What Causes Hypertrophic Cardiomyopathy?

Maron, Bradley A.; Wang, Rui-Sheng; Carnethon, Mercedes R.; Rowin, Ethan J.; Loscalzo, Joseph; Maron, Barry J.; Maron, Martin S.

doi:10.1016/j.amjcard.2022.06.017

Cited by 19 publications

(19 citation statements)

References 87 publications

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“…Interestingly, we determined that <0.1% of all PPIs involved these genes. 67 By contrast, network features, such as the prevalence of fibrosis pathways in each individual network, correlated strongly with phenotypic parameters and prognostic clinical variables, such as cardiac output and pulmonary vascular resistance. In this regard, interfacing genotype with functional PPI data (derived from affected tissue) contextualized the contribution of individual gene variant(s) to the wider molecular milieu underpinning patient-level phenotype.…”

Section: Network Medicine-based Integration Of Multiomics Datamentioning

confidence: 94%

Multiomics Network Medicine Approaches to Precision Medicine and Therapeutics in Cardiovascular Diseases

Wang

Maron

Loscalzo

2023

ATVB

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Cardiovascular diseases (CVD) are the leading cause of death worldwide and display complex phenotypic heterogeneity caused by many convergent processes, including interactions between genetic variation and environmental factors. Despite the identification of a large number of associated genes and genetic loci, the precise mechanisms by which these genes systematically influence the phenotypic heterogeneity of CVD are not well understood. In addition to DNA sequence, understanding the molecular mechanisms of CVD requires data from other omics levels, including the epigenome, the transcriptome, the proteome, as well as the metabolome. Recent advances in multiomics technologies have opened new precision medicine opportunities beyond genomics that can guide precise diagnosis and personalized treatment. At the same time, network medicine has emerged as an interdisciplinary field that integrates systems biology and network science to focus on the interactions among biological components in health and disease, providing an unbiased framework through which to integrate systematically these multiomics data. In this review, we briefly present such multiomics technologies, including bulk omics and single-cell omics technologies, and discuss how they can contribute to precision medicine. We then highlight network medicine-based integration of multiomics data for precision medicine and therapeutics in CVD. We also include a discussion of current challenges, potential limitations, and future directions in the study of CVD using multiomics network medicine approaches.

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Section: Network Medicine-based Integration Of Multiomics Datamentioning

confidence: 94%

Multiomics Network Medicine Approaches to Precision Medicine and Therapeutics in Cardiovascular Diseases

Wang

Maron

Loscalzo

2023

ATVB

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“…On the other hand, ischemic cardiomyopathy (ICM) is a form of HF associated with inadequate blood flow to the cardiac muscle, often due to atherosclerosis of the coronary arteries 7 . Finally, hypertrophic cardiomyopathy (HCM) is characterized by excessive thickening of the cardiac muscle, making it more difficult for the heart to pump blood 8 .…”

Section: Introductionmentioning

confidence: 99%

A meta-analysis approach to gene regulatory network inference identifies key regulators of cardiovascular diseases

Pepe,

Appierdo,

Ausiello

et al. 2024

Preprint

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Cardiovascular diseases (CVDs) represent a major concern for global health whose mechanistic understanding is complicated by a complex interplay between genetic predisposition and environmental factors.Specifically, heart failure (HF), encompassing dilated cardiomyopathy (DC), ischemic cardiomyopathy (ICM), and hypertrophic cardiomyopathy (HCM), is a topic of substantial interest in basic and clinical research. Here we used a Partial Correlation Coefficient-based algorithm (PCC) within the context of a meta-analysis framework, to construct a Gene Regulatory Network (GRN) that identifies key regulators whose activity is perturbed in Heart Failure. By integrating data from multiple independent studies, our approach unveiled crucial regulatory associations between transcription factors (TFs) and structural genes, emphasizing their pivotal roles in regulating metabolic pathways, such as fatty acid metabolism, oxidative stress response, epithelial-to-mesenchymal transition, and coagulation. In addition to known associations, our analysis also identified novel regulators, including the identification of TFs FPM315 and MOVO-B, which are implicated in dilated cardiomyopathies, and TEAD1 and TEAD2 in both dilated and ischemic cardiomyopathies. Moreover, we uncovered alterations in adipogenesis and oxidative phosphorylation pathways in hypertrophic cardiomyopathy, and discovered a role for IL2 STAT5 signaling in heart failure.Our findings underscore the importance of TFs activity in the initiation and progression of cardiac disease, highlighting their potential as pharmacological targets.

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“…Interestingly, valsartan, an afterload reducing agent, has been found to inhibit the progression of the HCM phenotype, but only when the drug was given before the HCM phenotype manifested in animal models, suggesting that afterload may play a critical role in disease manifestation (16,17). Nevertheless, the precise molecular mechanisms through which these drugs can reduce and potentially prevent hypertrophic remodeling and/or abnormal calcium handling is not clear (18,19).…”

Section: Introductionmentioning

confidence: 99%

Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

Guo,

Jiang,

Schuftan

et al. 2023

Preprint

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Hypertrophic cardiomyopathy is the most common cause of sudden death in the young. Because the disease exhibits variable penetrance, there are likely nongenetic factors that contribute to the manifestation of the disease phenotype. Clinically, hypertension is a major cause of morbidity and mortality in patients with HCM, suggesting a potential synergistic role for the sarcomeric mutations associated with HCM and mechanical stress on the heart. We developed anin vitrophysiological model to investigate how the afterload that the heart muscle works against during contraction acts together with HCM-linked MYBPC3 mutations to trigger a disease phenotype. Micro-heart muscle arrays (μHM) were engineered from iPSC-derived cardiomyocytes bearing MYBPC3 loss-of-function mutations and challenged to contract against mechanical resistance with substrates stiffnesses ranging from the of embryonic hearts (0.4 kPa) up to the stiffness of fibrotic adult hearts (114 kPa). Whereas MYBPC3+/-iPSC-cardiomyocytes showed little signs of disease pathology in standard 2D culture, μHMs that included components of afterload revealed several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in the MYBPC3+/-μHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+intake through membrane-embedded channels, rather than sarcoplasmic reticulum Ca2+ATPase (SERCA) dysfunction or Ca2+buffering at myofilaments underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease mechanisms with iPSC technology.

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What Causes Hypertrophic Cardiomyopathy?

Cited by 19 publications

References 87 publications

Multiomics Network Medicine Approaches to Precision Medicine and Therapeutics in Cardiovascular Diseases

Multiomics Network Medicine Approaches to Precision Medicine and Therapeutics in Cardiovascular Diseases

A meta-analysis approach to gene regulatory network inference identifies key regulators of cardiovascular diseases

Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

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