The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy
Eijgenraam, Tim R; Boukens, Bastiaan J; Boogerd, Cornelis J; Schouten, E Marloes; van de Kolk, Cees W A; Stege, Nienke M; Te Rijdt, Wouter P; Hoorntje, Edgar T; van der Zwaag, Paul A; van Rooij, Eva; van Tintelen, Peter; van den Berg, Maarten P; van der Meer, Peter; van der Velden, Jolanda; Silljé, Herman H W; de Boer, Rudolf A
(2020) Scientific Reports, volume 10, issue 1
(Article)
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
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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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Keywords: General, Journal Article
ISSN: 2045-2322
Publisher: Nature Publishing Group
Note: Funding Information: The authors thank Martin M. Dokter and Noa Keijzer for their technical assistance. The authors thank the Utrecht Sequencing Facility for providing sequencing service and data. This work was supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (CVON DOSIS grant 2014-40, CVON e-DETECT grant 2015-12, CVON SHE-PREDICTS-HF grant 2017-21 and CVON RED-CVD grant 2017-11), the Leducq Foundation (CURE-PLaN), the de Boer Foundation, the Ubbo Emmius Fund and the PLN Foundation. B.J.B. was supported by the Dutch Heart Foundation (grant 2016T047). C.J.B. was supported by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant 751988). W.P.t.R. was supported by the Young Talent Program of the Dutch Heart Foundation (CVON PREDICT grant 2017T001) and a Postdoctoral Fellowship of the Leducq Foundation (CURE-PLaN). R.A.d.B. receives support from the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI grant 917.13.350) and the European Research Council (SECRETE-HF Consolidator grant 818715). The Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, the Hubrecht Institute, the University of Utrecht, and The Netherlands X-omics Initiative (NWO project 184.034.019). Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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