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Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy
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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: closed (31 January 2022) | Viewed by 34799

Special Issue Editor

Prof. Dr. Michael T. Chin

E-Mail Website
Guest Editor
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02145, USA
Interests: inherited cardiomyopathies; heart failure; cardiac hypertrophy; gene expression; genetics; molecular biology; single cell transcriptomics; spatial transcriptomics; proteomics; metabolomics
Special Issues, Collections and Topics in MDPI journals

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

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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

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

2 pages, 161 KiB  
Editorial
Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy
by Chun Chou and Michael Thomas Chin
Int. J. Mol. Sci. 2023, 24(3), 2522; https://doi.org/10.3390/ijms24032522 - 28 Jan 2023
Cited by 3 | Viewed by 3081
Abstract
The intention of this Special Issue is to highlight novel approaches and new paradigms for understanding the pathogenesis of hypertrophic cardiomyopathy (HCM) [...] Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)

Research

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24 pages, 4237 KiB  
Article
Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation–Contraction Coupling
by Jarrod Moore, Jourdan Ewoldt, Gabriela Venturini, Alexandre C. Pereira, Kallyandra Padilha, Matthew Lawton, Weiwei Lin, Raghuveera Goel, Ivan Luptak, Valentina Perissi, Christine E. Seidman, Jonathan Seidman, Michael T. Chin, Christopher Chen and Andrew Emili
Int. J. Mol. Sci. 2023, 24(5), 4724; https://doi.org/10.3390/ijms24054724 - 1 Mar 2023
Cited by 9 | Viewed by 4752
Abstract
Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To [...] Read more.
Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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23 pages, 28514 KiB  
Article
Common and Distinctive Intercellular Communication Patterns in Human Obstructive and Nonobstructive Hypertrophic Cardiomyopathy
by Christina J. Codden and Michael T. Chin
Int. J. Mol. Sci. 2022, 23(2), 946; https://doi.org/10.3390/ijms23020946 - 15 Jan 2022
Cited by 10 | Viewed by 3213
Abstract
Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy with or without left ventricular outflow tract (LVOT) obstruction. Single-nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples has revealed alterations in communication between various cell types, [...] Read more.
Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy with or without left ventricular outflow tract (LVOT) obstruction. Single-nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples has revealed alterations in communication between various cell types, but no direct and integrated comparison between the two HCM phenotypes has been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility, and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding, and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication, and in endothelial cell communication to other cell types, largely through changes in the expression of integrin-β1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for the personalized management of different HCM phenotypes. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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17 pages, 4984 KiB  
Article
Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation
by Wei-Wen Lim, Melissa Neo, Shivshankar Thanigaimani, Pawel Kuklik, Anand N. Ganesan, Dennis H. Lau, Tatiana Tsoutsman, Jonathan M. Kalman, Christopher Semsarian, David A. Saint and Prashanthan Sanders
Int. J. Mol. Sci. 2021, 22(13), 6941; https://doi.org/10.3390/ijms22136941 - 28 Jun 2021
Cited by 9 | Viewed by 3579
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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22 pages, 3949 KiB  
Article
Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation
by Amy Larson, Towia A. Libermann, Heather Bowditch, Gaurav Das, Nikolaos Diakos, Gordon S. Huggins, Hassan Rastegar, Frederick Y. Chen, Ethan J. Rowin, Martin S. Maron and Michael T. Chin
Int. J. Mol. Sci. 2021, 22(5), 2474; https://doi.org/10.3390/ijms22052474 - 1 Mar 2021
Cited by 15 | Viewed by 3158
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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17 pages, 1034 KiB  
Review
Mass-Spectrometry-Based Functional Proteomic and Phosphoproteomic Technologies and Their Application for Analyzing Ex Vivo and In Vitro Models of Hypertrophic Cardiomyopathy
by Jarrod Moore and Andrew Emili
Int. J. Mol. Sci. 2021, 22(24), 13644; https://doi.org/10.3390/ijms222413644 - 20 Dec 2021
Cited by 3 | Viewed by 3282
Abstract
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease thought to be principally caused by mutations in sarcomeric proteins. Despite extensive genetic analysis, there are no comprehensive molecular frameworks for how single mutations in contractile proteins result in the diverse assortment of cellular, phenotypic, [...] Read more.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease thought to be principally caused by mutations in sarcomeric proteins. Despite extensive genetic analysis, there are no comprehensive molecular frameworks for how single mutations in contractile proteins result in the diverse assortment of cellular, phenotypic, and pathobiological cascades seen in HCM. Molecular profiling and system biology approaches are powerful tools for elucidating, quantifying, and interpreting dynamic signaling pathways and differential macromolecule expression profiles for a wide range of sample types, including cardiomyopathy. Cutting-edge approaches combine high-performance analytical instrumentation (e.g., mass spectrometry) with computational methods (e.g., bioinformatics) to study the comparative activity of biochemical pathways based on relative abundances of functionally linked proteins of interest. Cardiac research is poised to benefit enormously from the application of this toolkit to cardiac tissue models, which recapitulate key aspects of pathogenesis. In this review, we evaluate state-of-the-art mass-spectrometry-based proteomic and phosphoproteomic technologies and their application to in vitro and ex vivo models of HCM for global mapping of macromolecular alterations driving disease progression, emphasizing their potential for defining the components of basic biological systems, the fundamental mechanistic basis of HCM pathogenesis, and treating the ensuing varied clinical outcomes seen among affected patient cohorts. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Hypertrophic Cardiomyopathy)
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13 pages, 869 KiB  
Review
Genetic Testing in Patients with Hypertrophic Cardiomyopathy
by Jiri Bonaventura, Eva Polakova, Veronika Vejtasova and Josef Veselka
Int. J. Mol. Sci. 2021, 22(19), 10401; https://doi.org/10.3390/ijms221910401 - 27 Sep 2021
Cited by 30 | Viewed by 5554
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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14 pages, 1778 KiB  
Review
Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction
by Chun Chou and Michael T. Chin
Int. J. Mol. Sci. 2021, 22(16), 8933; https://doi.org/10.3390/ijms22168933 - 19 Aug 2021
Cited by 21 | Viewed by 6875
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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