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Sudden cardiac death (SCD) is a known risk of hypertrophic cardiomyopathy (HCM), especially in asymptomatic and younger (<35 years old) populations. There are several mutations that cause HCM, most notably within the MYBPC3 and MYH7 genes. ALPK3 (alpha protein kinase 3) has been identified as a gene of interest in HCM, specifically associated with late-onset adult HCM or pediatric cases which typically present with musculoskeletal and facial deformities. In this report, we present a case of SCD due to HCM in a young, reportedly asymptomatic patient without dysmorphia that had a specific mutation of the ALPK3 gene and a striking gross pathological appearance previously undiscussed in literature. Show less

Sudden cardiac arrest (SCA) is a leading cause of mortality in young individuals, often linked to structural heart disease or primary electrical disorders. However, in some cases, the etiology remains unidentified despite extensive diagnostic efforts. This case report describes a 23-year-old male with a family history of hypertrophic cardiomyopathy (HCM) who experienced a sudden cardiac arrest without prior symptoms and had negative genetic testing. The patient, previously healthy, suffered a cardiac arrest while traveling to college. Advanced cardiopulmonary resuscitation (CPR) and multiple defibrillator shocks were necessary to achieve return of spontaneous circulation (ROSC). Transthoracic echocardiography performed immediately post-ROSC showed global hypokinesia with reduced ejection fraction (35%). Coronary angiography at 24 hours post-ROSC was normal. Transient ST-segment elevations resolved within hours and were attributed to post-resuscitation myocardial stunning, with no evidence of ischemia or myocarditis on cardiac magnetic resonance imaging (MRI), which revealed mild interventricular septal hypertrophy without left ventricular outflow tract obstruction. Genetic testing, including a targeted cardiomyopathy panel and whole exome sequencing, did not identify any pathogenic variants, including in MYH7 or MYBPC3. The patient was treated with amiodarone and received an implantable cardioverter-defibrillator (ICD) for secondary prevention. He recovered fully, with no neurologic deficits. This case underscores the challenges of diagnosing and managing SCA in young adults, emphasizing the critical role of genetic and structural assessments. Early intervention, multidisciplinary care, and comprehensive follow-up are essential to reduce recurrence and improve patient outcomes. Show less

Activation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress-induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy. We utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3) We discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were negatively correlated with p21 expression. Mechanistically, we discovered that p21 bound to PCNA (proliferating cell nuclear antigen), which led to a reduction of PCNA binding to POLD1 (DNA polymerase delta 1). Directly targeting PCNA or POLD1 prevented cardiomyocyte DNA synthesis and hypertrophic cardiomyocyte growth. Cardiomyocyte-selective overexpression of p21 using an adeno-associated virus vector reduced long-term pathological left ventricular hypertrophy and improved diastolic function in a preclinical murine model of hypertrophic cardiomyopathy (Myh6 Our results demonstrate that PCNA-POLD1-mediated cardiomyocyte endoreplication drives hypertrophic cardiomyocyte growth, and p21 serves as a negative regulator of this process. Targeting these pathways demonstrates therapeutic potential in preventing pathological myocardial hypertrophy. Show less

Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which may overlook other pathogenic variants. This study explores the gene sequencing strategy in a three-generation family based on genetic carrier status and examines the relationship between phenotypic characteristics and genotype. High-throughput second-generation sequencing was performed on the proband to analyze HCM-related pathogenic genes. Subsequently, the identified pathogenic variants were validated by Sanger sequencing in the proband and family members. Clinical, electrocardiographic, and echocardiographic assessments were conducted for family members. Second-generation sequencing of the proband (III7) revealed a pathogenic variant MYBPC3-P453Lfs. Initially, no HCM-related pathogenic variants were detected in another patient (III11), prompting additional sequencing of III11, which identified the MYH7-G823E pathogenic variant. Both patients had severe left ventricular outflow tract obstruction. Sanger sequencing showed that five family members carried both mutations. Among them, three died suddenly before age 40, one required an implantable cardioverter defibrillator for arrhythmias, and one developed HCM before adulthood. Cardiac magnetic resonance imaging (MRI) of patients carrying both mutations showed myocardial fibrosis of 32.75%, significantly higher than the 6.98% observed in patients carrying only one mutation. In families with varying HCM phenotypes, second-generation sequencing should be considered for all members. In this family, carrying one variant led to outflow tract obstruction, while carrying both variants resulted in severe disease, including sudden death and early onset. Cardiac MRI is crucial for assessing the severity of the disease within the family. Show less

This study examines pediatric cardiomyopathies by analyzing genetic and clinical data from 55 patients (2021-2024) at Beijing Anzhen Hospital. Four subtypes were studied: dilated (DCM, 24), hypertrophic (HCM, 22), arrhythmogenic right ventricular (ARVC, 7), and restrictive (RCM, 2). Clinical data, imaging, labs, and family histories were collected, with whole-exome sequencing (WES) identifying disease-causing variants classified via ACMG guidelines. Statistical analysis revealed a median age of 11 years, a proportion of 58% male participants, and ethnic diversity (21 northern Han, 29 southern Han, 5 minorities). In the cohort, 13 cases had an LVEF below 35%. Pathogenic/likely pathogenic (P/LP) variants were found in 21.8% of the patients, and variants of uncertain significance (VUS) were present in 38.2%, with Show less

