Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

Abstract

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.

Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells

“…Additionally, adult human primary ventricular myocytes were isolated enzymatically from the left and right ventricles. 103 , 104 , 105 Tissues and cardiomyocytes were immediately submerged in liquid nitrogen for approximately 30 s and then removed carefully with liquid nitrogen tongs and placed on dry ice. Next, the samples were quickly transferred and stored in a −80°C freezer.…”

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca2+

“…Late Na + current can be enhanced by drugs or mutations that delay inactivation. Recent experiments support arrhythmogenic effects of this pathway [ 91 , 92 ].…”

Exploring the Coordination of Cardiac Ion Channels With Action Potential Clamp Technique

“…The method gained popularity in a short time and grew into a valuable tool for mapping the ion currents that shape AP in various cells types including the cardiac myocytes ( Doerr et al, 1990 ; Bouchard et al, 1995 ), neurons ( Barra, 1996 ), and plant cells ( Thiel, 2004 ). The subtraction method is used with various command pulses including rectangular steps or ramps especially to isolate small currents ( Wagner et al, 2006 ; Maltsev and Kyle, 2009 ; Ton et al, 2021 ). Combined with fluorescent techniques, the AP clamp method became a powerful tool for studying the Ca 2+ dynamics in cardiac myocytes ( Arreola et al, 1991 ; Grantham and Cannell, 1996 ; Puglisi et al, 1999 ).…”