RARE DISEASE
Rare familial disorder with hypertrophic cardiomyopathy
Rare familial disorder with hypertrophic cardiomyopathy
Rare familial disorder with hypertrophic cardiomyopathy
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Synonyms: Rare familial disorder with hypertrophic obstructive cardiomyopathy, Rare familial disorder with hypertrophic subaortic stenosis
Drug discovery
4
drugs
With orphan designations
Overview
Familial Hypertrophic Cardiomyopathy (HCM) is an autosomal-dominant genetic disorder caused by mutations in sarcomere proteins (e.g., MYH7, MYBPC3). It manifests as asymmetric left ventricular hypertrophy, myocardial disarray, and fibrosis [1][5][9]. Clinical features include arrhythmias, heart failure, and sudden cardiac death [1][5][9]. Diagnosis relies on echocardiography, cardiac MRI, and genetic testing [9][12][15]. Management targets symptom relief, obstruction reduction, and sudden death risk stratification [2][7][15].
Therapies
First-line: β-blockers, non-dihydropyridine calcium channel blockers, or disopyramide for obstruction [2][7][15].
Septal reduction (myectomy/alcohol ablation) for refractory symptoms [2][7][11].
Implantable cardioverter-defibrillators (ICDs) for high sudden death risk; anticoagulation for atrial fibrillation [2][11][15].
Emerging therapies: Cardiac myosin inhibitors (e.g., mavacamten) [2][15].
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
266 drug discovery papers about Rare familial disorder with hypertrophic cardiomyopathy, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
266 drug discovery papers about Rare familial disorder with hypertrophic cardiomyopathy, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-25 | A new insight of hypertrophic cardiomyopathy: integrated analysis of differentially expressed genes, expression quantitative trait loci, and mendelian randomization.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) has a genetic basis, with pathogenic variants identified in the majority of familial cases and unclear mechanism. This study aimed to identify the genetic contributors underlying HCM pathogenesis and to identify novel genetic targets of HCM via integrated analysis of microarray datasets. METHODS: Three independent HCM datasets were used for comprehensive analysis by using R software. Differentially expressed genes (DEGs) between HCM and control, expression quantitative trait loci (eQTL) analysis, and Two-Sample Mendelian Randomization (TSMR) analyses were performed to identify the novel genes. CIBERSORT was utilized for immune cell infiltration analysis. Finally, the identified genes were verified, and their targeted drugs were explored. RESULTS: TSMR analysis revealed that four significantly HCM co-expressed genes, TNNT1, KCNK17, GADD45B, and CXCL6, were enriched in essential biological processes and pathways, including macrophage activation and neural system regulation. TNNT1 and CXCL6 genes were validated as the novel genes, enhancing the reliability of our findings. The candidate compounds with predicted binding affinity (Atorvastatin, Zearalenone, Cotinine, and S-1,2-Dichlorovinyl-N-acetylcysteine) were predicted and molecular docking was performed to evaluate the binding ability of the drug to the protein. CONCLUSIONS: This study reveals a new molecular insight in the pathogenesis of HCM, highlighting TNNT1 and CXCL6 as candidate targets in specific molecular pathways for the interference of HCM.
2026-04-15 | Myosin Inhibitors in Hypertrophic Obstructive Cardiomyopathy: Experience with Mavacamten in a National Referral Center
Background: Hypertrophic cardiomyopathy (HCM) is defined by left ventricular wall thickening not attributable to other causes, with an estimated prevalence of 1 in 200-500 individuals.HCM is classified as obstructive (HOCM) when the left ventricular outflow tract (LVOT) gradient exceeds 30 mmHg. 1 Symptom presence correlates with worse prognosis. 2First-line treatment includes beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide to reduce LVOT obstruction and managing arrhythmias, atrial fibrillation, or embolic risk.Despite medical therapy, up to 50% of patients remain symptomatic and/or exhibit significant LVOT obstruction. 3Septal reduction therapies such as surgical myectomy or alcohol septal ablation are in those cases requiredprocedures carrying risks even in experienced centers. 4cently, European cardiomyopathies guidelines incorporated myosin ATPase inhibitors, such as mavacamten, as a novel alternative therapy.Objective: To describe the initial experience of a national referral centre for familial cardiomyopathies using mavacamten in the treatment of HOCM. Methods:A retrospective, single-centre study was conducted including patients with HOCM treated with mavacamten.Clinical and demographic data were collected at baseline and during follow-up, including left ventricular ejection fraction (LVEF), peak LVOT gradient, NT-proBNP, highsensitivity troponin T, NYHA functional class, and 6-minute walk test.Adherence and tolerance to therapy were assessed.Follow-up occurred at 4, 8, and 12 weeks, with extended data at 18 and 24 weeks for some patients.Results: 8 patients were included.All started mavacamten at 5 mg/day.None required dose reduction due to LVEF deterioration, and the drug was well tolerated without significant adverse effects.All patients experienced marked clinical and functional improvement, with a reduction in LVOT gradients and NT-proBNP levels.Notably, all reached NYHA class I-II, and none required invasive septal reduction therapy (see table ).The cohort was clinically and genetically heterogeneous, supporting the efficacy of the new treatment. Conclusion:This case series demonstrates that mavacamten is a safe and effective non-invasive treatment option for symptomatic HOCM patients in a real-world setting.The observed improvements in clinical status, biomarkers, and echocardiographic parameters align with findings from clinical trials.Mavacamten may reduce the need for invasive septal reduction in appropriately selected patients.
