Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

Abstract

This is the second of the two White Papers from the fourth UC Davis Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was 'K channels and regulation', and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K channel in health and disease, as well as K channels as therapeutic targets, were contributed by Ye Chen-Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state-of-the-art knowledge and controversies on the functional roles of cardiac K channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.

Calcium Signaling and Cardiac Arrhythmias

“…by increased inward I Ca,L 37 and late Na + -current I Na,L or I NCX , 38, 39 or by reduced K + -currents (I K ), allowing I Ca,L to recover from inactivation and depolarize the cardiomyocyte by allowing Ca 2+ to enter. 40 CaMKII-dependent I Ca,L phosphorylation slows inactivation and accelerates recovery from inactivation, further enhancing the likelihood of EADs. 37 At membrane potentials negative to the threshold of I Ca,L activation, spontaneous SR Ca 2+ release-activated NCX favors the non-equilibrium reactivation of I Na , driving phase-3 EADs induction.…”

Doctoral Dissertation

“…Beside the noticeable differences between nodal, atrial and ventricular action potentials there are variations in action potential shape between the ventricles. Action potentials from the canine right ventricle have longer duration and a larger early repolarization compared to those from the left ventricle and differences in apex to base have been reported, with shorter APD in the apical regions in human and canine hearts …”

“…The chronotropy of the heart is increased by binding of cAMP directly to the HCN channels resulting in increased I f and an acceleration of the spontaneous depolarization in the SAN pacemaker cells . It is crucial to ensure adequate diastolic filling time during fast heart rates and action potentials are markedly shortened by sympathetic stimulation; this is mainly because of PKA‐mediated phosphorylation of K V 7.1 resulting in increased I Ks . I Kr is relatively insensitive to β 1 stimulation but the effect of increased rate alone increases I Kr .…”

Mechanics and energetics in cardiac arrhythmias and heart failure

“…In 2014 the topic was Na + channel and Na + transport and the conference produced three White Papers (Chen- Clancy et al 2015;Shattock et al 2015). The 2016 topic was K + channels and regulation ) and produced two White Papers Chiamvimonvat et al 2017). The 2018 topic was on Mechanics and Energetics.…”