Iron deficiency as a promoter of cadmium-induced cardiotoxicity

Abstract

This commentary refers to ‘Iron deficiency and cardiovascular disease’, by G. Savarese et al., https://doi.org/10.1093/eurheartj/ehac569 and the discussion piece ‘Iron deficiency as a promoter of cardiotoxicity: not only cadmium-induced’, by G. Savarese et al., https://doi.org/10.1093/eurheartj/ehad297. An adequate intracellular level of iron in each body cell is extremely important since iron is an integral part of cytochrome c and iron-sulfur (Fe-S) clusters. Cytochrome c and Fe-S clusters are located within the inner mitochondrial membrane and are included in cellular respiration. When the cellular level of iron is below normal [iron deficiency (ID)], the process of ATP synthesis is disturbed, which is similar to the situation when a cell lacks oxygen. So, ID leads to cytochrome c and Fe-S clusters synthesis to a lesser extent and as a consequence cardiomyocytes may experience hypoxic conditions. Recently, Savarese et al. published a comprehensive review on numerous aspects of adverse effects of ID in various cardiovascular diseases.1 Nevertheless, the cardiotoxicological side of ID remains undiscussed; namely, individuals with ID have an increased blood levels of cadmium (Cd2+).2 The pathophysiological mechanism of increased cadmium body burden in individuals with ID implies an increased intestinal expression of divalent metal transporter 1 (DMT1); DMT1 was initially described as iron carrier, however later it was shown that DMT1 has a greater affinity for cadmium than for iron and that it is overexpressed in case of ID. Namely, ID promotes intestinal accumulation of hypoxia-inducible factor-2 which in turn induces DMT1 overexpression. Gallagher et al. showed that body iron and serum ferritin concentrations negatively correlated with blood and urine cadmium levels in humans.3 It is known that cadmium is highly toxic to cardiomyocytes. Cadmium has pro-atherosclerotic effects on the coronary arteries; on the other side, the results of the study which involved over 12 000 individuals (age range: 45–68 years) indicated that subjects with ID had an increased risk of coronary artery disease.4 Moreover, cadmium induces endothelial dysfunction5 (Figure 1), while ID is frequent among subjects with either pulmonary or arterial hypertension. So, apparently cadmium may be considered as a potent cardiotoxicant; also, we have to mention that hazardous cadmium effects are dose-dependent, so it is reasonable to expect more deleterious effects of cadmium-induced cardiotoxicity in ID individuals compared to non-ID subjects. Additionally, cadmium elimination from the human body takes decades and if ID is not treated properly on time, cadmium deleterious effects to the heart are inevitable. Apart from ID, individuals who smoke have increased blood levels of cadmium and smoking is a well-known risk factor for various heart diseases such as sudden cardiac death, heart failure, and coronary artery disease. Schematic approach of pathophysiological mechanisms involved in attenuation of cardiac function in individuals with ID. Cadmium-induced cardiotoxicity may be considered as contributing mechanism in cardiological disorders in ID individuals, at least to a certain extent; nevertheless, in the future appropriately designed clinical studies are necessary to evaluate our hypothesis. No funding to report. No new data were generated or analyzed in support of this research. All authors declare no funding for this contribution.

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