Willis B Cicero, Pandit Sandeep V, Ponce-Balbuena Daniela, Zarzoso Manuel, Guerrero-Serna Guadalupe, Limbu Bijay, Deo Makarand, Camors Emmanuel, Ramirez Rafael J, Mironov Sergey, Herron Todd J, Valdivia Héctor H, Jalife José
From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
Circulation. 2016 Jun 14;133(24):2348-59. doi: 10.1161/CIRCULATIONAHA.116.021936. Epub 2016 May 11.
In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca(2+) dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether PC intracellular Ca(2+) ([Ca(2+)]i) dysregulation results from a constitutive [Na(+)]i surplus relative to VMs.
Simultaneous optical mapping of voltage and [Ca(2+)]i in CPVT hearts showed that spontaneous Ca(2+) release preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca(2+) imaging, early and delayed afterdepolarizations trailed spontaneous Ca(2+) release and were more frequent in CPVT PCs than CPVT VMs. As a result of increased activity of mutant ryanodine receptor type 2 channels, sarcoplasmic reticulum Ca(2+) load, measured by caffeine-induced Ca(2+) transients, was lower in CPVT VMs and PCs than respective controls, and sarcoplasmic reticulum fractional release was greater in both CPVT PCs and VMs than respective controls. [Na(+)]i was higher in both control and CPVT PCs than VMs, whereas the density of the Na(+)/Ca(2+) exchanger current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na(+)]i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca(2+) release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na(+)]i monotonically increased delayed afterdepolarization frequency. Confocal imaging experiments showed that postpacing Ca(2+) spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-induced membrane permeabilization, indicating that differences in [Na(+)]i played a central role.
In CPVT mice, the constitutive [Na(+)]i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.
在儿茶酚胺能多形性室性心动过速（CPVT）中，心脏浦肯野细胞（PCs）似乎比心室肌细胞（VMs）更容易受到Ca(2+)功能障碍的影响。其潜在机制尚不清楚。我们使用一只CPVT小鼠（RyR2(R4496C+/Cx40eGFP)），测试PC细胞内Ca(2+)（[Ca(2+)]i）失调是否源于相对于VMs而言的持续性细胞内[Na(+)]过剩。
对CPVT心脏进行电压和[Ca(2+)]i的同步光学映射显示，在心室心内膜下PCs中，自发性Ca(2+)释放先于起搏诱导的触发活动。在同时进行电流钳制和Ca(2+)成像时，早期和延迟后去极化跟随自发性Ca(2+)释放之后出现，且在CPVT PCs中比在CPVT VMs中更频繁。由于突变的2型兰尼碱受体通道活性增加，通过咖啡因诱导的Ca(2+)瞬变测量的肌浆网Ca(2+)负荷在CPVT VMs和PCs中均低于各自的对照组，且肌浆网分数释放在CPVT PCs和VMs中均高于各自的对照组。对照组和CPVT PCs中的[Na(+)]i均高于VMs，而PCs和VMs之间的Na(+)/Ca(2+)交换电流密度没有差异。使用PC模型进行的计算机模拟预测，PCs升高的[Na(+)]i会促进延迟后去极化，而延迟后去极化总是先于高活性2型兰尼碱受体通道的自发性Ca(2+)释放事件。[Na(+)]i的增加会单调增加延迟后去极化频率。共聚焦成像实验表明，完整的CPVT PCs中起搏后Ca(2+)火花频率最高，但在皂素诱导的膜通透化后这种差异会逆转，表明[Na(+)]i的差异起核心作用。
在CPVT小鼠中，PCs持续性的细胞内[Na(+)]过量比VMs在更低的应激水平下促进触发活动和心律失常的发生。
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