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Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are no...

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Autores principales: Ušaj, Marko, Moretto, Luisa, Månsson, Alf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880276/
https://www.ncbi.nlm.nih.gov/pubmed/35216312
http://dx.doi.org/10.3390/ijms23042195
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author Ušaj, Marko
Moretto, Luisa
Månsson, Alf
author_facet Ušaj, Marko
Moretto, Luisa
Månsson, Alf
author_sort Ušaj, Marko
collection PubMed
description Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.
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spelling pubmed-88802762022-02-26 Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy Ušaj, Marko Moretto, Luisa Månsson, Alf Int J Mol Sci Review Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful. MDPI 2022-02-16 /pmc/articles/PMC8880276/ /pubmed/35216312 http://dx.doi.org/10.3390/ijms23042195 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Ušaj, Marko
Moretto, Luisa
Månsson, Alf
Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title_full Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title_fullStr Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title_full_unstemmed Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title_short Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
title_sort critical evaluation of current hypotheses for the pathogenesis of hypertrophic cardiomyopathy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880276/
https://www.ncbi.nlm.nih.gov/pubmed/35216312
http://dx.doi.org/10.3390/ijms23042195
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