Impaired right ventricular calcium cycling is an early risk factor in r14del-phospholamban arrhythmias

Kobra Haghighi, George Gardner, Elizabeth Vafiadaki, Mohit Kumar, Lisa C. Green, Jianyong Ma, Jeffrey S. Crocker, Sheryl Koch, Demetrios A. Arvanitis, Phillip Bidwell, Jack Rubinstein, Rutger van de Leur, Pieter A. Doevendans, Fadi G. Akar, Michael Tranter, Hong Sheng Wang, Sakthivel Sadayappan, Deeptankar Demazumder, Despina Sanoudou, Roger J. HajjarFrancesca Stillitano, Evangelia G. Kranias

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Article number502
JournalJournal of Personalized Medicine
Issue number6
StatePublished - Jun 2021
Externally publishedYes

Bibliographical note

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.


  • Arrhythmia
  • Calcium
  • Mutant
  • Phospholamban


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