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Special Issue "Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 January 2022.

Special Issue Editor

Prof. Dr. Michael T. Chin
E-Mail Website
Guest Editor
Tufts Medical Center, Boston, MA, USA
Interests: inherited cardiomyopathies; gene regulation; transcription; cardiovascular biology; mitochondria; genomics; genetics

Special Issue Information

Dear Colleagues,

Hypertrophic cardiomyopathy (HCM) is a common inherited genetic disorder affecting approximately 1 in 500 live births, manifest as left ventricular hypertrophy without any underlying cause. The hypertrophy is often asymmetric, most commonly affecting the interventricular septum, and is often associated with left ventricular outflow tract obstruction. Associated findings include myocardial fibrosis, sudden cardiac death, microvascular ischemia, and mitral valve abnormalities. Although the majority of known mutations occur in sarcomeric genes, the pleiotropic manifestations of this disorder that occur in both myocytes and nonmyocyte tissues are not easily explained by these mutations. The majority of patients also do not have identifiable disease-causing mutations, raising questions about other genetic, epigenetic or nongenetic causes. Despite significant advances in understanding how HCM sarcomeric mutations affect sarcomere function and myocardial contractility, the downstream molecular mechanisms that lead to asymmetric hypertrophy, cardiac arrhythmias, mitral valve abnormalities, and microvascular dysfunction are poorly understood. This issue calls for studies that address current gaps in knowledge.

Prof. Dr. Michael T. Chin
Guest Editor

Manuscript Submission Information

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Keywords

  • hypertrophic cardiomyopathy
  • cardiac hypertrophy
  • cardiomyopathy
  • sarcomere
  • cardiac fibrosis
  • sudden cardiac death
  • inherited cardiomyopathy
  • interventricular septum
  • left ventricular outflow tract obstruction
  • genetic disorder

Published Papers (4 papers)

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Research

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Article
Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation
Int. J. Mol. Sci. 2021, 22(13), 6941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136941 - 28 Jun 2021
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Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser [...] Read more.
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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Article
Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation
Int. J. Mol. Sci. 2021, 22(5), 2474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052474 - 01 Mar 2021
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Abstract
Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics [...] Read more.
Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-γ, TGF-β1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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Review

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Review
Genetic Testing in Patients with Hypertrophic Cardiomyopathy
Int. J. Mol. Sci. 2021, 22(19), 10401; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910401 - 27 Sep 2021
Viewed by 372
Abstract
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in [...] Read more.
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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Review
Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction
Int. J. Mol. Sci. 2021, 22(16), 8933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168933 - 19 Aug 2021
Viewed by 465
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, [...] Read more.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset, and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large-scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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