstract

Systemic iron deficiency (SID), even in the absence of anemia, worsens the prognosis and increases mortality in heart failure (HF). Recent clinical-epidemiological studies, however, have shown that a myocardial iron deficiency (MID) is frequently present in cases of severe HF even in the absence of SID and without anemia. In addition, experimental studies have shown a poor correlation between the state of systemic and myocardial iron. MID in animal models may lead to severe mitochondrial dysfunction, alterations of mitophagy and mitochondrial biogenesis, with profound alterations in cardiac mechanics and the occurrence of a fatal cardiomyopathy, all effects prevented by intravenous administration of iron. This shifts the focus to the myocardial state of iron, in the absence of anemia, as an important factor in prognostic worsening and mortality in HF. There is now epidemiological evidence that SID worsens prognosis and mortality also in patients with acute and chronic coronary heart disease, and experimental evidence that MID aggravates acute myocardial ischemia as well as post-ischemic remodeling. Intravenous administration of ferric carboxymaltose or ferric dextrane improves post-ischemic adverse remodeling. We here review such evidence, propose that MID worsens ischemia/reperfusion injury, and discuss possible molecular mechanisms, such as chronic hyperactivation of HIF1-α; exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD+] ratio, and depletion of energy status and NAD+ content with inhibition of sirtuin 1-3 activity. Such evidence now portrays iron metabolism as a core factor not only in heart failure, but also in myocardial ischemia.

Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection

“…When the aorta is in ID and subjected to external stimulation such as AngII, it will rapidly promote the phenotypic transformation of cells, resulting in increased disease occurrence and expanded lesion involvement. Since iron is an important component of hemoglobin, which is the main component of transporting oxygen, ID and hypoxia should be closely related (Corradi et al 2023 ). Our experimental results also prove that the increase of ROS and 8-OHdg in the body during ID induces oxidative stress.…”