Prooxidant Mechanisms in Iron Overload Cardiomyopathy

Abstract

Iron overload cardiomyopathy (IOC), defined as the presence of systolic or diastolic cardiac dysfunction secondary to increased deposition of iron, is emerging as an important cause of heart failure due to the increased incidence of this disorder seen in thalassemic patients and in patients of primary hemochromatosis. At present, although palliative treatment by regular iron chelation was recommended; whereas IOC is still the major cause for mortality in patient with chronic heart failure induced by iron-overloading. Because iron is a prooxidant and the associated mechanism seen in iron-overload heart is still unclear; therefore, we intend to delineate the multiple signaling pathways involved in IOC. These pathways may include organelles such as calcium channels, mitochondria; paracrine effects from both macrophages and fibroblast, and novel mediators such as thromboxane A2 and adiponectin; with increased oxidative stress and inflammation found commonly in these signaling pathways. With further understanding on these complex and inter-related molecular mechanisms, we can propose potential therapeutic strategies to ameliorate the cardiac toxicity induced by iron-overloading.

Increased iron stores prolong the QT interval – a general population study including 20 261 individuals and meta‐analysis of thalassaemia major

“…A biological plausible mechanism for the association between elevated ferritin concentration and transferrin saturation and prolonged QT interval may be iron induced oxidative stress via the Fenton reaction(Broedbaek et al , ; Poulsen et al , ). Free radicals causing oxidative stress have been suggested to cause damage of proteins and DNA, including mitochondrial DNA in the myocardium (Oudit et al , ; Lekawanvijit & Chattipakorn, ; Murphy & Oudit, ; Cheng & Lian, ). Also, the accumulation per se of iron in the myocytes may impair myocyte function(James, ; Cecchetti et al , ).…”

“…Also, the accumulation per se of iron in the myocytes may impair myocyte function(James, ; Cecchetti et al , ). Furthermore, oxidative stress may cause low grade inflammation(Cheng & Lian, ) leading to fibrosis by activating myocardial macrophages and fibroblasts(Oudit et al , ; Cheng & Lian, ). Lastly, in animal models, increased iron stores have been shown to increase PR interval, QRS interval and QT interval(Obejero‐Paz et al , ).…”

Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral?

“…The activity of mitochondrial Fe/S cluster proteins is reduced in failing hearts, an effect attributed to the lack of an Fe/S cluster centre . On the other hand, clinical data and evidence from animal models with specific genetic defects have suggested that myocardial iron overload or accumulation of iron in the mitochondria can induce or exacerbate cardiomyopathy, presumably as a consequence of ROS‐dependent mechanisms. The question of whether iron accumulates in the mitochondria of failing hearts due to a shared aetiology, such as hypertension or myocardial infarction, has not been examined.…”

Inflammatory and oxidative status in European captive black rhinoceroses: a link with Iron Overload Disorder?

“…High levels of oxidative stress can predispose to diseases and rapid ageing [17] and should be taken into consideration for husbandry, health care and more globally ex-situ conservation of endangered species like the BR. Oxidative stress is reported to worsen iron overload syndromes like iron overload cardiomyopathies in humans [65], which themselves favour reactive oxygen metabolite formation and thus oxidative stress increase [17]. IOD could then be self-sustained through the oxidative stress induced, leading to a vicious circle.…”