Gender-associated variations in phenotypic expression and their consequences are established in numerous cardiac circumstances. However, their impact is questionable in the case of HCM. To investigate the demographic and clinical profiles of the HCM patients. Also, to compare the echocardiographic features according to the HCM subtypes in the study populace. The present study was conducted at the DMCH, Ludhiana, from March 2019 to May 2021, using a prospective observational and non-blinded design. The data regarding demographic and clinical profile are gathered for the specified duration. The clinical features are confirmed through the Echocardiography. The gathered data are analyzed through chi-square to determine the differences among the groups with the aid of the SPSS tool. The demographic profiles and clinical assessment of 103 patients are analyzed. The subjective assessment reveals that HCM is predominantly in males in a ratio of 2.1:1. Dyspnea is a chief complaint of both genders (77.67%). Apical type is prevalent in male HCM patients. MYBPC3 and MYH7 are the general mutations found in the genetic tests. SCD is found in patients possessing this type of genetic mutation. The non-obstructive type is more common than the obstructive type. HCM is a chronic disease and causes morbidity as well as mortality globally. HCM patients are vulnerable to SCD and stroke. These risk factors rely on the diagnosis associated with age, gender, obstruction, obesity, and coronary diseases. Hence, the present research on the demographic characteristics of HCM patients promotes awareness regarding the complications among the Indian populace. Show less

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder marked by left ventricular hypertrophy and hypercontractility. This excessive mechanical workload creates an energetic mismatch in which consumption exceeds production, leading to myocardial energy depletion. Although CK (creatine kinase) plays a key role in cardiac energy homeostasis, its involvement in HCM remains unclear. This study investigates how hypercontractility-driven mitochondrial stress and the resulting increase in mitochondrial H CK function was analyzed using myocardial left ventricular tissue from 92 patients with HCM (with and without pathogenic sarcomere variants) and 30 non-failing human controls. Myofilament and mitochondrial CK isoforms were measured using mRNA analysis, protein immunoblotting, enzyme activity assays, mass spectrometry, and redox-sensitive proteomics. To explore links between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction, we used isolated cardiomyocytes from wild-type, mitochondrial-targeted catalase-overexpressing, CK knockout (myofilament and mitochondrial CK deletion), HCM-associated Our analysis revealed significant reductions in myofilament and mitochondrial CK protein levels, as well as CK activity, in myocardium of patients with HCM, primarily because of oxidative modifications of CK. In isolated mouse cardiomyocytes from wild-type and CK knockouts, hypercontractility induced by EMD-57033 elevated mitochondrial H This study reveals a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction in HCM, perpetuating a cycle of energetic dysfunction. Targeting hypercontractility and oxidative stress through myosin inhibition offers a strategy to restore energy balance and reduce arrhythmic risk in HCM. Show less

Primary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exist on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indian (SAI) patients, which are necessary for minimizing disparities in interpreting ancestry-specific variants. The ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel categorized HCM-causing genes into 5 categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI patients are lacking. Whole-exome sequencing was performed for 335 primary SAI patients with HCM, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. SAI HCM exomes revealed a total of 193 pathogenic/likely pathogenic variants and variants of uncertain significance across 26 clinically actionable genes in 119 (35.52%) of 335 cases. The SAI HCM exhibited significantly fewer variants in the 12 definitive category genes compared with other global HCM cohorts (15.77% versus 43.23%; The clinically actionable gene variants in SAI HCM differed significantly from other global HCM cohorts, specifically Show less

