Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias

被引：15

作者：

Haghighi, Kobra ^{[1
]}

Gardner, George ^{[1
]}

Vafiadaki, Elizabeth ^{[2
]}

Kumar, Mohit ^{[1
]}

Green, Lisa C. ^{[1
]}

Ma, Jianyong ^{[1
]}

Crocker, Jeffrey S. ^{[1
]}

Koch, Sheryl ^{[3
]}

Arvanitis, Demetrios A. ^{[2
]}

Bidwell, Phillip ^{[1
]}

Rubinstein, Jack ^{[3
]}

van de Leur, Rutger ^{[4
,5
]}

Doevendans, Pieter A. ^{[4
,5
]}

Akar, Fadi G. ^{[6
]}

Tranter, Michael ^{[3
]}

Wang, Hong-Sheng ^{[1
]}

Sadayappan, Sakthivel ^{[3
]}

DeMazumder, Deeptankar ^{[3
]}

Sanoudou, Despina ^{[2
,7
]}

Hajjar, Roger J. ^{[8
]}

Stillitano, Francesca ^{[6
]}

Kranias, Evangelia G. ^{[1
,2
]}

机构：

[1] Univ Cincinnati, Coll Med, Dept Pharmacol & Syst Physiol, Cincinnati, OH 45267 USA

[2] Acad Athens, Biomed Res Fdn, Mol Biol Div, Athens 11527, Greece

[3] Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH 45267 USA

[4] Netherlands Heart Inst, NL-3581 HG Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Dept Cardiol, NL-3581 HG Utrecht, Netherlands

[6] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA

[7] Natl & Kapodistrian Univ Athens, Med Sch, Ctr New Biotechnol & Precis Med, Athens 11517, Greece

[8] Phospholamban Heart Fdn, Postbus 66, NL-1775 ZH Middenmeer, Netherlands

来源：

JOURNAL OF PERSONALIZED MEDICINE | 2021年 / 11卷 / 06期

基金：

美国国家卫生研究院;

关键词：

arrhythmia; calcium; phospholamban; mutant; PHOSPHOLAMBAN R14DEL MUTATION; CARDIOMYOPATHY; MECHANISMS; VARIANTS; ABLATION;

D O I：

10.3390/jpm11060502

中图分类号：

R19 [保健组织与事业（卫生事业管理）];

学科分类号：

摘要：

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.

引用

页数：23