2026-03-01 | PO54 Phenotype and outcome of Hypertrophic Cardiomyopathy patients with MYH7 Variants: a longitudinal Cohort Study
Abstract Introduction and Aim Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to delineate the clinical features and long-term cardiovascular outcome of patients with MYH7-related HCM, and to look for clinical and prognostic implications of specific variants. Methods A retrospective longitudinal analysis was conducted on 30 unrelated HCM families with pathogenic/likely pathogenic (P/LP) MYH7 mutations. A composite endpoint encompassing heart failure hospitalisation, cardiovascular admissions, or all-cause mortality was evaluated. Kaplan–Meier survival analysis was used to compare outcomes across prevalent variants and genetic profiles. Results Among 118 individuals (30 probands, 88 relatives), 77 carried P/LP MYH7 variants — 69% with HCM (G+/Ph+) at diagnosis and 31% just carriers (G+/Ph-). Thirteen P/LP variants were identified, with four (p.Ile263Thr, p.Ala797Thr, p.Glu1356Lys, p.Arg663His) accounting for two-thirds of cases. HCM patients had a mean age at diagnosis of 40.4±18.1 years and 49% were male. Baseline maximal wall thickness (MWT) was 18.6±0.8 mm, left atrial diameter (LAD) was 41.3±9.4 mm, and 23% exhibited resting left ventricular outflow tract obstruction (LVOTO); 68% had abnormal ECGs, but only one patient had atrial fibrillation (AF). Probands showed significantly larger LAD than relatives (p=0.004). A history of premature familial sudden cardiac death (SCD) was reported in 43% families. During a median follow-up of 9.5 years (IQR 3.4-24.7, range 0.2-46.8 years), 35% of patients reached the composite endpoint, including 16 deaths (1 SCD) and 6 heart failure (HF) - related hospitalisations; 30% of patients developed AF, 17% received an ICD for primary prevention of SCD and 17% had a pacemaker implantation. Older age at diagnosis (p<0.01) and increased LAD (p=0.048) predicted poorer outcomes. The composite endpoint was similar between probands and relatives with HCM (p=0.08) and across the main variants (p=0.06). Overall penetrance was 70%, with only one carrier progressing to mild HCM. ESC HCM Risk-SCD scores were similar across variants, both at baseline (p=0.60) and at last follow-up (p=0.29). Conclusion Most patients with MYH7-related HCM presented with a benign phenotype over the long term. Nonetheless, the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may help tailored management strategies.
2026-02-19 | Cardiovascular diseases and risk factors associated with sudden cardiac death in amateur athletes: a scoping review.
Sudden cardiac death (SCD) is a rare but devastating event in the sports setting, often affecting apparently healthy and physically active individuals. Although regular physical activity is widely promoted as a protective factor against cardiovascular disease, cases of SCD continue to be reported not only in elite athletes but also in amateur and recreational athletes, who frequently lack systematic cardiovascular screening. To map the available evidence on the most prevalent cardiovascular diseases and the associated risk factors related to sudden cardiac death in amateur athletes. A scoping review was conducted following the PRISMA-ScR guidelines and the methodological framework proposed by the Joanna Briggs Institute (JBI). The research question was structured using the PCC framework (Population: amateur athletes aged ≥18 years; Concept: cardiovascular diseases and associated risk factors; Context: sudden cardiac death). Systematic searches were performed in PubMed, Scopus, SciELO, and Springer, with no restrictions on publication date and including studies published in English, Spanish, and Portuguese. Study selection, data extraction, and methodological quality assessment were independently performed by two reviewers, with disagreements resolved by a third reviewer. Methodological quality was assessed using JBI critical appraisal tools for observational cohort studies. A total of 1,807 records were identified, of which five observational studies met the inclusion criteria. The most frequently reported cause of SCD in amateur athletes was hypertrophic cardiomyopathy, followed by atherosclerotic coronary artery disease-particularly in athletes older than 35 years-and myocarditis, mainly in younger individuals with recent respiratory infections. Football was the sport most commonly associated with SCD events. The main risk factors identified included male sex, intense physical exertion, traditional cardiovascular risk factors (smoking, hypertension, dyslipidemia, prior myocardial infarction, and coronary stenosis), family history of premature coronary disease, and the absence of early cardiopulmonary resuscitation or defibrillation at the event site. Overall methodological quality ranged from moderate to high. Sudden cardiac death in amateur athletes is predominantly associated with underlying cardiovascular diseases, particularly hypertrophic cardiomyopathy, and with a combination of modifiable and non-modifiable risk factors. These findings highlight that SCD is not exclusive to elite sports and underscore the need for preventive strategies in amateur athletes, including cardiovascular screening, risk factor control, education in cardiopulmonary resuscitation, and availability of automated external defibrillators in sports settings.
2026-01-25 | Emerging Relationships of Sarcomeric Mutations and the Cardiomyocyte Transcriptome in the Setting of Familial Hypertrophic Cardiomyopathy
Familial hypertrophic cardiomyopathy (FHC) is the most common inherited cardiac disease and is largely driven by mutations in sarcomeric proteins, especially β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). This review synthesizes emerging data on how these mutations alter cardiomyocyte mechanics and gene expression. MYH7 mutations reduce force generation and myofibrillar density, while MYBPC3 haploinsufficiency produces hypercontractile, energetically inefficient myocytes. Transcriptomic and microRNA profiling reveal early changes in stress-response, fibrosis, and electrical remodeling pathways. The article also highlights evolving therapies, including cardiac myosin inhibitors like mavacamten and experimental gene-editing approaches, that target upstream molecular drivers rather than downstream structural consequences.
proteins
2025-11-03 | Abstract 4370706: Calsarcin-1 modulates the muscle LIM protein/Z-disc complex in familial hypertrophic cardiomyopathy
Introduction: Hypertrophic cardiomyopathy (HCM) is a hereditary disorder of cardiac muscle and is typically caused by mutations in genes encoding sarcomere proteins. Despite calsarcin-1 being identified as an important modulator of HCM, its role in HCM patients has not been well studied. Hypothesis: We hypothesize that the deficiency of calsarcin-1 leads to destabilization of the muscle LIM protein/Z-disc complex, which subsequently contributes to the development of HCM. Methods: Calsarcin-1 expression level in the HCM proband heart, cardiomyocytes derived from patient-specific induced pluripotent stem cells (iPSC-CMs), was measured. Isogenic control iPSCs were generated by gene editing. In combination with viral infection and various other techniques, we explored the potential role of calsarcin-1 in HCM. Results: Immunofluorescence staining revealed largely disrupted striated patterns of myofilaments in the MLP-W4R;MYH7-R723C proband heart, in contrast to the well-defined striated patterns and organized myofilaments observed in the healthy control (CTL) heart. In MLP-W4R;MYH7-R723C iPSC-CMs, mRNA levels of atrial natriuretic factor ( ANF ) and brain natriuretic peptide ( BNP ) were elevated, confirming that the hypertrophic phenotype was maintained in proband iPSC-CMs. Importantly, calsarcin-1 protein expression in the proband iPSC-CMs was significantly decreased compared to that in the CTL iPSC-CMs. Moreover, ectopic expression of calsarcin-1 was able to significantly rescue the HCM phenotype, including the enlarged cardiomyocyte size and the elevated ANF and BNP mRNA levels in MLP-W4R;MYH7-R723C iPSC-CMs. Calsarcin-1 significantly enhanced MLP expression in the proband iPSC-CMs. Importantly, the effects of MLP on decreasing cell size and BNP mRNA level in the MLP-W4R;MYH7-R723C iPSC-CMs were markedly blunted when calsarcin-1 was knocked down using the shRNA lentivirus targeting calsarcin-1. Two additional iPSC lines generated from HCM patients carrying pathogenic variants in MYH7-R663H (myosin heavy chain) and MYBPC3-V321M (myosin-binding protein C) were investigated. Notably, calsarcin-1 was able to significantly reduce the hypertrophic phenotype of cardiomyocytes derived from these two iPSC lines. Conclusions: Calsarcin-1 is reduced in MLP-W4R;MYH7-R723C iPSC-CMs. Elevating the expression level of calsarcin-1 may have a broader role in mitigating hypertrophic cardiomyopathic defects and could be an attractive therapeutic target for treating HCM.
