Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Abstract

Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca 2+ homeostasis, excitation–contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Cardiac arrhythmogenesis: roles of ion channels and their functional modification

“…Identified clinical or novel physiological phenomena initiate the development of representative experimental physiological models. These insights, in turn, prompt innovative clinical testing, management, and treatment, themselves prompting further iterations of experimental testing to identify novel physiological targets, investigational new drugs, and interventions ( Huang et al, 2020 ; Huang and Lei, 2023 ). Future such cycles could add immunotherapeutic approaches, including antibody-based agents with further enhanced target specificities even targeting particular channel isoforms ( Presta, 2008 ) and micro-RNAs/shRNAs knocking down protein expression at the mRNA level provided suitable delivery methods become available ( Chakraborty et al, 2017 ).…”

“…It also activates protein kinase A (PKA) whose widespread phosphorylation actions excite Nav1.5, Kv11.1, Kv7.1, and Cav1.2, increasing rapid inward I Na and slow outward I Kr and I Ks and I CaL , increasing ventricular AP amplitudes but shortening the AP plateau durations. It also accelerates SAN pacemaker potentials ( Huang and Lei, 2023 ). In excitation–contraction coupling , sympathetic activity increases I CaL and net cellular Ca 2+ entry increasing rates and force of subsequent muscle contraction.…”