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


Haghighi K, Gardner G, Vafiadaki E, Kumar M, Green LC, Ma J, Crocker JS, Koch S, Arvanitis DA, Bidwell P, et al. Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias. J Pers MedJ Pers MedJ Pers Med. 2021;11.


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.


Haghighi, KobraGardner, GeorgeVafiadaki, ElizabethKumar, MohitGreen, Lisa CMa, JianyongCrocker, Jeffrey SKoch, SherylArvanitis, Demetrios ABidwell, PhillipRubinstein, Jackvan de Leur, RutgerDoevendans, Pieter AAkar, Fadi GTranter, MichaelWang, Hong-ShengSadayappan, SakthivelDeMazumder, DeeptankarSanoudou, DespinaHajjar, Roger JStillitano, FrancescaKranias, Evangelia Geng1R01 HL149344/NH/NIH HHS/18CVD01/CUREPLaN by the Leducq Foundation for Cardiovascular ResearchSwitzerland2021/07/03 06:00J Pers Med. 2021 Jun 3;11(6). pii: jpm11060502. doi: 10.3390/jpm11060502.