2024-08-28 | Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart.
Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury.
2023-03-30 | Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8-10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R2 = 0.60, P < 0.01) and III (R2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R2 = 0.28, P = 0.05) and interstitial (R2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (-15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer (-8.9%, P < 0.001) collagen fibres. The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.
2021-10-15 | Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.
Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
2021-10-06 | RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes.
Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at -70 mV. Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of ∼220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (<40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy. Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation.
gene therapies
2025-11-27 | Genetic Engineering with CRISPR-Cas9: Methodologies, Genetic Techniques, and Bioethics
For the last ten years, the precision of genome engineering in human embryos has increased tenfold using the CRISPR-Cas9 genome editing tool. Commonly used as an intervention strategy for disease prevention, CRISPR-Cas9’s precision to target disease-carrying genes far exceeds that of its predecessors, ZFNs and TALENs, and has been used for conditions like β-thalassemia, familial hypertrophic cardiomyopathy (FHC), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and many others. As its utilization increases, additions to its procedure to refine its efficacy have also continued, as explained by adding homology-directed repair (HDR), high fidelity Cas9 variants, and chemical enhancers to further increase the success rate, while reducing the off-target effects. Despite current progress, the risk of genomic instability, large deletions, and variable repair mechanisms is still high. Another concern is how the current ethical and regulatory frameworks within the United States do not account for this technological advancement. This review aims to examine current CRISPR-Cas9 methodologies and genetic techniques, to evaluate the associated limitations and challenges, and to explore the ethical implications of this technique in the advancing field. KeyWords: CRISPR-Cas9, Germline Editing, Homology-Directed Repair (HDR), Genomic Instability, Bioethics
2025-10-30 | Clustered Regularly Interspaced Short Palindromic Repeats Genome Editing for Cardiovascular Disease: The Future Is Here.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has expanded from experimental biology to early clinical application, raising the possibility of durable therapies for cardiovascular disease. Because many cardiac conditions are monogenic, they provide clear targets for allele-specific correction or modulation. In hypertrophic cardiomyopathy, preclinical research has shown that base editing of pathogenic MYH7 and MYBPC3 mutations can restore sarcomere function; concurrently, RNA-targeting approaches selectively suppress mutant transcripts. Dilated cardiomyopathy is more heterogeneous: TTN truncations cause haploinsufficiency that can be offset by CRISPR activation, while RBM20 and LMNA mutations require precise correction or interference to restore splicing and nuclear stability. Genome editing is also being tested in familial hypercholesterolemia, where inactivation of PCSK9 using lipid nanoparticle-delivered base editors has now advanced to first-in-human trials, achieving sustained LDL-C lowering. Concurrently, efforts targeting ANGPTL3 and APOB highlight the prospect of multigene modulation of lipid metabolism. In arrhythmic syndromes, patient-derived cardiomyocytes edited at SCN5A and KCNQ1 genes have enabled high-fidelity disease models, while in vivo correction of RYR2 in catecholaminergic polymorphic ventricular tachycardia confirms the viability of editing an arrhythmia substrate. In cardiac regeneration, CRISPR activation of developmental transcription factors has enabled direct reprogramming of fibroblasts into cardiomyocyte-like cells within scar tissue. Even with these advances, delivery remains a bottleneck due to immune responses to viral vectors, limitations in the efficiency of lipid nanoparticles in the heart, and the precision required to target cardiomyocytes or conduction cells, all of which slow progress. Future work will depend as much on technical refinement as on navigating ethical, regulatory, and societal concerns.
2025-05-15 | Utility and Limitations of Genetic Testing in the Routine Care of Cardiovascular Disease Patients in a General Hospital.
Genetic diagnosis is becoming more prevalent in the routine care of cardiovascular disease (CVD) but is still limited to specialized institutions. Therefore, general cardiologists are also expected to acquire fundamental knowledge for incorporating genomics into the clinical practice of inherited to multifactorial CVDs. To accomplish this, the present study evaluated the utility and limitations of genetic testing in a general hospital setting.We examined 2 clinical issues: 1) the diagnostic potential of genetic tests for known inherited CVDs across 4 disease entities, i.e., familial hypercholesterolemia (FH), hypertrophic cardiomyopathy (HCM), suspected lethal arrhythmia, and aortic aneurysm/dissection (total n = 84) and 2) the genetic components associated with 2 multifactorial pathologies, cardiac hypertrophy and atrial fibrillation (AF), through a case-control study (total n = 594). We first performed targeted gene panel tests or whole-exome sequencing to identify causative gene variants for inherited CVDs; this yielded a positive test rate of 14 to 40%. The diagnosis rate for FH increased to 70% if strict eligibility criteria were adopted. The diagnosis rate for HCM also markedly increased by modifying the interpretation criteria for genetic variant pathogenicity. Furthermore, we performed gene-based burden tests and polygenic risk score (PRS) calculations for cardiac hypertrophy and AF. For example, the PRS-based genetic risk was significantly increased in early-onset (≤ 60 years) AF compared to non-AF controls (per-SD odds ratio in standardized PRS: 1.83, P = 2.6 × 10-4).Genetic tests for CVDs may complement the diagnosis based on traditional laboratory-based diagnostics, although the currently limited capabilities of variant interpretation necessitate careful attention.
