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本文引用的文献

1
The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2).常染色体隐性遗传儿茶酚胺依赖性多形性室性心动过速（CPVT2）中突变蛋白水平的作用。
Biochem Pharmacol. 2013 Dec 1;86(11):1576-83. doi: 10.1016/j.bcp.2013.09.012. Epub 2013 Sep 23.
2
α₁A-adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion.α₁A-肾上腺素能受体通过白细胞介素-6 的分泌调节体内心肌肥厚。
Mol Pharmacol. 2013 May;83(5):939-48. doi: 10.1124/mol.112.084483. Epub 2013 Feb 12.
3
Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice.运动训练可改善 CPVT 小鼠的心脏功能并减弱心律失常。
J Appl Physiol (1985). 2012 Dec 1;113(11):1677-83. doi: 10.1152/japplphysiol.00818.2012. Epub 2012 Oct 4.
4
Role of inositol 1,4,5-trisphosphate in the regulation of ventricular Ca(2+) signaling in intact mouse heart.三磷酸肌醇在调节完整小鼠心脏心室 Ca(2+)信号中的作用。
J Mol Cell Cardiol. 2012 Dec;53(6):768-79. doi: 10.1016/j.yjmcc.2012.08.019. Epub 2012 Aug 31.
5
α- and β-Adrenergic receptors differentially modulate the emission of spontaneous and amphetamine-induced 50-kHz ultrasonic vocalizations in adult rats.α-和β-肾上腺素受体在调节成年大鼠自发和安非他命诱导的 50-kHz 超声波发声方面存在差异。
Neuropsychopharmacology. 2012 Feb;37(3):808-21. doi: 10.1038/npp.2011.258. Epub 2011 Oct 26.
6
Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments.儿茶酚胺多形性室性心动过速患者的治疗方法：现状与未来发展。
Europace. 2012 Feb;14(2):175-83. doi: 10.1093/europace/eur277. Epub 2011 Sep 4.
7
Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.肌浆网 Ca2+ 处理功能遗传性缺陷与心律失常发生。
Circ Res. 2011 Apr 1;108(7):871-83. doi: 10.1161/CIRCRESAHA.110.226845.
8
Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure.α1-肾上腺素能受体：治疗心力衰竭的激动剂药物的作用靶点。
J Mol Cell Cardiol. 2011 Oct;51(4):518-28. doi: 10.1016/j.yjmcc.2010.11.014. Epub 2010 Nov 28.
9
Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice.优化肌浆网钙结合蛋白突变型小鼠儿茶酚胺多形性室性心动过速的治疗。
Heart Rhythm. 2010 Nov;7(11):1676-82. doi: 10.1016/j.hrthm.2010.07.004. Epub 2010 Jul 8.
10
Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia.儿茶酚胺能多形性室性心动过速心律失常事件的发生率及危险因素
Circulation. 2009 May 12;119(18):2426-34. doi: 10.1161/CIRCULATIONAHA.108.829267. Epub 2009 Apr 27.

α受体阻断增强了钙结合蛋白突变小鼠的儿茶酚胺能多形性室性心动过速（CPVT）治疗效果。

Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice.

作者信息

Kurtzwald-Josefson Efrat, Hochhauser Edith, Bogachenko Katia, Harun-Khun Shiraz, Katz Guy, Aravot Dan, Seidman Jonathan G, Seidman Christine E, Eldar Michael, Shainberg Asher, Arad Michael

机构信息

Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

出版信息

Heart Rhythm. 2014 Aug;11(8):1471-9. doi: 10.1016/j.hrthm.2014.04.030. Epub 2014 Apr 21.

DOI:10.1016/j.hrthm.2014.04.030
PMID:24768611
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4108570/
Abstract

BACKGROUND

Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation.

OBJECTIVE

To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Δ/Δ)) mouse model of CPVT2.

METHODS

A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy.

RESULTS

Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice (P < .05).

CONCLUSION

We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

摘要

背景

自发钙释放引发延迟后去极化被认为会导致儿茶酚胺能多形性室性心动过速（CPVT），这是一种由运动或情绪应激诱发的致命性人类心律失常。β-肾上腺素能阻滞剂是首选药物，但在一些患者中未能实现心律失常的完全控制。这些个体通常需要使用氟卡尼、植入装置和/或交感神经去神经支配。

目的

通过在CPVT2的纯合型肌集钙蛋白基因敲除（CASQ2(Δ/Δ)）小鼠模型中对交感神经系统进行药理学抑制来优化心律失常治疗。

方法

植入心脏遥测装置以在静息时和激发试验期间连续记录心电图。对成年小鼠分离的心肌细胞研究钙瞬变和异常钙释放。通过蛋白质印迹法和共聚焦显微镜确定肾上腺素能受体表达。

结果

成年CASQ2(Δ/Δ)小鼠在静息时患有复杂室性心律失常，在跑步机运动期间和注射肾上腺素后发生室性心动过速。β-肾上腺素能阻滞剂普萘洛尔和美托洛尔可减轻静息时的心律失常，但在应激后无效。利血平对控制心律失常无效。具有α阻断活性的药物酚妥拉明或拉贝洛尔可消除运动和肾上腺素诱发的心律失常。相反，注射α-肾上腺素能激动剂去氧肾上腺素可反复诱发室性心动过速。来自CASQ2(Δ/Δ)小鼠的分离心肌细胞在暴露于交感激动剂时具有延迟的钙释放波，酚妥拉明可消除这些波。肌集钙蛋白突变小鼠的心脏比野生型对照小鼠表达更多的α1-肾上腺素能受体（P <.05）。

结论

我们确定了α-肾上腺素能途径在儿茶酚胺诱发的心律失常发病机制中的作用。α-阻断在CPVT2小鼠模型中成为一种有效的治疗方法，应在对β-阻滞剂耐药的人类中进行尝试。