The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Tim R Eijgenraam,Maarten P Van Den Berg,Eva Van Rooij,Bastiaan J Boukens,Rudolf A De Boer,Nienke M Stege,E Marloes Schouten,Paul A Van Der Zwaag,Cees W A Van De Kolk,J Peter Van Tintelen,Peter Van Der Meer,Herman H W Silljé,Jolanda Van Der Velden,Wouter P Te Rijdt,Cornelis J Boogerd,Edgar T Hoorntje

doi:10.1038/s41598-020-66656-9

Abstract

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.

Highlights

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/ endoplasmic reticulum Ca2+-ATPase (SERCA)
The c.40_42delAGA pathogenic variant, a heterozygous deletion of arginine 14 (p.(Arg14del)) of the PLN protein, was originally described in a Greek family in 20063. This pathogenic variant has been identified in the USA4, Canada[5], China[6], Germany[7], Spain[8] and the Netherlands[9]. This pathogenic variant was described as a founder mutation in the Netherlands, and was identified in ±14% of Dutch patients with dilated cardiomyopathy (DCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC), which translates into thousands of carriers[9]
Presence of the PLN-R14del pathogenic variant was confirmed by Sanger sequencing of left ventricular (LV) genomic DNA

Summary

Introduction

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/ endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. We generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments. As myocardial fibrosis is considered to be an early disease manifestation in this cardiomyopathy[7,11,14], the i-PHORECAST study aims to test the efficacy of the mineralocorticoid receptor antagonist (MRA) eplerenone, which has been shown to exert anti-fibrotic effects[15], in reducing disease progression or postponing onset of overt disease in asymptomatic mutation carriers

Methods

Results

Conclusion