Measures of repolarization variability predict ventricular arrhythmogenesis in heptanol-treated Langendorff-perfused mouse hearts.

Gary Tse,Sharen Lee,Wing Tak Wong,Jiandong Zhou,Guoliang Hao,Shuk Han Cheng,Tong Liu,Qingpeng Zhang,Yimei Du

doi:10.1016/j.crphys.2021.04.001

Abstract

BackgroundTime-domain and non-linear methods can be used to quantify beat-to-beat repolarization variability but whether measures of repolarization variability can predict ventricular arrhythmogenesis in mice have never been explored.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during constant right ventricular 8 Hz pacing in Langendorff-perfused mouse hearts, in the presence or absence of the gap junction and sodium channel inhibitor heptanol (0.1, 0.5, 1 or 2 mM).ResultsUnder control conditions, mean action potential duration (APD) was 39.4 ± 8.1 ms. Standard deviation (SD) of APDs was 0.3 ± 0.2 ms, coefficient of variation was 0.9 ± 0.8% and the root mean square (RMS) of successive differences in APDs was 0.15 ± 0.14 ms. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with a SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ± 2.1. Approximate and sample entropy were 0.61 ± 0.12 and 0.76 ± 0.26, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.49 ± 0.27 and 0.81 ± 0.36, respectively. Heptanol at 2 mM induced ventricular tachycardia in five out of six hearts. None of the above parameters were altered by heptanol during which reproducible electrical activity was observed (KW-ANOVA, P > 0.05). Contrastingly, SD2/SD1 decreased to 2.03 ± 0.41, approximate and sample entropy increased to 0.82 ± 0.12 and 1.45 ± 0.34, and short-term fluctuation slope decreased to 0.82 ± 0.19 during the 20-s period preceding spontaneous ventricular tachy-arrhythmias (n = 6, KW-ANOVA, P < 0.05).ConclusionMeasures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention.

Highlights

Beat-to-beat variations in the repolarization time-course is an inherent property of cardiac electrophysiological function (Couderc, 2009)
action potential duration (APD) variability can be affected by different physiological states, such as the extent of intercellular coupling (Zaniboni et al, 2000), redox changes (Kistamas et al, 2015a), abnormal calcium dynamics (Kistamas et al, 2015b) or time taken for full repolarization (Abi-Gerges et al, 2010)
Since our previous analysis used the mean duration of repolarization without assessing its beat-to-beat variability, in this study we tested the hypothesis that repolarization variability by non-linear measures can predict heptanol-induced ventricular arrhythmias in Langendorff-perfused mouse hearts

Summary

Introduction

Beat-to-beat variations in the repolarization time-course is an inherent property of cardiac electrophysiological function (Couderc, 2009). Since our previous analysis used the mean duration of repolarization without assessing its beat-to-beat variability, in this study we tested the hypothesis that repolarization variability by non-linear measures can predict heptanol-induced ventricular arrhythmias in Langendorff-perfused mouse hearts. Conclusion: Measures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention

Methods

Results

Discussion

Conclusion