Iron overload and arrhythmias: Influence of confounding factors

Abstract

Arrhythmias as a cardiac complication of iron overload (IO) have been well described for decades in the clinical literature. They are assumed to be directly associated with the myocardial accumulation of iron. However, the influence of heart failure and elevated oxidative stress, which are major arrhythmogenic confounding factors associated with IO on arrhythmias, has not been critically reviewed in the published literature. A comprehensive narrative review of published articles in PubMed was conducted to address the influence of confounding factors of IO on arrhythmias. The previous data may have been largely confounded by the other cardiac complications of IO, particularly heart failure. The previous studies on IO‐related arrhythmias lack proper age‐gender–matched control subjects and/or comparison groups with properly controlled confounding factors to assess accurately their etiology and clinical significance. Given the above considerations, further mechanistic investigations to clarify the etiology and clinical relevance of IO‐induced arrhythmias are needed. In addition, investigations to develop arrhythmia management strategy specific to IO, are warranted.

Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

“…While it has been well acknowledged that IO results in cardiomyopathy [ 1 , 2 , 3 ], it remains unclear whether IO may play a causal role in cardiac arrhythmogenesis and how mitochondrial dysfunction might be involved [ 4 , 5 ]. Clinical studies have reported the occurrence of atrial and ventricular tachyarrhythmias in patients with IO conditions [ 4 , 29 , 30 , 31 , 32 , 33 , 34 ].…”

“…The resultant non-transferrin bound iron accumulates in organs and tissues, leading to organ damage and potentially organ failure. It has been suggested that IO leads to cardiomyopathy and heart failure [ 1 , 2 , 3 ], and its role in cardiac arrhythmogenesis remains controversial [ 4 , 5 ]…”

Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias

“…Such changes indicating oxidative stress have been linked with atrial fibrillation [ 7 , 8 ], arrhythmias occurring in failing hearts [ 9 , 10 , 11 , 12 ] and rhythm disturbances in acute myocardial ischemia/reperfusion injury [ 13 , 14 ]. Likewise, other conditions being related to oxidative stress and ventricular arrhythmias include high levels of catecholamines [ 15 , 16 , 17 ], homocysteine [ 18 , 19 ] or iron overload [ 20 ]; arrhythmic changes under these situations are comparable to those observed upon treatment of the hearts with H 2 O 2 [ 21 ], showing association with diminished electrical stability. These observations are consistent with the antiarrhythmic effects of different substances such as glutathione, superoxide dismutase, catalase, allopurinol and mito-tempo, which are known to react with reactive oxygen species (ROS) directly, and/or indirectly as inhibitors of the free radical generating enzymes, and/or activators of intracellular antioxidant enzymes [ 12 , 14 , 22 , 23 , 24 ].…”

Iron Administration Affects Cardiac Calcium Channel Expression in Mice: The Role of Cardiac Calcium Channel Expression in The Heart of Iron Overload Mice Model

“…(9) Another life-threatening condition in iron overload patients such as arrhythmias, which may occur simultaneously with acute heart failure, leads to sudden cardiac death. (10,11) The mechanism of IOC is mediated by reactive oxidative stress whereby iron accumulation at the cytoplasm becomes more available and fulfill component for Fenton Reaction, leading to the conversion of Fe 2+ into Fe 3+ produces free radical including the hydroxyl radicals in which leading to increase peroxidation and triggering cellular damage and antioxidants depletion. In the state of iron overload, transferrin is completely saturated, and the non-transferrin-bound iron (NTBI) is found in plasma.…”

“…These conditions lead to cardiomyopathy. (6,11,12) During cardiomyopathy, several compensatory mechanisms might be occurred, including neurohormonal activation and ventricular remodelling. (13,14) Cardiac calcium channels, including LTCCs and TTCCs, are the important organelles that must be produced in suboptimal cardiac function.…”