Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

Abstract

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome

“…ROS, in addition to their role as a messenger in cell signal transduction and the cell cycle, regulate both cellular metabolism and ion homeostasis in excitable cells. An elevated presence of ROS within the cells can be highly toxic, and they can lead to arrhythmogenic triggers, such as alterations of ion channels (Na, Ca 2+ , and K + ), dysfunction of the mitochondria, and gap junction remodeling [ 74 ]. Therefore, an excessive production of ROS and ineffective ROS scavenging can culminate in cell death [ 52 ].…”

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity

“…ROS themselves induce further mitochondrial damage that, in turn, may predispose to cardiac arrhythmias [ 46 , 47 , 48 ]. The incidence of atrial fibrillation (which is treated with amiodarone) increases with ageing [ 2 , 49 ], thus amiodarone will be used in patients with already impaired mitochondria due to advanced age.…”

Disturbed Cardiac Metabolism Triggers Atrial Arrhythmogenesis in Diabetes Mellitus: Energy Substrate Alternate as a Potential Therapeutic Intervention

“…Mitochondria is the primary target of free radical production, and damaged mitochondrial DNA and dysfunctional mitochondria result in disrupted mitochondrial membrane potentials, reduced ATP production capacity, and mitochondrial respiration [ 72 , 73 ]. The subsequent aberrant mitochondrial signaling predisposes the myocardium to arrhythmias [ 74 ]. Moreover, under the metabolic stress condition, sensing the cellular energy deprivation, the sarcoK ATP channels are triggered to open, leading to significantly shortened APD, which promotes the development of cardiac arrhythmia [ 75 ].…”