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Abstract
Aging of the heart is associated with a blunted response to sympathetic stimulation, reduced contractility, and increased propensity for arrhythmias, with the risk of sudden cardiac death significantly increased in the elderly population. The altered cardiac structural and functional phenotype, as well as age-associated prevalent comorbidities including hypertension and atherosclerosis, predispose the heart to atrial fibrillation, heart failure, and ventricular tachyarrhythmias. At the cellular level, perturbations in mitochondrial function, excitation-contraction coupling, and calcium homeostasis contribute to this electrical and contractile dysfunction. Major determinants of cardiac contractility are the intracellular release of Ca2+ from the sarcoplasmic reticulum by the ryanodine receptors (RyR2), and the following sequestration of Ca2+ by the sarco/endoplasmic Ca2+-ATPase (SERCa2a). Activity of RyR2 and SERCa2a in myocytes is not only dependent on expression levels and interacting accessory proteins, but on fine-tuned regulation via post-translational modifications. In this paper, we review how aberrant changes in intracellular Ca2+ cycling via these proteins contributes to arrhythmogenesis in the aged heart.
Highlights
Heart disease remains the leading cause of death in the US [1], in part due to the aging population
Triggering action potentials depolarize the cell and open L-type Ca2+ channels (LTCCs) at the sarcolemma, which initiates Ca2+ release from the sarcoplasmic reticulum (SR) Ca2+ release channels and the cardiac ryanodine receptors (RyR2s)
We provide a more concentrated focus on aberrant intracellular Ca2+ release and mechanisms of arrhythmogenesis that occur in the aged heart
Summary
Heart disease remains the leading cause of death in the US [1], in part due to the aging population. The cardiac disease phenotype is a culmination of altered response to β-adrenergic stimulation [4,5,6], mitochondrial dysfunction [7], increased reactive oxygen species (ROS) emission [8,9], and dysregulated Ca2+ homeostasis [10] This causes impaired systolic and diastolic function, impaired relaxation, and cardiac arrhythmia. We and others have comprehensively reviewed the function, post-translational modifications, and role of excitation-contraction coupling proteins in the development of cardiac arrhythmia [12,13,14,15,16] In this case, we provide a more concentrated focus on aberrant intracellular Ca2+ release and mechanisms of arrhythmogenesis that occur in the aged heart
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