Unravelling the molecular basis for cardiac iron metabolism and deficiency in heart failure

This editorial refers to ‘Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure’†, by S. Haddad et al., on page 362. Major physiological functions of iron include oxygen transport as a component of haemoglobin in blood (and myoglobin in striated muscle), energy production through oxidative phosphorylation as an integral component of iron–sulphur cluster-containing enzymes such as cytochromes, NADPH, and succinate dehydrogenases, and as a component of peroxide- and nitric oxide-generating enzymes.1 Iron metabolism is a balancing act, and biological systems have evolved exquisite regulatory mechanisms to maintain iron homeostasis. Once iron is absorbed via the enterocyte, it is bound to specific iron transport proteins (transferrin) and iron storage proteins (ferritin) in a tightly regulated system that controls iron availability to the cells and tissues including the bone marrow for erythropoiesis. Two iron-regulatory proteins, IRP-1 and IRP-2, have important roles in maintaining intracellular iron homeostasis. In response to changes in iron availability and redox signals, IRP-1 and IRP-2 bind iron-response elements that regulate transcription of the transferrin receptor, ferritin, and other proteins.2 Disturbances in iron metabolism can have dramatic pathological effects on the heart: iron overload leading to cardiomyopathy2–4 and iron deficiency exacerbating clinical outcomes in patients with heart failure.5,6 In patients with chronic heart failure, anaemia is an independent predictor of mortality and hospitalizations for HF, and iron deficiency, either absolute or functional, is an independent predictor of clinical outcomes and exercise intolerance, even in the absence of anaemia.5,6 Relationship between myocardial iron homeostasis and the development of heart failure. (A) Cellular homeostasis of iron and ATP production in normal, IRP1/2-deficent, and IRP1/2-deficient with iron-supplemented cardiomyocytes. (B) Link between IRP1/2 deficiency, iron homeostasis, ATP production, and heart failure. (C) Therapeutic strategies aimed at improving myocardial iron levels and clinical outcomes in patients with heart failure. IRP1/2, iron response protein 1 and 2; Trf1, transferrin receptor 1; Fpn, ferroportin; DMT1, divalent metal transporter 1; ACEi, angiotensin-converting enzyme inhibitor; MRA, mineralocorticoid receptor antagonist. The heart has the highest metabolic demands in the body, and energy production determined largely by mitochondrial function must closely match energy requirements.11,12,In vivo magnetic resonance spectroscopy showed a decline in the left ventricular (LV) phosphocreatine/ATP ratio in response to dobutamine challenge which correlated with reduced mitochondrial complex I activity10 which is clearly associated with heart disease as seen in patients with complex I deficiencies. These metabolic perturbations sensitize the IRP1/2-deficient heart and resulted in reduced survival, worsened systolic function, and heart failure in response to myocardial infarction.10 The importance of these findings are further supported by the myocardial iron deficiency and aggressive cardiomyopathy reported in cardiac-specific deletion of the transferrin receptor, a phenotype also rescued by systemic iron supplementation.9 The protein levels of mitochondrial ferritin and mitochondrial ATP-binding cassette transporter 7 were increased, and direct disturbance in mitochondrial iron metabolism and mitophagy may have also contributed to the maladaptive responses seen in the IRP1/2-deficient hearts. Haddad et al. demonstrated that in the absence of iron-deficiency anaemia, increased systemic iron treatment rescued the myocardial iron deficiency in the IRP1/2-deficient hearts, and restored mitochondrial function and the ability of the heart to respond to metabolic demands and injury (Figure 1B).10 These pre-clinical findings, which are consistent with the clinical benefits seen with iron supplementation in patients with iron deficiency and heart failure, raise the intriguing idea that systemic iron replacement should be tried in HF before the onset of systemic iron deficiency, especially in the setting of acute injury and stress to the myocardium. Based on the findings in the cardiac-specific IRP1/210 and transferrin-deficient9 mice, clinical trials of systemic iron supplementation in patients with heart failure in the absence of iron deficiency are certainly warranted. Iron deficiency affects up to 50% of heart failure patients, and use of i.v. iron has favourable effects on the functional status, quality of life, and exercise capacity in heart failure patients, and iron supplementation therapy has emerged as an important therapy in heart failure.6 The ability of iron supplementation to replenish depleted cardiac iron stores even when myocardial transferrin receptor expression is low suggests that non-transferrin-bound iron uptake may become more important under these circumstances. Myocardial L-type Ca2+ channels are a major mediator of non-transferrin-bound iron uptake,7 and antagonizing this compensatory pathway is consistent with the worsened clinical outcomes in heart failure patients treated with calcium channel blockers. In explanted failing human hearts, myocardial iron content was reduced in heart failure accompanied by a significant reduction in the myocardial mRNA expression of transferrin receptor, which plays a key role in cellular iron transport.13 The use of human explanted hearts adds clinical relevance to the experimental findings from pre-clinical studies and represents an important translational bridge for cardiovascular medicine that should be incorporated routinely in the evaluation of pre-clinical models of human disease. In the context of heart failure, both catecholamines and aldosterone down-regulated transferrin receptor expression in isolated cardiomyocytes.13 These molecular signalling findings provide further validation of the importance of the blockade of these pathways by using angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic receptor blockers, and mineralocorticoid receptor antagonists as key therapeutic agents for patients with heart failure (Figure 1C).14,15 The identification of pathological signalling pathways continues to be a holy grail in the elucidation of the key pathophysiological events in heart failure, and the findings of Haddad et al. have certainly added to this. Future studies may need to consider how other potential mechanisms for iron transport, such as the divalent metal transporter and ferroportin, impact on myocardial iron metabolism and heart disease. While we aimed to optimize myocardial iron levels in HF patients, we must be cautious against overcorrection which would lead to myocardial iron overload and worsening clinical outcomes. Close monitoring of haemoglobin levels, biochemical assessment of iron stores, and clinical assessment should be used regularly in order to attain an iron-repleted state while avoiding iron overload in HF patients. We acknowledge financial support from the Canadian Institutes of Health Research, Heart and Stroke Foundation, and Alberta Innovates-Health Solutions. Conflict of interest: none declared.

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