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.
Highlights
Aging is the progressive decline in the fitness of an organism due to cumulative organ-specific physiological deterioration [1, 2]
It is associated with major morbidity by increasing the risk of stroke and heart failure, as well as all-cause mortality [11,12,13]. Ventricular arrhythmias such as ventricular tachycardia often degenerating into ventricular fibrillation (VF) are a major public health concern. They constitute the primary cause of sudden cardiac death (SCD), which accounts for 4–5 million deaths/year worldwide [14] representing over 5% of overall mortality [15]
Age-related mitochondrial dysfunction and reactive oxygen species (ROS) generation may account for the activation abnormalities that appear later in life in long QT syndrome 3 (LQT3) patients and associated with increased arrhythmic risk
Summary
Aging is the progressive decline in the fitness of an organism due to cumulative organ-specific physiological deterioration [1, 2]. As the aging population continues to increase, with the number of elderly people predicted to double in the 25 years in the United States age related cardiovascular diseases will continue to represent a major public health concern [5, 8]. Ventricular arrhythmias such as ventricular tachycardia often degenerating into ventricular fibrillation (VF) are a major public health concern They constitute the primary cause of sudden cardiac death (SCD), which accounts for 4–5 million deaths/year worldwide [14] representing over 5% of overall mortality [15]. Select channelopathies demonstrate an excellent paradigm to study the effects of agerelated molecular changes on susceptible hearts with inherent proarrhythmic tendency This will elucidate the molecular mechanisms underlying proarrhythmic changes with age and offer novel anti-arrhythmic pharmacological targets
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