Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation.
Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation.
复制标题
磷蛋白R14del突变所致遗传性心肌病人源化小鼠模型的心律失常机制和动力学。
DOI：
10.1161/circulationaha.119.043502
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发表时间：
2021-08-10
期刊：
影响因子：
37.8
通讯作者：
Akar FG
中科院分区：
文献类型：
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作者：
Raad N;Bittihn P;Cacheux M;Jeong D;Ilkan Z;Ceholski D;Kohlbrenner E;Zhang L;Cai CL;Kranias EG;Hajjar RJ;Stillitano F;Akar FG
钙调节蛋白受磷蛋白 (hPLNR14del) 中的精氨酸 (Arg) 14 缺失 (R14del) 已被确定为遗传性心肌病患者的致病突变。早期致心律失常表型使这种突变携带者在没有明显结构重塑的情况下容易发生猝死，其背后的机制仍不清楚。为了解决这个问题，我们在用异丙肾上腺素和快速起搏进行离体攻击之前和之后，对携带人类 PLNWT（WT，N = 12）或杂合人类 PLNR14del 突变（R14del，N = 12）的成年敲入小鼠的完整心脏进行了高时空分辨率光学测绘。在没有显着的结构或血流动力学变化的情况下，不良的电生理重塑是明显的。与 WT 相比，R14del 心脏表现出心律失常敏感性增加。这种易感性的基础是右心室 (RV) 动作电位优先延长，而对 β-肾上腺素能刺激无反应。左心室/右心室界面处陡峭的复极梯度为心室间激活延迟和快速起搏期间最终的局部传导阻滞提供了基础。随后是支持 VT 发生的大折返回路的启动。一旦持续，这些电路就会演变成高频转子，其中大部分固定在房车上。重要的是，这些转子表现出独特的时空动力学，与 WT 心脏相比，提高了 R14del 中的稳定性。我们的研究结果强调了 hPLNR14del 突变引起的初级电重塑的关键作用。这些固有的致心律失常特征形成了 PLNR14del 诱导的心肌病早期肾上腺素介导的 VT 的基础。
Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLNR14del) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. To address this, we performed high spatio-temporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLNWT (WT, N=12) or the heterozygous human PLNR14del mutation (R14del, N=12) before and after ex-vivo challenge with isoproterenol and rapid pacing. Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared to WT. Underlying this susceptibility was preferential right ventricular (RV) action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the LV/RV interface provided the substrate for inter-ventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of VT. Once sustained, these circuits evolved into high frequency rotors, which in their majority were pinned to the RV. Importantly, these rotors exhibited unique spatio-temporal dynamics that promoted their increased stability in R14del compared to WT hearts. Our findings highlight the crucial role of primary electrical remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLNR14del induced cardiomyopathy.