Heterogeneous distribution of INa-L determines interregional differences in rate adaptation of repolarization

Qi, Datun; Yang, Zhen; Robinson, Victoria M.; Li, Jing; Gao, Chuanyu; Guo, Dan; Kowey, Peter R.; Yan, Gan‐Xin

doi:10.1016/j.hrthm.2015.02.013

Cited by 29 publications

(28 citation statements)

References 35 publications

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“…6 Consistent with this finding is our observation in the intact animals that the PT a interval, which correlates with atrial APD (r ¼ 0.94), 11 is significantly shortened, with parallel shortening of the ventricular repolarization duration measure QT interval ( Figure 3). These findings are in agreement with those of Qi et al, 24 who demonstrated the presence of late I Na in the left and right atria as well as ventricles using whole-cell patch clamp techniques. The observation by Sicouri et al 19 that GS-967, a compound related to eleclazine, was found to be highly effective in suppressing catecholamine-induced AF triggers, specifically early and delayed afterdepolarization-mediated extrasystolic activity in pulmonary vein preparations, is consistent with the anti-AF actions observed in the present study.…”

Section: Effects Of Eleclazine On Atrial Repolarization Alternans Andsupporting

confidence: 93%

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

et al. 2016

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Section: Effects Of Eleclazine On Atrial Repolarization Alternans Andsupporting

confidence: 93%

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

et al. 2016

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“…In rabbit heart, the basal APD is longer, and the slope of APD rate adaptation is steeper in the LV compared to the RV chamber . These dissimilarities are likely attributed to a greater density of the late Na + current in LV myocytes.…”

Section: Electrical Restitutionmentioning

confidence: 95%

“…), a difference which is attributed to the greater expression of I K1 , the inward rectifier K + current, in LV cells . In rabbit heart, the published data on interventricular difference in repolarization are quite inconclusive, with APD shown to be similar in both ventricular chambers, or to exhibit a greater value in either RV or LV myocytes …”

Section: Spatial Repolarization Gradientsmentioning

confidence: 99%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

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“…Furthermore, recent work suggests that regional heterogeneity in I Na,L density may modulate the response of atrial and ventricular cardiomyocytes to class III antiarrhythmics. 42 Further work on regional differences in the consequences of NCB-KCB interaction would be of interest.…”

Section: Study Limitationsmentioning

confidence: 99%

Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade

Aguilar

Xiong

et al. 2015

Circulation

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Background— The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K + -channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na + -channel blockers. Methods and Results— Realistic cardiomyocyte-, tissue-, and state-dependent Na + -channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na + -current ( I Na ) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K + currents ( I Kr and I Kur , respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na + -channel blocker. Combining optimized Na + -channel blocker with I Kr block increased rate-dependent and atrium-selective peak I Na reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na + -channel blocker alone. Combining optimized Na + -channel blocker with I Kur block had similar effects but without I Kr block–induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective I Kr blocker) to pilsicainide (selective I Na blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible. Conclusions— K + -channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na + -channel blockade. Combining optimized Na + -channel block with blockade of atrial K + currents is a potentially valuable AF-selective antiarrhythmic drug strategy.

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Heterogeneous distribution of INa-L determines interregional differences in rate adaptation of repolarization

Cited by 29 publications

References 35 publications

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade

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