Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor
Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor
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DOI：
10.1161/01.res.0000169067.51055.72
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发表时间：
2005-05-27
影响因子：
20.1
通讯作者：
Priori, SG
中科院分区：
文献类型：
--
作者：
Cerrone, M;Colombi, B;Priori, SG
儿茶酚胺能多形性室性心动过速（CPVT）是一种遗传性疾病，其特征是肾上腺素能介导的多形性室性心动过速，导致晕厥和心源性猝死。CPVT的常染色体显性形式是由编码兰尼碱受体心脏亚型的RyR 2基因突变引起的。突变RyR 2通道的体外功能表征显示，肾上腺素能刺激和咖啡因给药的行为改变，肌浆网钙释放增强。到目前为止，还没有实验证据证明RyR 2突变可以重现在CPVT患者中观察到的心律失常。我们开发了一种R4496 C突变的条件性敲入小鼠模型携带者，该小鼠相当于在CPVT家族中鉴定的R4497 C突变，以评估动物是否会产生CPVT表型以及β受体阻滞剂是否会预防心律失常。26只小鼠（12只野生型（WT）和14只RyR（R4496 C））进行运动应激试验，然后给予肾上腺素：WT小鼠中无1只发生室性心动过速（VT），而RyR（R4496 C）小鼠中有5只发生室性心动过速（VT）（P = 0.02）。21只小鼠（8只WT、8只RyRR 4496 C和5只RyR（R4496 C），经β受体阻滞剂预处理）接受肾上腺素和咖啡因：4/8（50%）只RyR（R4496 C）小鼠，但WT小鼠均未发生VT（P = 0.02）; 4/5只RyR（R4496 C）小鼠经普萘洛尔预处理后发生VT（P = 0.56，与RyR（R4496 C）小鼠相比无显著性）。这些数据提供了第一个实验证明，R4496 C RyR 2突变倾向于小鼠心脏VT和VF响应咖啡因和/或肾上腺素能刺激。此外，结果表明，类似于在患者中观察到的情况，β肾上腺素能刺激似乎在预防危及生命的心律失常方面无效。
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice (P = 0.02). Twenty-one mice (8 WT, 8 RyRR4496C, and 5 RyR(R4496C) pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) mice but none of the WT developed VT (P = 0.02); 4/5 RyR(R4496C) mice pretreated with propranolol developed VT (P = 0.56 nonsignificant versus RyR(R4496C) mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias.