Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation

Abstract

Rhythmic and effective cardiac contraction depends on appropriately timed generation and spread of cardiac electrical activity. The basic cellular unit of such activity is the action potential, which is shaped by specialized proteins (channels and transporters) that control the movement of ions across cardiac cell membranes in a highly regulated fashion. Cardiac disease modifies the operation of ion channels and transporters in a way that promotes the occurrence of cardiac rhythm disturbances, a process called "arrhythmogenic remodeling." Arrhythmogenic remodeling involves alterations in ion channel and transporter expression, regulation and association with important protein partners, and has important pathophysiological implications that contribute in major ways to cardiac morbidity and mortality. We review the changes in ion channel and transporter properties associated with three important clinical and experimental paradigms: congestive heart failure, myocardial infarction, and atrial fibrillation. We pay particular attention to K+, Na+, and Ca2+ channels; Ca2+ transporters; connexins; and hyperpolarization-activated nonselective cation channels and discuss the mechanisms through which changes in ion handling processes lead to cardiac arrhythmias. We highlight areas of future investigation, as well as important opportunities for improved therapeutic approaches that are being opened by an improved understanding of the mechanisms of arrhythmogenic remodeling.

Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling

“…Decreases in both mRNA 84 and protein 90 of these subunits have been reported in human and animal AF, corresponding to a decreased current response to M2 receptor stimulation 83,84 . Furthermore, all three muscarinic receptor subtypes (M2, M3, M4) which are coupled to K + currents in atrial cells from LA and PV undergo an ATR downregulation process 92 .…”

“…Therefore, atrial myocytes put forward different mechanisms in order to protect themselves from Ca 2+ . Yue et al 79 , studying an animal The voltage gated transient outward K + current I to is consistently decreased in ATR 83 . Its role in promoting AF is not well established.…”

“…Stimulation of cardiac M 2 muscarinic cholinergic receptors with cholinergic agonists in the VS model elicits a large inward rectifier K + current, I KAch , which strongly promotes AF 38,83 . Similarly, constitutively activated inward rectifier K + current I KAch,c is also upregulated in cardiomyocytes from AF patients 93 and contributes to ATR-induced APD abbreviation and atrial-tachyarrhythmia promotion in canine atrium 83,95 . However, Are there any electrophysiological differences between the models that can be paralleled to different clinical forms of AF or that can justify a different AF promotion?…”

“…Stimulation of cardiac M 2 muscarinic cholinergic receptors by cholinergic agonists elicits a large inward rectifier K + current, I KACh , which strongly promotes AF 38,83 . In a mouse knockout model lack of I KACh prevented AF 137 .…”

Ion Channel Remodeling—A Potential Mechanism Linking Sleep Apnea and Sudden Cardiac Death

“…I C a indicates inward calcium current L‐type; I K r , delayed inward rectifier K + ; I K s , slowly activating K + channel; I N a , inward voltage‐dependent sodium channel; I NCX , sodium‐calcium exchanger; I to , transient outward; LA , left atrium; LV , left ventricle; RA , right atrium; RV , right ventricle. Adapted from Dumotier, Heart 12 by permission from BMJ Publishing Group Limited, and from Nattel et al, Physiological Reviews ,13 with permission by the American Physiological Society.…”