TY - JOUR
T1 - Impaired right ventricular calcium cycling is an early risk factor in r14del-phospholamban arrhythmias
AU - Haghighi, Kobra
AU - Gardner, George
AU - Vafiadaki, Elizabeth
AU - Kumar, Mohit
AU - Green, Lisa C.
AU - Ma, Jianyong
AU - Crocker, Jeffrey S.
AU - Koch, Sheryl
AU - Arvanitis, Demetrios A.
AU - Bidwell, Phillip
AU - Rubinstein, Jack
AU - van de Leur, Rutger
AU - Doevendans, Pieter A.
AU - Akar, Fadi G.
AU - Tranter, Michael
AU - Wang, Hong Sheng
AU - Sadayappan, Sakthivel
AU - Demazumder, Deeptankar
AU - Sanoudou, Despina
AU - Hajjar, Roger J.
AU - Stillitano, Francesca
AU - Kranias, Evangelia G.
N1 - Funding Information:
Funding: This work was supported by CUREPLaN, a grant from the Leducq Foundation for Cardiovascular Research (18CVD01 to E.G.K., P.A.D., D.S. and F.S.), American Heart Association (18TPA34230062 to F.S.) and the National Institutes of Health (1R01 HL149344 to F.G.A).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Calcium
KW - Mutant
KW - Phospholamban
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U2 - 10.3390/jpm11060502
DO - 10.3390/jpm11060502
M3 - Article
C2 - 34204946
AN - SCOPUS:85108238572
SN - 2075-4426
VL - 11
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 6
M1 - 502
ER -