Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a(+/-) hearts.
Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a(+/-) hearts.
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DOI：
10.1113/jphysiol.2013.254938
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Huang CL
中科院分区：
文献类型：
--
作者：
Matthews GD;Guzadhur L;Sabir IN;Grace AA;Huang CL
心电动作电位波长的减少和随之而来的波断与心律失常有关。快速性心律失常在Brugada综合征中更为常见，特别是在药物刺激后，以前使用Scn5a+/−小鼠心脏建模。利用单相动作电位记录的传播潜伏期和动作电位持续时间（apd）来评估langendorff灌注野生型（WT）和Scn5a+/−心脏的波长随心率的变化。记录右（RV）和左（LV）心室，心外膜和心内膜表面在增量起搏期间，之前和之后的弗来卡因或奎尼丁挑战。传导速度（θ′）、动作电位波长（λ′= APD ×θ′）及其对应的交替与舒张期（DI）呈非线性关系。Scn5a+/−RV心外膜最大θ′小于心内膜。氟卡因胺进一步降低θ′，加重右心室传导阻滞。奎尼丁降低了WT的最大θ′值，并导致Scn5a+/ -和WT的RV更早的传导失败。使用恢复波长（λ ' 0= DI ×θ ‘）而不是DI，提供了新的λ ’对λ ' 0的λ恢复图，其和基本周期距离允许反馈分析。与APD和θ恢复梯度相比，λ恢复梯度与交替量级的相关性更好。未治疗的心脏和奎尼丁治疗的WT心脏在θ′和APD恢复上差异很大，而在最大λ′上差异很小。引人注目的是，所有区域和条件都汇聚到一个共同的不稳定点，这意味着一种守恒关系。Flecainide或quinidine通过减少Scn5a+/−RV心外膜的基本周期距离来降低发生这种情况的起搏速率，直接预测其心律失常表型。
Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a+/− murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a+/− hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (θ′), action potential wavelengths (λ′= APD ×θ′), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum θ′ was lower in Scn5a+/− RV epicardium than endocardium. Flecainide further reduced θ′, accentuating this RV conduction block. Quinidine reduced maximum θ′ in WT and caused earlier conduction failure in the RV of both Scn5a+/− and WT. Use of recovery wavelengths (λ′0= DI ×θ′) rather than DI, provided novel λ restitution plots of λ′ against λ′0, which sum to a basic cycle distance permitting feedback analysis. λ′ restitution gradient better correlated with alternans magnitude than either APD or θ restitution gradient. The large differences in θ′ and APD restitution contrasted with minor differences in maximum λ′ between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a+/− RV epicardium, directly predictive of its arrhythmic phenotype.
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