2025-04-17 | Exploring the Potential of CRISPR-Cas9 in the Genetic Modification of Cardiac Cells for Heart Disease Treatment
This study explores the potential of CRISPR-Cas9 technology in the genetic modification of cardiac cells for the treatment of heart diseases, specifically those caused by genetic mutations such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and familial hypercholesterolemia (FH). A quantitative research design was adopted, utilizing a probability sampling technique with a sample size of 110 healthcare professionals, including cardiologists, geneticists, medical researchers, and general physicians from Punjab, Pakistan. The study investigates the awareness of CRISPR-Cas9, its perceived usefulness, and the attitudes of healthcare professionals toward its application in treating genetic heart diseases. Data were analyzed using demographic analysis, correlation analysis, chi-square tests, and regression analysis to assess the relationships between variables. The findings indicate a strong positive correlation between awareness of CRISPR-Cas9 and favorable attitudes toward its application, with perceived usefulness emerging as a key predictor of positive attitudes. However, challenges such as delivery methods, off-target effects, and the long-term safety of CRISPR-based therapies in cardiac cells remain significant obstacles. This study provides valuable insights into the adoption of CRISPR-Cas9 in cardiovascular medicine and underscores the need for further research to address technical and ethical concerns. The results suggest that CRISPR-Cas9 holds great promise for revolutionizing the treatment of genetic heart diseases but requires more development before becoming a mainstream clinical tool.
2024-05-16 | Emerging Themes in Genetics of Hypertrophic Cardiomyopathy: Current Status and Clinical Application.
Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered.
oligonucleotides
2025-08-12 | Identification of candidate cardiomyopathy modifier genes through genome sequencing and RNA profiling.
Phenotypic heterogeneity is apparent among individuals with putative monogenic disease, such as familial hypertrophic cardiomyopathy. Genome sequencing (GS) allows interrogation of the full spectrum of inborn genetic variation in an individual and RNA profiling provides a snapshot of the cardiac-specific pathogenic effects on gene expression. Identify candidate genetic modifiers of hypertrophic cardiomyopathy phenotype. We performed GS of 48 individuals with variants in MYH7, the gene encoding beta myosin heavy chain, and a personal or family history of cardiomyopathy. The genome sequences were annotated with a custom pipeline optimized for cardiovascular gene variant detection. We utilized multiple lines of evidence to prioritize genes together with rare variant gene-based association testing to identify candidate genetic modifiers. GS identified the MYH7 variant in all 48 cases. Several variants were reclassified based on best available data. We identified known disease-associated genes (MYBPC3, FHOD3), a priori candidate modifiers (ATP1A2, RYR2), and novel candidate modifiers of cardiomyopathy including PACSIN3 and SORBS2. We identified regulatory variants and intergenic regions associated with the phenotypes. Using RNA profiling, we show that several genes identified through gene-based association testing are differentially regulated in human hypertrophic cardiomyopathy, and in models of disease. Evaluation of the whole genome, even in the case of alleged monogenic disease, leads to important new insights. The identified variants, regions, and genes are candidates to modify disease presentation in cardiomyopathy.
2024-07-22 | Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy.
Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.
2022-10-28 | [Molecular cardiology: from decoding the genetic nature and mechanisms of the diseases development to the introduction into the clinic].
In recent decades, advances in molecular biology have led to a change in understanding the inheritance mechanisms and development of cardiological diseases of predominantly genetic origin, such as hypertrophic and dilated cardiomyopathies, familial hypercholesterolemia, etc. This knowledge made it possible to develop fundamentally new drug interventions. Programs for detecting cardiac diseases of predominantly genetic origin have been created, including genetic counseling and testing. Competence in this area is becoming a necessary part of a cardiologist's job. Достижения молекулярной биологии последних десятилетий привели к изменению представлений о механизмах наследования и развития кардиологических заболеваний преимущественно генетического происхождения, таких как гипертрофическая и дилатационная кардиомиопатии, семейная гиперхолестеринемия и пр. Эти знания сделали возможной разработку принципиально новых лекарственных вмешательств. Созданы программы выявления кардиологических заболеваний преимущественно генетического происхождения, включающие генетическое консультирование и тестирование. Компетенции в данной области становятся необходимой частью работы кардиолога.
2022-06-16 | Filamin C in cardiomyopathy: from physiological roles to DNA variants.
Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.
2012-04-10 | [Clinical relevance of genetic testing in hypertrophic cardiomyopathy].
More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.
other
2024-10-25 | Patient-derived induced pluripotent stem cells to study non-canonical splicing variants associated with Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression.
2024-03-19 | Establishment and characterization of induced pluripotent stem cells from an individual with familial hypertrophic cardiomyopathy carrying the MYBPC3 c.772G>A mutation
Abstract Familial hypertrophic cardiomyopathy (HCM), the most common genetic heart disorder, is defined by left ventricular hypertrophy in individuals without abnormal loading conditions. This condition can progress to heart failure and sudden cardiac death. In the context of heart disease, availability of patient heart tissues is scarce and hampers cardiac research progression. An alternative is the generation of induced pluripotent stem cells (iPSCs) from patients, that can be differentiated into cardiac cells and used to study disease mechanisms and regenerative medicine approaches as well as platforms for drug development and toxicity assays. In this study, we generated two induced pluripotent stem cell lines from peripheral blood mononuclear cells (PBMCs) of a 64-year-old female carrying the MYBPC3 c.772G > A HCM pathogenic splicing mutation. The generated iPSC lines exhibit a normal karyotype and display hallmark characteristics of pluripotency, including the ability to undergo trilineage differentiation. These new iPSC lines provide a valuable resource for understanding the role of the MYBPC3 c.772G > A mutation in initiating HCM and exploring potential targeted therapeutic strategies.
2014-12-09 | Human-induced pluripotent stem cell models of inherited cardiomyopathies.
This article provides an overview of the latest advances in in-vitro modeling of inherited cardiomyopathies using human-induced pluripotent stem cells (iPSCs). Inherited cardiomyopathies have been recently modeled by generating iPSCs from patients harboring mutations in genes associated with the pathogenesis of hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. Patient-specific iPSCs and their differentiated cardiomyocytes (induced pluripotent stem cell-derived cardiomyocytes) now provide a novel model to study the underlying molecular mechanism of the pathogenesis of familial cardiomyopathies as well as for in-vitro drug screening and drug discovery.
1999-02-10 | The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains.
Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is adjacent to the ELC, we scanned HCM patient DNA for mutations in either the ELC or RLC. Linkage analysis showed that a unique mutation in the ELC caused a rare phenotype of HCM in one family. Other mutations in either light chain were also associated with the same rare phenotype in other families. Through several lines of reasoning we hypothesized that the light chain mutations interfere with the stretch-activation response of papillary muscle and adjacent ventricular tissue. This property is critical to oscillatory power output of insect flight muscle. We conjectured that this property is also exploited by portions of the heart to increase power output. In order to test this hypothesis we constructed transgenic mouse lines expressing either the human normal or mutant ELC. The cardiac morphology and mechanical properties of the transgenic mouse papillary muscle is now being studied.
small molecules
2026-04-25 | A new insight of hypertrophic cardiomyopathy: integrated analysis of differentially expressed genes, expression quantitative trait loci, and mendelian randomization.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) has a genetic basis, with pathogenic variants identified in the majority of familial cases and unclear mechanism. This study aimed to identify the genetic contributors underlying HCM pathogenesis and to identify novel genetic targets of HCM via integrated analysis of microarray datasets. METHODS: Three independent HCM datasets were used for comprehensive analysis by using R software. Differentially expressed genes (DEGs) between HCM and control, expression quantitative trait loci (eQTL) analysis, and Two-Sample Mendelian Randomization (TSMR) analyses were performed to identify the novel genes. CIBERSORT was utilized for immune cell infiltration analysis. Finally, the identified genes were verified, and their targeted drugs were explored. RESULTS: TSMR analysis revealed that four significantly HCM co-expressed genes, TNNT1, KCNK17, GADD45B, and CXCL6, were enriched in essential biological processes and pathways, including macrophage activation and neural system regulation. TNNT1 and CXCL6 genes were validated as the novel genes, enhancing the reliability of our findings. The candidate compounds with predicted binding affinity (Atorvastatin, Zearalenone, Cotinine, and S-1,2-Dichlorovinyl-N-acetylcysteine) were predicted and molecular docking was performed to evaluate the binding ability of the drug to the protein. CONCLUSIONS: This study reveals a new molecular insight in the pathogenesis of HCM, highlighting TNNT1 and CXCL6 as candidate targets in specific molecular pathways for the interference of HCM.
2026-04-15 | Myosin Inhibitors in Hypertrophic Obstructive Cardiomyopathy: Experience with Mavacamten in a National Referral Center
Background: Hypertrophic cardiomyopathy (HCM) is defined by left ventricular wall thickening not attributable to other causes, with an estimated prevalence of 1 in 200-500 individuals.HCM is classified as obstructive (HOCM) when the left ventricular outflow tract (LVOT) gradient exceeds 30 mmHg. 1 Symptom presence correlates with worse prognosis. 2First-line treatment includes beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide to reduce LVOT obstruction and managing arrhythmias, atrial fibrillation, or embolic risk.Despite medical therapy, up to 50% of patients remain symptomatic and/or exhibit significant LVOT obstruction. 3Septal reduction therapies such as surgical myectomy or alcohol septal ablation are in those cases requiredprocedures carrying risks even in experienced centers. 4cently, European cardiomyopathies guidelines incorporated myosin ATPase inhibitors, such as mavacamten, as a novel alternative therapy.Objective: To describe the initial experience of a national referral centre for familial cardiomyopathies using mavacamten in the treatment of HOCM. Methods:A retrospective, single-centre study was conducted including patients with HOCM treated with mavacamten.Clinical and demographic data were collected at baseline and during follow-up, including left ventricular ejection fraction (LVEF), peak LVOT gradient, NT-proBNP, highsensitivity troponin T, NYHA functional class, and 6-minute walk test.Adherence and tolerance to therapy were assessed.Follow-up occurred at 4, 8, and 12 weeks, with extended data at 18 and 24 weeks for some patients.Results: 8 patients were included.All started mavacamten at 5 mg/day.None required dose reduction due to LVEF deterioration, and the drug was well tolerated without significant adverse effects.All patients experienced marked clinical and functional improvement, with a reduction in LVOT gradients and NT-proBNP levels.Notably, all reached NYHA class I-II, and none required invasive septal reduction therapy (see table ).The cohort was clinically and genetically heterogeneous, supporting the efficacy of the new treatment. Conclusion:This case series demonstrates that mavacamten is a safe and effective non-invasive treatment option for symptomatic HOCM patients in a real-world setting.The observed improvements in clinical status, biomarkers, and echocardiographic parameters align with findings from clinical trials.Mavacamten may reduce the need for invasive septal reduction in appropriately selected patients.
2026-03-01 | PO54 Phenotype and outcome of Hypertrophic Cardiomyopathy patients with MYH7 Variants: a longitudinal Cohort Study
Abstract Introduction and Aim Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in MYH7 and MYBPC3 genes which exhibit diverse clinical expression and prognosis. This study aims to delineate the clinical features and long-term cardiovascular outcome of patients with MYH7-related HCM, and to look for clinical and prognostic implications of specific variants. Methods A retrospective longitudinal analysis was conducted on 30 unrelated HCM families with pathogenic/likely pathogenic (P/LP) MYH7 mutations. A composite endpoint encompassing heart failure hospitalisation, cardiovascular admissions, or all-cause mortality was evaluated. Kaplan–Meier survival analysis was used to compare outcomes across prevalent variants and genetic profiles. Results Among 118 individuals (30 probands, 88 relatives), 77 carried P/LP MYH7 variants — 69% with HCM (G+/Ph+) at diagnosis and 31% just carriers (G+/Ph-). Thirteen P/LP variants were identified, with four (p.Ile263Thr, p.Ala797Thr, p.Glu1356Lys, p.Arg663His) accounting for two-thirds of cases. HCM patients had a mean age at diagnosis of 40.4±18.1 years and 49% were male. Baseline maximal wall thickness (MWT) was 18.6±0.8 mm, left atrial diameter (LAD) was 41.3±9.4 mm, and 23% exhibited resting left ventricular outflow tract obstruction (LVOTO); 68% had abnormal ECGs, but only one patient had atrial fibrillation (AF). Probands showed significantly larger LAD than relatives (p=0.004). A history of premature familial sudden cardiac death (SCD) was reported in 43% families. During a median follow-up of 9.5 years (IQR 3.4-24.7, range 0.2-46.8 years), 35% of patients reached the composite endpoint, including 16 deaths (1 SCD) and 6 heart failure (HF) - related hospitalisations; 30% of patients developed AF, 17% received an ICD for primary prevention of SCD and 17% had a pacemaker implantation. Older age at diagnosis (p<0.01) and increased LAD (p=0.048) predicted poorer outcomes. The composite endpoint was similar between probands and relatives with HCM (p=0.08) and across the main variants (p=0.06). Overall penetrance was 70%, with only one carrier progressing to mild HCM. ESC HCM Risk-SCD scores were similar across variants, both at baseline (p=0.60) and at last follow-up (p=0.29). Conclusion Most patients with MYH7-related HCM presented with a benign phenotype over the long term. Nonetheless, the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may help tailored management strategies.
