蒲肯野细胞钙调节异常是儿茶酚胺多形性室性心动过速的细胞机制。
Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia.
机构信息
Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48108, USA.
出版信息
Heart Rhythm. 2010 Aug;7(8):1122-8. doi: 10.1016/j.hrthm.2010.06.010. Epub 2010 Jun 9.
BACKGROUND
Inherited arrhythmias can be caused by mutations in the cardiac ryanodine receptor (RyR2). The cellular source of these arrhythmias is unknown. Isolated RyR2(R4496C) mouse ventricular myocytes display arrhythmogenic activity related to spontaneous Ca(2+) release during diastole. On the other hand, recent whole-heart epicardial and endocardial optical mapping data demonstrate that ventricular arrhythmias in the RyR2(R4496C) mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) originate in the His-Purkinje system, suggesting that Purkinje cells, and not ventricular myocytes, may be the cellular source of arrhythmogenic activity. The relative effect of the RyR2(R4496C) mutation on calcium homeostasis in ventricular myocytes versus Purkinje cells is unknown.
OBJECTIVE
This study sought to determine which cardiac cell type is more severely affected, in terms of calcium handling, by expression of the RyR2(R4496C) mutant channel: the ventricular myocytes or the Purkinje cells.
METHODS AND RESULTS
To discriminate Purkinje cells from ventricular myocytes, we crossed the RyR2(R4496C) mouse model of CPVT with the Cx40(EGFP/+) transgenic mouse. This genetic cross yields Purkinje cells that express eGFP, and therefore fluoresce green when excited by the appropriate wavelength; ventricular myocytes, which do not express connexin 40, are not green. Intracellular calcium was measured in each cell type using calcium-sensitive probes. Purkinje cells of the RyR2(R4496C) mouse model of CPVT show an approximately 2x greater rate (P < .05) and approximately 2x to 3x greater amplitude (P < .000001) of spontaneous calcium release events than ventricular myocytes isolated from the same heart.
CONCLUSION
These results demonstrate that focally activated arrhythmias originate in the specialized electrical conducting cells of the His-Purkinje system in the RyR2(R4496C) mouse model of CPVT.
背景
遗传性心律失常可能是由心脏兰尼碱受体（RyR2）的突变引起的。这些心律失常的细胞来源尚不清楚。分离的 RyR2（R4496C）小鼠心室肌细胞在舒张期表现出与自发性 Ca（2+）释放相关的致心律失常活性。另一方面，最近的全心外膜和心内膜光学映射数据表明，儿茶酚胺多形性室性心动过速（CPVT）的 RyR2（R4496C）小鼠模型中的室性心律失常起源于希氏-浦肯野系统，表明浦肯野细胞，而不是心室肌细胞，可能是致心律失常活性的细胞来源。RyR2（R4496C）突变对心室肌细胞和浦肯野细胞钙稳态的相对影响尚不清楚。
目的
本研究旨在确定 RyR2（R4496C）突变体通道表达对哪种心脏细胞类型的钙处理影响更严重：心室肌细胞还是浦肯野细胞。
方法和结果
为了将 CPVT 的 RyR2（R4496C）小鼠模型与 Cx40（EGFP/+）转基因小鼠区分开来，我们进行了交叉。这种基因交叉产生表达 eGFP 的浦肯野细胞，因此当用适当的波长激发时会发出绿色荧光；不表达连接蛋白 40 的心室肌细胞不是绿色的。使用钙敏探针测量每种细胞类型的细胞内钙。CPVT 的 RyR2（R4496C）小鼠模型中的浦肯野细胞自发钙释放事件的频率约增加 2 倍（P <.05），幅度约增加 2 至 3 倍（P <.000001），比从同一心脏分离的心室肌细胞大。
结论
这些结果表明，局灶性激活的心律失常起源于 CPVT 的 RyR2（R4496C）小鼠模型中的希氏-浦肯野系统的特殊电传导细胞。
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