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

Sci Rep. 2020 Jun 17;10(1):9819

Tim R Eijgenraam ¹ , Bastiaan J Boukens ² , Cornelis J Boogerd ³ , E Marloes Schouten ¹ , Cees W A van de Kolk ⁴ ,

Tim R Eijgenraam ¹ , Bastiaan J Boukens ² , Cornelis J Boogerd ³ , E Marloes Schouten ¹ , Cees W A van de Kolk ⁴ , Nienke M Stege ¹ , Wouter P Te Rijdt ⁵ , Edgar T Hoorntje ⁶ , Paul A van der Zwaag ⁵ , Eva van Rooij ³ , J Peter van Tintelen ⁷ , Maarten P van den Berg ¹ , Peter van der Meer ¹ , Jolanda van der Velden ⁸ , Herman H W Silljé ¹ , Rudolf A de Boer ⁹

+ et al

Author information

¹ Department of Experimental Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
² Department of Experimental Cardiology, University of Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands.
³ Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Groningen Small Animal Imaging Facility, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁶ Netherlands Heart Institute, Utrecht, the Netherlands.
⁷ Department of Genetics, University of Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands.
⁸ Department of Physiology, University of Amsterdam, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
⁹ Department of Experimental Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. r.a.de.boer@umcg.nl.

摘要

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.

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