Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112-5000, USA.
Heart Rhythm. 2010 Oct;7(10):1428-1435.e1. doi: 10.1016/j.hrthm.2010.03.044. Epub 2010 Apr 7.
Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity. Previous ex vivo studies in drug-induced Andersen-Tawil syndrome (DI-ATS1) models have proposed that arrhythmia propensity in DI-ATS1 derives from cytosolic Ca(2+) (Ca(2+)) accumulation leading to increased triggered activity.
The purpose of this study was to test the hypothesis that elevated Ca(2+) with concomitant APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.
DI-ATS1 was induced in isolated guinea pig ventricles by perfusion of 2 mM KCl Tyrode solution containing 10 μM BaCl(2). APD and Ca(2+) from the anterior epicardium were quantified by ratiometric optical voltage (di-4-ANEPPS) or Ca(2+) (Indo-1) mapping during right ventricular pacing with or without the ATP-sensitive potassium channel opener pinacidil (15 μM).
APD gradients under all conditions were insufficient for arrhythmia induction by programmed stimulation. However, 38% of DI-ATS1 preparations experienced ventricular tachycardias (VTs), and all preparations experienced a high incidence of premature ventricular complexes (PVCs). Pinacidil decreased APD and APD dispersion and reduced VTs (to 6%), and PVC frequency (by 79.5%). However, PVC frequency remained significantly greater relative to control (0.5% ± 0.3% of DI-ATS1). Importantly, increased arrhythmia propensity during DI-ATS1 was associated with diastolic Ca(2+) accumulation and increased Ca(2+) transient amplitudes. Pinacidil partially attenuated the former but did not alter the latter.
The study data suggest that arrhythmias during DI-ATS1 may be a result of triggered activity secondary to prolonged APD and altered Ca(2+) cycling and less likely dependent on large epicardial APD gradients forming the substrate for reentry. Therefore, therapies aimed at reducing Ca(2+) rather than APD gradients may prove effective in treatment of ATS1.
Andersen-Tawil 综合征（ATS1）相关的室性心律失常是由频繁的、低钾血症加重的、触发活动引起的。在药物诱导的 Andersen-Tawil 综合征（DI-ATS1）模型的体外研究之前，已经提出 DI-ATS1 中的心律失常倾向源于细胞质 Ca(2+) (Ca(2+)) 积累导致的触发活动增加。
本研究旨在检验以下假设，即在 DI-ATS1 期间，导致心律失常倾向的是升高的 Ca(2+) 伴有动作电位时程（APD）延长，而不是 APD 离散度。
通过在含有 10 μM BaCl(2) 的 2mM KCl Tyrode 溶液中灌流，在分离的豚鼠心室中诱导 DI-ATS1。通过比率光学电压（di-4-ANEPPS）或 Ca(2+)（Indo-1）映射来量化右心室起搏时心外膜前表面的 APD 和 Ca(2+)，起搏时有无三磷酸腺苷敏感性钾通道开放剂匹那地尔（15 μM）。
在所有条件下，APD 梯度都不足以通过程控刺激诱导心律失常。然而，38%的 DI-ATS1 制剂发生了室性心动过速（VTs），所有制剂均发生了过早的室性搏动（PVCs）的高发生率。匹那地尔降低了 APD 和 APD 离散度，并减少了 VTs（至 6%）和 PVC 频率（减少了 79.5%）。然而，PVC 频率相对于对照仍显著增加（0.5%±0.3%的 DI-ATS1）。重要的是，在 DI-ATS1 期间，心律失常倾向的增加与舒张期 Ca(2+) 积累和 Ca(2+) 瞬变幅度增加有关。匹那地尔部分减轻了前者，但没有改变后者。
研究数据表明，DI-ATS1 期间的心律失常可能是由于延长的 APD 和改变的 Ca(2+) 循环引起的触发活动的结果，而不太可能依赖于形成折返底物的大心外膜 APD 梯度。因此，旨在降低 Ca(2+) 而不是 APD 梯度的治疗方法可能在治疗 ATS1 方面有效。
