Cerrone Marina, Noujaim Sami F, Tolkacheva Elena G, Talkachou Arkadzi, O'Connell Ryan, Berenfeld Omer, Anumonwo Justus, Pandit Sandeep V, Vikstrom Karen, Napolitano Carlo, Priori Silvia G, Jalife José
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Circ Res. 2007 Nov 9;101(10):1039-48. doi: 10.1161/CIRCRESAHA.107.148064. Epub 2007 Sep 13.
Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca2+ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2(R4496C)) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2(R4496C) and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca2+and isoproterenol; 66% of 12 RyR2/RyR2(R4496C) and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (P=0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2(R4496C) mice. Under current clamp, single Purkinje cells from RyR2/RyR2(R4496C) mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
儿茶酚胺能多形性室性心动过速（VT）是一种致死性家族性疾病，其特征为双向VT、多形性VT和心室颤动。儿茶酚胺能多形性VT是由通过有缺陷的兰尼碱受体（RyR2）通道增强的Ca2+释放所引起。我们在一个敲入（RyR2/RyR2（R4496C））小鼠模型中，使用心外膜和心内膜光学标测、用卢戈氏溶液进行心内膜下化学消融以及膜片钳技术，来研究儿茶酚胺能多形性VT的致心律失常机制。在离体心脏中，在灌注Ca2+和异丙肾上腺素的13只RyR2/RyR2（R4496C）小鼠中有54%发生自发性室性心律失常，而在11只野生型同窝小鼠中有9%发生（P = 0.03）；在灌注咖啡因和肾上腺素的12只RyR2/RyR2（R4496C）小鼠中有66%出现心律失常，而在10只野生型心脏中有20%出现心律失常（P = 0.04）。心外膜标测显示，单形性VT、双向VT和多形性VT表现为同心性心外膜突破模式，提示起源于一个或两个心室的希氏-浦肯野网络中的局灶。单形性VT明显为单灶性，而双向VT为双灶性。多形性VT最初为多灶性，但最终变为折返并恶化为心室颤动。心内膜标测证实了局灶性心律失常起源于浦肯野纤维。用卢戈氏溶液对4只麻醉的RyR2/RyR2（R4496C）小鼠的右心室心内膜腔进行化学消融，诱发了完全性右束支传导阻滞，并将双向VT转变为单形性VT。在电流钳制下，与野生型相比，来自RyR2/RyR2（R4496C）小鼠心脏的单个浦肯野细胞在更低的频率和肾上腺素能刺激水平下产生延迟后去极化诱导的触发活动。总体而言，数据表明希氏-浦肯野系统是儿茶酚胺能多形性VT中局灶性心律失常的一个重要来源。
