Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

Chou, Chun Chung; Chin, Michael T.

doi:10.3390/ijms22168933

Cited by 28 publications

(26 citation statements)

References 91 publications

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“…Such progress has led to therapies targeting sarcomere dysfunction 22 . Little progress, however, has been made in understanding how these sarcomere mutations and other mutations causing sarcomere dysfunction result in the dysfunction of noncardiomyocyte cell types, although multiple nonsarcomeric mechanisms have been proposed 23 . To address this gap in knowledge, we performed single nuclei RNA-sequencing and identified gene expression changes in various cell types from Normal IVS tissue and HCM myectomy tissue.…”

Section: Discussionmentioning

confidence: 99%

Altered intercellular communication and extracellular matrix signaling as a potential disease mechanism in human hypertrophic cardiomyopathy

Larson

Codden

Huggins

et al. 2022

Sci Rep

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Hypertrophic cardiomyopathy (HCM) is considered a primary disorder of the sarcomere resulting in unexplained left ventricular hypertrophy but the paradoxical association of nonmyocyte phenotypes such as fibrosis, mitral valve anomalies and microvascular occlusion is unexplained. To understand the interplay between cardiomyocyte and nonmyocyte cell types in human HCM, single nuclei RNA-sequencing was performed on myectomy specimens from HCM patients with left ventricular outflow tract obstruction and control samples from donor hearts free of cardiovascular disease. Clustering analysis based on gene expression patterns identified a total of 34 distinct cell populations, which were classified into 10 different cell types based on marker gene expression. Differential gene expression analysis comparing HCM to Normal datasets revealed differences in sarcomere and extracellular matrix gene expression. Analysis of expressed ligand-receptor pairs across multiple cell types indicated profound alteration in HCM intercellular communication, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes and involving integrin β1 and its multiple extracellular matrix (ECM) cognate ligands. These findings provide a paradigm for how sarcomere dysfunction is associated with reduced cardiomyocyte secretion of ECM ligands, altered fibroblast ligand-receptor interactions with other cell types and increased fibroblast to lymphocyte signaling, which can further alter the ECM composition and promote nonmyocyte phenotypes.

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Section: Discussionmentioning

confidence: 99%

Altered intercellular communication and extracellular matrix signaling as a potential disease mechanism in human hypertrophic cardiomyopathy

Larson

Codden

Huggins

et al. 2022

Sci Rep

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“…Patients diagnosed with HCM due to rare truncated TTN variants have been reported [36][37][38], but, as also occurs in other IASs, rare missense TTN variants have not been deeply analyzed and thus, currently remain as VUS following the ACMG recommendations. In our study, 54.16% of variants classified previously as VUS in HCM now increase to VUS-LP, suggesting potential pathogenicity.…”

Section: Cardiomyopathiesmentioning

confidence: 99%

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Martínez-Barrios

Sarquella-Brugada

Pérez-Serra

et al. 2022

JPM

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The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

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“…HCM has long been considered a disease of the sarcomere based on the association of sarcomere gene mutations with HCM, but the contributions from other loci are increasingly appreciated [ 2 , 3 ], as are potential mechanisms aside from sarcomere dysfunction [ 33 ]. We have previously examined single nuclei gene expression patterns in obstructive HCM.…”

Section: Discussionmentioning

confidence: 99%

Single Nucleus RNA-sequencing Reveals Altered Intercellular Communication and Dendritic Cell Activation in Nonobstructive Hypertrophic Cardiomyopathy

Codden¹,

Larson²,

Awata³

et al. 2022

Cardiol Cardiovasc Med

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End stage, nonobstructive hypertrophic cardiomyopathy (HCM) is an intractable condition with no disease-specific therapies. To gain insights into the pathogenesis of nonobstructive HCM, we performed single nucleus RNA-sequencing (snRNA-seq) on human HCM hearts explanted at the time of cardiac transplantation and organ donor hearts serving as controls. Differential gene expression analysis revealed 64 differentially expressed genes linked to specific cell types and molecular functions. Analysis of ligand-receptor pair gene expression to delineate potential intercellular communication revealed significant reductions in expressed ligand-receptor pairs likely affecting the extracellular matrix, growth factor binding, peptidase regulator activity, platelet-derived growth factor binding and protease binding in the HCM tissue. Changes in Integrin-β1 receptor expression were responsible for many observed changes related to extracellular matrix interactions, by increasing in dendritic, smooth muscle and pericyte cells while decreasing in endothelial and fibroblast cells, suggesting potential mechanisms for fibrosis and microvascular disease in HCM and a potential role for dendritic cells. In contrast, there was an increase in ligand-receptor pair expression associated with adenylate cyclase binding, calcium channel molecular functions, channel inhibitor activity, ion channel inhibitor activity, phosphatase activator activity, protein kinase activator activity and titin binding, suggesting important shifts in various signaling cascades in nonobstructive, end stage HCM.

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Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

Cited by 28 publications

References 91 publications

Altered intercellular communication and extracellular matrix signaling as a potential disease mechanism in human hypertrophic cardiomyopathy

Altered intercellular communication and extracellular matrix signaling as a potential disease mechanism in human hypertrophic cardiomyopathy

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Single Nucleus RNA-sequencing Reveals Altered Intercellular Communication and Dendritic Cell Activation in Nonobstructive Hypertrophic Cardiomyopathy

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