2026-02-19 | Cardiovascular diseases and risk factors associated with sudden cardiac death in amateur athletes: a scoping review.
Sudden cardiac death (SCD) is a rare but devastating event in the sports setting, often affecting apparently healthy and physically active individuals. Although regular physical activity is widely promoted as a protective factor against cardiovascular disease, cases of SCD continue to be reported not only in elite athletes but also in amateur and recreational athletes, who frequently lack systematic cardiovascular screening. To map the available evidence on the most prevalent cardiovascular diseases and the associated risk factors related to sudden cardiac death in amateur athletes. A scoping review was conducted following the PRISMA-ScR guidelines and the methodological framework proposed by the Joanna Briggs Institute (JBI). The research question was structured using the PCC framework (Population: amateur athletes aged ≥18 years; Concept: cardiovascular diseases and associated risk factors; Context: sudden cardiac death). Systematic searches were performed in PubMed, Scopus, SciELO, and Springer, with no restrictions on publication date and including studies published in English, Spanish, and Portuguese. Study selection, data extraction, and methodological quality assessment were independently performed by two reviewers, with disagreements resolved by a third reviewer. Methodological quality was assessed using JBI critical appraisal tools for observational cohort studies. A total of 1,807 records were identified, of which five observational studies met the inclusion criteria. The most frequently reported cause of SCD in amateur athletes was hypertrophic cardiomyopathy, followed by atherosclerotic coronary artery disease-particularly in athletes older than 35 years-and myocarditis, mainly in younger individuals with recent respiratory infections. Football was the sport most commonly associated with SCD events. The main risk factors identified included male sex, intense physical exertion, traditional cardiovascular risk factors (smoking, hypertension, dyslipidemia, prior myocardial infarction, and coronary stenosis), family history of premature coronary disease, and the absence of early cardiopulmonary resuscitation or defibrillation at the event site. Overall methodological quality ranged from moderate to high. Sudden cardiac death in amateur athletes is predominantly associated with underlying cardiovascular diseases, particularly hypertrophic cardiomyopathy, and with a combination of modifiable and non-modifiable risk factors. These findings highlight that SCD is not exclusive to elite sports and underscore the need for preventive strategies in amateur athletes, including cardiovascular screening, risk factor control, education in cardiopulmonary resuscitation, and availability of automated external defibrillators in sports settings.
2026-01-25 | Emerging Relationships of Sarcomeric Mutations and the Cardiomyocyte Transcriptome in the Setting of Familial Hypertrophic Cardiomyopathy
Familial hypertrophic cardiomyopathy (FHC) is the most common inherited cardiac disease and is largely driven by mutations in sarcomeric proteins, especially β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). This review synthesizes emerging data on how these mutations alter cardiomyocyte mechanics and gene expression. MYH7 mutations reduce force generation and myofibrillar density, while MYBPC3 haploinsufficiency produces hypercontractile, energetically inefficient myocytes. Transcriptomic and microRNA profiling reveal early changes in stress-response, fibrosis, and electrical remodeling pathways. The article also highlights evolving therapies, including cardiac myosin inhibitors like mavacamten and experimental gene-editing approaches, that target upstream molecular drivers rather than downstream structural consequences.
proteins
2025-11-03 | Abstract 4370706: Calsarcin-1 modulates the muscle LIM protein/Z-disc complex in familial hypertrophic cardiomyopathy
Introduction: Hypertrophic cardiomyopathy (HCM) is a hereditary disorder of cardiac muscle and is typically caused by mutations in genes encoding sarcomere proteins. Despite calsarcin-1 being identified as an important modulator of HCM, its role in HCM patients has not been well studied. Hypothesis: We hypothesize that the deficiency of calsarcin-1 leads to destabilization of the muscle LIM protein/Z-disc complex, which subsequently contributes to the development of HCM. Methods: Calsarcin-1 expression level in the HCM proband heart, cardiomyocytes derived from patient-specific induced pluripotent stem cells (iPSC-CMs), was measured. Isogenic control iPSCs were generated by gene editing. In combination with viral infection and various other techniques, we explored the potential role of calsarcin-1 in HCM. Results: Immunofluorescence staining revealed largely disrupted striated patterns of myofilaments in the MLP-W4R;MYH7-R723C proband heart, in contrast to the well-defined striated patterns and organized myofilaments observed in the healthy control (CTL) heart. In MLP-W4R;MYH7-R723C iPSC-CMs, mRNA levels of atrial natriuretic factor ( ANF ) and brain natriuretic peptide ( BNP ) were elevated, confirming that the hypertrophic phenotype was maintained in proband iPSC-CMs. Importantly, calsarcin-1 protein expression in the proband iPSC-CMs was significantly decreased compared to that in the CTL iPSC-CMs. Moreover, ectopic expression of calsarcin-1 was able to significantly rescue the HCM phenotype, including the enlarged cardiomyocyte size and the elevated ANF and BNP mRNA levels in MLP-W4R;MYH7-R723C iPSC-CMs. Calsarcin-1 significantly enhanced MLP expression in the proband iPSC-CMs. Importantly, the effects of MLP on decreasing cell size and BNP mRNA level in the MLP-W4R;MYH7-R723C iPSC-CMs were markedly blunted when calsarcin-1 was knocked down using the shRNA lentivirus targeting calsarcin-1. Two additional iPSC lines generated from HCM patients carrying pathogenic variants in MYH7-R663H (myosin heavy chain) and MYBPC3-V321M (myosin-binding protein C) were investigated. Notably, calsarcin-1 was able to significantly reduce the hypertrophic phenotype of cardiomyocytes derived from these two iPSC lines. Conclusions: Calsarcin-1 is reduced in MLP-W4R;MYH7-R723C iPSC-CMs. Elevating the expression level of calsarcin-1 may have a broader role in mitigating hypertrophic cardiomyopathic defects and could be an attractive therapeutic target for treating HCM.
2024-08-28 | Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart.
Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury.
2023-03-30 | Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8-10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R2 = 0.60, P < 0.01) and III (R2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R2 = 0.28, P = 0.05) and interstitial (R2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (-15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer (-8.9%, P < 0.001) collagen fibres. The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.
2021-10-15 | Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.
Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
2021-10-06 | RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes.
Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at -70 mV. Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of ∼220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (<40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy. Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation.
gene therapies
2025-11-27 | Genetic Engineering with CRISPR-Cas9: Methodologies, Genetic Techniques, and Bioethics
For the last ten years, the precision of genome engineering in human embryos has increased tenfold using the CRISPR-Cas9 genome editing tool. Commonly used as an intervention strategy for disease prevention, CRISPR-Cas9’s precision to target disease-carrying genes far exceeds that of its predecessors, ZFNs and TALENs, and has been used for conditions like β-thalassemia, familial hypertrophic cardiomyopathy (FHC), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and many others. As its utilization increases, additions to its procedure to refine its efficacy have also continued, as explained by adding homology-directed repair (HDR), high fidelity Cas9 variants, and chemical enhancers to further increase the success rate, while reducing the off-target effects. Despite current progress, the risk of genomic instability, large deletions, and variable repair mechanisms is still high. Another concern is how the current ethical and regulatory frameworks within the United States do not account for this technological advancement. This review aims to examine current CRISPR-Cas9 methodologies and genetic techniques, to evaluate the associated limitations and challenges, and to explore the ethical implications of this technique in the advancing field. KeyWords: CRISPR-Cas9, Germline Editing, Homology-Directed Repair (HDR), Genomic Instability, Bioethics
2025-10-30 | Clustered Regularly Interspaced Short Palindromic Repeats Genome Editing for Cardiovascular Disease: The Future Is Here.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has expanded from experimental biology to early clinical application, raising the possibility of durable therapies for cardiovascular disease. Because many cardiac conditions are monogenic, they provide clear targets for allele-specific correction or modulation. In hypertrophic cardiomyopathy, preclinical research has shown that base editing of pathogenic MYH7 and MYBPC3 mutations can restore sarcomere function; concurrently, RNA-targeting approaches selectively suppress mutant transcripts. Dilated cardiomyopathy is more heterogeneous: TTN truncations cause haploinsufficiency that can be offset by CRISPR activation, while RBM20 and LMNA mutations require precise correction or interference to restore splicing and nuclear stability. Genome editing is also being tested in familial hypercholesterolemia, where inactivation of PCSK9 using lipid nanoparticle-delivered base editors has now advanced to first-in-human trials, achieving sustained LDL-C lowering. Concurrently, efforts targeting ANGPTL3 and APOB highlight the prospect of multigene modulation of lipid metabolism. In arrhythmic syndromes, patient-derived cardiomyocytes edited at SCN5A and KCNQ1 genes have enabled high-fidelity disease models, while in vivo correction of RYR2 in catecholaminergic polymorphic ventricular tachycardia confirms the viability of editing an arrhythmia substrate. In cardiac regeneration, CRISPR activation of developmental transcription factors has enabled direct reprogramming of fibroblasts into cardiomyocyte-like cells within scar tissue. Even with these advances, delivery remains a bottleneck due to immune responses to viral vectors, limitations in the efficiency of lipid nanoparticles in the heart, and the precision required to target cardiomyocytes or conduction cells, all of which slow progress. Future work will depend as much on technical refinement as on navigating ethical, regulatory, and societal concerns.
2025-05-15 | Utility and Limitations of Genetic Testing in the Routine Care of Cardiovascular Disease Patients in a General Hospital.
Genetic diagnosis is becoming more prevalent in the routine care of cardiovascular disease (CVD) but is still limited to specialized institutions. Therefore, general cardiologists are also expected to acquire fundamental knowledge for incorporating genomics into the clinical practice of inherited to multifactorial CVDs. To accomplish this, the present study evaluated the utility and limitations of genetic testing in a general hospital setting.We examined 2 clinical issues: 1) the diagnostic potential of genetic tests for known inherited CVDs across 4 disease entities, i.e., familial hypercholesterolemia (FH), hypertrophic cardiomyopathy (HCM), suspected lethal arrhythmia, and aortic aneurysm/dissection (total n = 84) and 2) the genetic components associated with 2 multifactorial pathologies, cardiac hypertrophy and atrial fibrillation (AF), through a case-control study (total n = 594). We first performed targeted gene panel tests or whole-exome sequencing to identify causative gene variants for inherited CVDs; this yielded a positive test rate of 14 to 40%. The diagnosis rate for FH increased to 70% if strict eligibility criteria were adopted. The diagnosis rate for HCM also markedly increased by modifying the interpretation criteria for genetic variant pathogenicity. Furthermore, we performed gene-based burden tests and polygenic risk score (PRS) calculations for cardiac hypertrophy and AF. For example, the PRS-based genetic risk was significantly increased in early-onset (≤ 60 years) AF compared to non-AF controls (per-SD odds ratio in standardized PRS: 1.83, P = 2.6 × 10-4).Genetic tests for CVDs may complement the diagnosis based on traditional laboratory-based diagnostics, although the currently limited capabilities of variant interpretation necessitate careful attention.
2025-04-17 | Exploring the Potential of CRISPR-Cas9 in the Genetic Modification of Cardiac Cells for Heart Disease Treatment
This study explores the potential of CRISPR-Cas9 technology in the genetic modification of cardiac cells for the treatment of heart diseases, specifically those caused by genetic mutations such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and familial hypercholesterolemia (FH). A quantitative research design was adopted, utilizing a probability sampling technique with a sample size of 110 healthcare professionals, including cardiologists, geneticists, medical researchers, and general physicians from Punjab, Pakistan. The study investigates the awareness of CRISPR-Cas9, its perceived usefulness, and the attitudes of healthcare professionals toward its application in treating genetic heart diseases. Data were analyzed using demographic analysis, correlation analysis, chi-square tests, and regression analysis to assess the relationships between variables. The findings indicate a strong positive correlation between awareness of CRISPR-Cas9 and favorable attitudes toward its application, with perceived usefulness emerging as a key predictor of positive attitudes. However, challenges such as delivery methods, off-target effects, and the long-term safety of CRISPR-based therapies in cardiac cells remain significant obstacles. This study provides valuable insights into the adoption of CRISPR-Cas9 in cardiovascular medicine and underscores the need for further research to address technical and ethical concerns. The results suggest that CRISPR-Cas9 holds great promise for revolutionizing the treatment of genetic heart diseases but requires more development before becoming a mainstream clinical tool.
2024-05-16 | Emerging Themes in Genetics of Hypertrophic Cardiomyopathy: Current Status and Clinical Application.
Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered.
oligonucleotides
2025-08-12 | Identification of candidate cardiomyopathy modifier genes through genome sequencing and RNA profiling.
