A novel patient-patient network medicine approach to refine hypertrophic cardiomyopathy subgrouping: implications for risk stratification.
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ABSTRACT:
SUBMITTER: Wang RS
PROVIDER: S-EPMC10409890 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
Publications
A novel patient-patient network medicine approach to refine hypertrophic cardiomyopathy subgrouping: implications for risk stratification.
Wang Rui-Sheng RS Rowin Ethan J EJ Maron Barry J BJ Maron Martin S MS Maron Bradley A BA
Cardiovascular research 20230501 3
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Project description:Hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are phenotypically distinct inherited cardiac diseases. This case report presents a woman aged 51 years with coinheritance of pathogenic/likely pathogenic variants of the β-myosin heavy chain (MYH7 p.Glu924Lys) and plakophilin 2 (PKP2 p.Leu442Argfs∗5), each implicated in HCM and ARVC, respectively. Interestingly, she exhibits the classic HCM phenotype with a heavy arrhythmic burden but no diagnostic features of ARVC. The coinheritance of disease-causing variants in cardiomyopathies has been posited to result in an earlier disease onset and more aggressive clinical course. However, such a relationship has yet to be established when the variants are each robustly associated with different cardiomyopathy phenotypes. The limited existing literature on such cases paints a heterogenous picture of clinical phenotypes with no obvious trend. Here, we explore the interplay between coinheritance of disease-causing variants and resultant disease manifestation, particularly in the context of cardiomyopathies.
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Project description:Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. The wide spread of high-throughput sequencing casts doubt on its monogenic nature, suggesting the presence of mechanisms of HCM development independent from mutations in sarcomeric genes. From this point of view, HCM may arise from the interactions of several HCM-associated genes, and from disturbance of regulation of their expression. We developed a bioinformatic workflow to study the involvement of signaling pathways in HCM development through analyzing data on human heart-specific gene expression, miRNA-target gene interactions, and protein-protein interactions, available in open databases. Genes regulated by a pool of miRNAs contributing to human cardiac hypertrophy, namely hsa-miR-1-3p, hsa-miR-19b-3p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-93-5p, hsa-miR-133a-3p, hsa-miR-155-5p, hsa-miR-199a-3p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-451a, and hsa-miR-497-5p, were considered. As a result, we pinpointed a module of TGFβ-mediated SMAD signaling pathways, enriched by targets of the selected miRNAs, that may contribute to the cardiac remodeling in HCM. We suggest that the developed network-based approach could be useful in providing a more accurate glimpse on pathological processes in the disease pathogenesis.
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Project description:BackgroundHypertrophic cardiomyopathy (HCM) is a group of heterogeneous diseases that affects the myocardium. It is also a common familial disease. The symptoms are not common and easy to find.ObjectiveIn this paper, we aim to explore and analyze the dysfunctional gene network related to hypertrophic cardiomyopathy, and the key target genes with diagnostic and therapeutic significance for HCM were screened.MethodsThe gene expression profiles of 37 samples (GSE130036) were downloaded from the GEO database. Differential analysis was used to identify the related dysregulated genes in patients with HCM. Enrichment analysis identified the biological function and signaling pathway of these differentially expressed genes. Then, PPI network was built and verified in the GSE36961 dataset. Finally, the gene of single-nucleotide variants (SNVs) in HCM samples was screened by means of maftools.ResultsIn this study, 920 differentially expressed genes were obtained, and these genes were mainly related to metabolism-related signaling pathways. 187 interacting genes were identified by PPI network analysis, and the expression trends of C1QB, F13A1, CD163, FCN3, PLA2G2A, and CHRDL2 were verified by another dataset and quantitative real-time polymerase chain reaction. ROC curve analysis showed that they had certain clinical diagnostic ability, and they were the potential key dysfunctional genes of HCM. In addition, we found that PRMT5 mutation was the most frequent in HCM samples, which may affect the pathogenesis of HCM.ConclusionTherefore, the key genes and enrichment results identified by our analysis may provide a reference for the occurrence and development mechanism of HCM. In addition, mutations in PRMT5 may be a useful therapeutic and diagnostic target for HCM. Our results also provide an independent quantitative assessment of functional limitations in patients with unknown history.
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Project description:A 63-year-old symptomatic female with apical hypertrophic cardiomyopathy and diastolic disfunction was admitted to the hospital. What is the best way to manage this patient? This study is a literature review that was performed to answer this question. The following PubMed search strategy was used: 'Hypertrophic obstructive cardiomyopathy' [All Fields] OR 'apical myectomy' [All Fields], NOT 'animal [mh]' NOT 'human [mh]' NOT 'comment [All Fields]' OR 'editorial [All Fields]' OR 'meta-analysis [All Fields]' OR 'practice-guideline [All Fields]' OR 'review [All Fields]' OR 'pediatrics [mh]'. The natural history of the disease has a benign prognosis; however, a watchful strategy was associated with the risk of adverse cardiovacular events. Contrastingly, transapical myectomy was associated with low surgical risk and acceptable outcomes. In our case, the patient underwent transapical myectomy with an unconventional post-operative period. Control echocardiography showed marked left ventricular (LV) cavity enlargement: LV end-diastolic volume, 74 mL; LV ejection fraction, 65%; and LV stroke volume index increased to 27 mL/m2. The patient was discharged 7 days after myectomy. At 6 months post-operation, the patient was NYHA Class I, with a 6 min walk test score of 420 m. Therefore, transapical myectomy may be considered as a feasible procedure in patients with apical hypertrophic cardiomyopathy and progressive heart failure.
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Project description:The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype-phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.
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