Atrial-selective targeting of arrhythmogenic phase-3 early afterdepolarizations in human myocytes. (July 2016)

• Record Type: Journal Article
• Authors: Morotti, Stefano; McCulloch, Andrew D.; Bers, Donald M.; Edwards, Andrew G.; Grandi, Eleonora
• Is Part Of: Journal of molecular and cellular cardiology. Volume 96(2016:Jul.)
• Page Start: 63
• Page End: 71
• Publication Date: 2016-07
• Subjects: ACh acetylcholine -- AF atrial fibrillation -- AP action potential -- APD action potential duration -- [Ca2 +]i intracellular Ca2 + concentration -- CaMKII Ca2 +/calmodulin-dependent protein kinase II -- DAD delayed afterdepolarization -- EAD early afterdepolarization -- Em membrane potential -- ICa L-type Ca2 + current -- INa Na+ current -- IKr delayed rectifier K+ current -- INCX Na+/Ca2 + exchanger current -- ISO isoproterenol -- NCX Na+/Ca2 + exchanger -- pAF paroxysmal atrial fibrillation -- PV pulmonary vein -- RyR ryanodine receptor -- SR sarcoplasmic reticulum -- UDB use-dependent block; Na+ current -- Phase-3 EAD -- Atrial fibrillation -- Ranolazine -- Computer model; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.07.030
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: We have previously shown that non-equilibrium Na + current (INa ) reactivation drives isoproterenol-induced phase-3 early afterdepolarizations (EADs) in mouse ventricular myocytes. In these cells, EAD initiation occurs secondary to potentiated sarcoplasmic reticulum Ca 2 + release and enhanced Na + /Ca 2 + exchange (NCX). This can be abolished by tetrodotoxin-blockade of INa, but not ranolazine, which selectively inhibits ventricular late INa . Aim: Since repolarization of human atrial myocytes is similar to mouse ventricular myocytes in that it is relatively rapid and potently modulated by Ca 2 +, we investigated whether similar mechanisms can evoke EADs in human atrium. Indeed, phase-3 EADs have been shown to re-initiate atrial fibrillation (AF) during autonomic stimulation, which is a well-recognized initiator of AF. Methods: We integrated a Markov model of INa gating in our human atrial myocyte model. To simulate experimental results, we rapidly paced this cell model at 10 Hz in the presence of 0.1 μM acetylcholine and 1 μM isoproterenol, and assessed EAD occurrence upon return to sinus rhythm (1 Hz). Results: Cellular Ca 2 + loading during fast pacing results in a transient period of hypercontractility after return to sinus rhythm. Here, fast repolarization and enhanced NCX facilitate INa reactivation via the canonical gating mode (i.e., not late INa burst mode), which drives EAD initiation. Simulating ranolazine administration reduces atrial peak INa and leads to faster repolarization, during which INa fails to reactivate and EADs are prevented. Conclusions: Non-equilibrium INa reactivation can critically contribute to arrhythmias, specifically in human atrial myocytes. Ranolazine might be beneficial in this context by blocking peak (not late) atrial INa . Graphical abstract: Highlights: Combined ISO and ACh cause phase-3 EADs in human atrial myocyte simulations. Phase-3 EADs are favored by increased Ca 2 + transients and rapid Em repolarization. NCX-mediated long AP plateaus recruit non-equilibrium INa reactivation to favor EAD. Ranolazine prevents phase-3 EADs in an atrial selective manner.