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The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy
Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca(2+)-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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300032/ https://www.ncbi.nlm.nih.gov/pubmed/32555305 http://dx.doi.org/10.1038/s41598-020-66656-9 |
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author | 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, J. Peter van den Berg, Maarten P. van der Meer, Peter van der Velden, Jolanda Silljé, Herman H. W. de Boer, Rudolf A. |
author_facet | 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, J. Peter van den Berg, Maarten P. van der Meer, Peter van der Velden, Jolanda Silljé, Herman H. W. de Boer, Rudolf A. |
author_sort | Eijgenraam, Tim R. |
collection | PubMed |
description | Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca(2+)-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. |
format | Online Article Text |
id | pubmed-7300032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73000322020-06-22 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, J. Peter van den Berg, Maarten P. van der Meer, Peter van der Velden, Jolanda Silljé, Herman H. W. de Boer, Rudolf A. Sci Rep Article Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca(2+)-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. Nature Publishing Group UK 2020-06-17 /pmc/articles/PMC7300032/ /pubmed/32555305 http://dx.doi.org/10.1038/s41598-020-66656-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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, J. Peter van den Berg, Maarten P. van der Meer, Peter van der Velden, Jolanda Silljé, Herman H. W. de Boer, Rudolf A. The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title | The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title_full | The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title_fullStr | The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title_full_unstemmed | The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title_short | The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
title_sort | phospholamban p.(arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300032/ https://www.ncbi.nlm.nih.gov/pubmed/32555305 http://dx.doi.org/10.1038/s41598-020-66656-9 |
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