Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

Abstract

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells, and their underlying ionic mechanisms. It is therefore critical to further unravel the patho-physiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodelling) are discussed. The focus is human relevant findings obtained with clinical, experimental and computational studies, given that interspecies differences make the extrapolation from animal experiments to the human clinical settings difficult. Deepening the understanding of the diverse patholophysiology of human cellular electrophysiology will help developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

“…Aging is associated with remarkable electrical alterations leading to remodeling of both atrial and ventricular tissues [ 55 , 56 ]. In atrial myocardium, contradictory results on the effects of age on ionic currents have been described, with some studies indicating relevant changes in sodium currents and other studies showing no significant alterations in these currents with age [ 57 , 58 ].…”

“…Thus, age-associated ion channel remodeling in different cardiac regions involves alterations in several families of ion channels, with an impact on the AP [ 67 , 68 ]. Those channels could be potential targets to help to maintain cardiac function in aged hearts [ 56 ].…”

“…This substantiates that melatonin becomes a molecule worthy to be further explored for use in clinical applications. Elevated heterogeneities in cardiac conduction and AP repolarization, which may occur in relation to aging and other cardiac diseases, can be reduced by melatonin via its action in the modulation of myocardial Cx43 [ 198 ] and ion channels, improvement of cardiomyocyte physiology, and generation and conduction of APs, ultimately protecting against arrhythmogenesis [ 18 , 56 ].…”

Patch-Clamp Recordings of Action Potentials From Human Atrial Myocytes: Optimization Through Dynamic Clamp

“…Various in vitro (Papke and Smith-Maxwell, 2009;Ebert et al, 2012;Devalla et al, 2015;Hu et al, 2018) and in vivo animal models (Olgin and Verheule, 2002;Finet et al, 2009;Nishida et al, 2010), including AF models, are available for atrial drug testing, all with their individual strengths and limitations. While these models provide an excellent starting point for atrial and AFrelated drug studies, assessments of action potentials (APs) of native human atrial cardiomyocytes remain essential due to distinct inter-species differences in ion channel expression profiles (Varró et al, 2021), and because drugs frequently act through AP shortening or prolonging effects, which may be frequency dependent (Peyronnet and Ravens, 2019). Samples of human left or right atrial appendage can be readily obtained during cardiac surgery (Hatem et al, 2010;Voigt et al, 2015), and studies employing such samples have provided detailed knowledge of human atrial electrophysiology in healthy and diseased states, as reviewed elsewhere (Nattel et al, 2007;Schotten et al, 2011;Dobrev et al, 2012;Heijman et al, 2014).…”

Quantitative cross-species translators of cardiac myocyte electrophysiology: model training, experimental validation, and applications

“…9 To accommodate for these quite different working regimes, evolution has led to several differences in the ionic mechanisms controlling excitation-contraction coupling (ECC). 7,11 Specifically, varying expression and regulation of ion channels and transporters, notably K + channels, [12][13][14][15] is mechanistically associated with species-specific action potential (AP) properties. It has been shown, for example, that the presence of a more prominent "spike & dome" morphology is due to a large transient outward current Ito in species like rabbit and human, while Ito is virtually absent in the guinea pig, which lacks the AP notch.…”