Phenotypic heterogeneity is apparent among individuals with putative monogenic disease, such as familial hypertrophic cardiomyopathy. Genome sequencing (GS) allows interrogation of the full spectrum of inborn genetic variation in an individual and RNA profiling provides a snapshot of the cardiac-specific pathogenic effects on gene expression. Identify candidate genetic modifiers of hypertrophic cardiomyopathy phenotype. We performed GS of 48 individuals with variants in MYH7, the gene encoding beta myosin heavy chain, and a personal or family history of cardiomyopathy. The genome sequences were annotated with a custom pipeline optimized for cardiovascular gene variant detection. We utilized multiple lines of evidence to prioritize genes together with rare variant gene-based association testing to identify candidate genetic modifiers. GS identified the MYH7 variant in all 48 cases. Several variants were reclassified based on best available data. We identified known disease-associated genes (MYBPC3, FHOD3), a priori candidate modifiers (ATP1A2, RYR2), and novel candidate modifiers of cardiomyopathy including PACSIN3 and SORBS2. We identified regulatory variants and intergenic regions associated with the phenotypes. Using RNA profiling, we show that several genes identified through gene-based association testing are differentially regulated in human hypertrophic cardiomyopathy, and in models of disease. Evaluation of the whole genome, even in the case of alleged monogenic disease, leads to important new insights. The identified variants, regions, and genes are candidates to modify disease presentation in cardiomyopathy.
2024-07-22 | Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy.
Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.
2022-10-28 | [Molecular cardiology: from decoding the genetic nature and mechanisms of the diseases development to the introduction into the clinic].
In recent decades, advances in molecular biology have led to a change in understanding the inheritance mechanisms and development of cardiological diseases of predominantly genetic origin, such as hypertrophic and dilated cardiomyopathies, familial hypercholesterolemia, etc. This knowledge made it possible to develop fundamentally new drug interventions. Programs for detecting cardiac diseases of predominantly genetic origin have been created, including genetic counseling and testing. Competence in this area is becoming a necessary part of a cardiologist's job. Достижения молекулярной биологии последних десятилетий привели к изменению представлений о механизмах наследования и развития кардиологических заболеваний преимущественно генетического происхождения, таких как гипертрофическая и дилатационная кардиомиопатии, семейная гиперхолестеринемия и пр. Эти знания сделали возможной разработку принципиально новых лекарственных вмешательств. Созданы программы выявления кардиологических заболеваний преимущественно генетического происхождения, включающие генетическое консультирование и тестирование. Компетенции в данной области становятся необходимой частью работы кардиолога.
2022-06-16 | Filamin C in cardiomyopathy: from physiological roles to DNA variants.
Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.
2012-04-10 | [Clinical relevance of genetic testing in hypertrophic cardiomyopathy].
More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.
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2024-10-25 | Patient-derived induced pluripotent stem cells to study non-canonical splicing variants associated with Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression.
2024-03-19 | Establishment and characterization of induced pluripotent stem cells from an individual with familial hypertrophic cardiomyopathy carrying the MYBPC3 c.772G>A mutation
Abstract Familial hypertrophic cardiomyopathy (HCM), the most common genetic heart disorder, is defined by left ventricular hypertrophy in individuals without abnormal loading conditions. This condition can progress to heart failure and sudden cardiac death. In the context of heart disease, availability of patient heart tissues is scarce and hampers cardiac research progression. An alternative is the generation of induced pluripotent stem cells (iPSCs) from patients, that can be differentiated into cardiac cells and used to study disease mechanisms and regenerative medicine approaches as well as platforms for drug development and toxicity assays. In this study, we generated two induced pluripotent stem cell lines from peripheral blood mononuclear cells (PBMCs) of a 64-year-old female carrying the MYBPC3 c.772G > A HCM pathogenic splicing mutation. The generated iPSC lines exhibit a normal karyotype and display hallmark characteristics of pluripotency, including the ability to undergo trilineage differentiation. These new iPSC lines provide a valuable resource for understanding the role of the MYBPC3 c.772G > A mutation in initiating HCM and exploring potential targeted therapeutic strategies.
2014-12-09 | Human-induced pluripotent stem cell models of inherited cardiomyopathies.
This article provides an overview of the latest advances in in-vitro modeling of inherited cardiomyopathies using human-induced pluripotent stem cells (iPSCs). Inherited cardiomyopathies have been recently modeled by generating iPSCs from patients harboring mutations in genes associated with the pathogenesis of hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. Patient-specific iPSCs and their differentiated cardiomyocytes (induced pluripotent stem cell-derived cardiomyocytes) now provide a novel model to study the underlying molecular mechanism of the pathogenesis of familial cardiomyopathies as well as for in-vitro drug screening and drug discovery.
1999-02-10 | The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains.
Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is adjacent to the ELC, we scanned HCM patient DNA for mutations in either the ELC or RLC. Linkage analysis showed that a unique mutation in the ELC caused a rare phenotype of HCM in one family. Other mutations in either light chain were also associated with the same rare phenotype in other families. Through several lines of reasoning we hypothesized that the light chain mutations interfere with the stretch-activation response of papillary muscle and adjacent ventricular tissue. This property is critical to oscillatory power output of insect flight muscle. We conjectured that this property is also exploited by portions of the heart to increase power output. In order to test this hypothesis we constructed transgenic mouse lines expressing either the human normal or mutant ELC. The cardiac morphology and mechanical properties of the transgenic mouse papillary muscle is now being studied.
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Drug Discovery Landscape
4 orphan drug designations for Rare familial disorder with hypertrophic cardiomyopathy.
4 orphan drug designations for Rare familial disorder with hypertrophic cardiomyopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
S-Cibenzoline succinate | small molecules | FDA | 2026-07-21 | — | Celltrion, Inc. |
non-replicating AAV-based gene therapy vector with a single stranded DNA genome engineered to carry an expression cassette encoding for human cardiac myosin binding protein-C (cMyBP-C; hMYBPC3 transgene) | gene therapies | FDA | 2023-09-26 | — | BioMarin Pharmaceutical Inc. |
Adeno-associated virus serotype 9 containing human MYBPC3 gene | gene therapies | EMA | 2022-04-13 | — | Yes Pharmaceutical Development Services GmbH |
a native AAV9 capsid with a genomic cassette containing a cardiomyocyte-specific promoter and the wild-type human MYBPC3 gene | gene therapies | FDA | 2021-05-12 | — | Tenaya Therapeutics |
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