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in Show less

Previous studies have shown that individuals with a hypertrophic cardiomyopathy (HCM) pathogenic variant (PV) or likely pathogenic variant (LPV) without a HCM phenotype (PV/LPV carrier) have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Metabolic treatments improved exercise capacity in HCM patients, but evidence that such drugs correct reduced MEE is lacking. The ENERGY trial is a double-blind, placebo-controlled randomized clinical trial to define if the metabolic drug trimetazidine (TMZ) corrects reduced MEE in PV/LPV carriers for HCM. 51 MYBPC3 or MYH7 PV/LPV carriers were screened after which 40 were included and randomized into a treatment group (n = 20) or placebo group (n = 20) stratified for sex. Participants were treated with TMZ 20 mg or placebo three times daily during 8 weeks. The main outcome of this study was MEE as measured by [11C]-acetate positron emission tomography/computed tomography (PET/CT) and cardiac magnetic resonance (CMR) scan. Secondary outcomes were exercise parameters as measured by cardio-pulmonary exercise testing (CPET). Drug safety was monitored by (serious) adverse event registration. Treatment groups were comparable in terms of age, sex, body mass index, P/LP gene variant, and echocardiographic parameters without significant differences. Baseline CMR parameters and MEE were not significantly different between treatment groups. Eight weeks of treatment with TMZ did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3 ± 3.8 to 29.8 ± 4.3% in the placebo group and from 30.1 ± 4 to 29.1 ± 4% in the TMZ group. Compared to placebo, the TMZ group did not have a significantly different MEE (difference -0.44, 95% interaction CI, -2.863 to 1.986, P = 0.68). The mean V'O2max as a percentage of predicted V'O2max (V'O2max %pred) changed from 108 ± 17 to 111 ± 19 (95% CI, -6 to 10, P = 0.84) percent in the placebo group and from 105 ± 17 to 113 ± 14 (95% CI, 1 to 16, P = 0.03) percent in the TMZ group. After adjustment for baseline, the TMZ group had a significantly increased V'O2max %pred (difference 6.37, 95% interaction CI, -3 to 16, P = 0.04). The ENERGY trial is the first proof-of-concept randomized controlled trial to test the hypothesis that TMZ improves MEE in MYBPC3 or MYH7 PV/LPV carriers. We conclude that metabolic therapy with TMZ may not correct the P/LP gene variant-related decrease in MEE. Netherlands Trial Register NL7492 (URL https://onderzoekmetmensen.nl/nl/trial/25078). Show less

Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Show less

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Although most cMyBP-C mutations produce truncated proteins and cause HCM via haploinsufficiency, the mechanisms by which missense mutations result in disease remain poorly understood. Here, we have evaluated three mutations in immunoglobulin-like domains C1 (P161S, Y237S) and C2 (P371R), predicted to be pathogenic for HCM, assessing their effects on cMyBP-C actin-binding function, protein thermal stability, and residue mobility. Using a fluorescence lifetime-based actin-binding assay, we found that N-terminal mutants P161S, Y237S, and P371R enhanced C0-C2 interactions with actin in both unphosphorylated and phosphorylated states, suggesting that the mutations strengthen actin binding and make the binding resistant to phosphorylation-mediated regulation. Differential scanning calorimetry revealed that mutants exhibit destabilized thermal melting profiles with reduced unfolding temperature, energy, and cooperativity. Molecular dynamics simulations indicated that these mutations induce allosteric effects, increasing fluctuations of unstructured loops in C1 or C2 that contain key actin-binding residues. These alterations in protein stability and residue mobility may promote domains to visit binding-competent conformations more frequently, reduce the energetic cost of complex formation, and/or expose actin-interacting interfaces, thereby enhancing C0-C2 binding and contributing to HCM pathogenesis. Show less

The genetic etiology of hypertrophic cardiomyopathy (HCM) and the critical role of sarcomeric variants in its pathogenesis are well recognized (1). Among these, loss-of-function variants in the myosin binding protein C gene ( This was a prospective, cross-sectional study of 100 adults (aged 18-65 years) with symptomatic Pre-existing anti-AAV9 NAb were undetectable in 50% of patients. Among those with detectable titers (range: 1:10-1:720), only 16% exceeded 1:40. TAb were undetectable in 53%; titers ranged from 1:10 to 1:65,600. A strong correlation was observed between NAb and TAb titers (r = 0.671, Pre-existing immunity to AAV9 was absent or low in most Show less

Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Show less

Hypertrophic cardiomyopathy (HCM), associated with left ventricular hypertrophy, can lead to significant morbidity. Given the hereditary association, identifying population-specific genetic markers and gender disparities could enable better screening and management strategies. The study aimed to observe the genetic patterns of HCM and investigate its gender associations among the Indian population. A prospective analysis was performed based on the medical records of patients with HCM. Genetic testing was conducted among those with a family history of HCM or sudden cardiac death. Genetic testing results, echocardiography, and clinical outcomes were documented. The prevalence of HCM types and genetic abnormalities were estimated in the study population and were compared between the two genders. The study included 103 patients with a mean age of 56.3 ± 13.9 years. Genetic analysis was conducted in 48/103 individuals based on the hereditary linkage. Only 50% of the 48 individuals had known genes associated with HCM. About 48% had apical or midapical HCM, and 31.1% had reverse curvature HCM. About 38% of apical and 60% of neutral or reverse curvature were associated with genetic abnormalities. The more commonly associated genes were MYBPC3 and MYH7. The current study also identified genetic variants in several emerging genes in Indian HCM patients. Our study findings indicate that the prevalence of different types of HCM is different in the Indian population. With only 50% of the hereditary HCM linked to known genes, the study calls for further screening of genes associated with HCM in the Indian population. Show less

Cardiomyopathy (CM) is a heterogeneous group of diseases characterized by structural and functional changes in the heart, with the exact cause often remaining unknown. CM can arise from both inherited and acquired metabolic disturbances. Alterations in energy production and substrate utilization impair the heart's contractile function and limit its ability to respond to stress. Given the complexity and dynamic nature of CM, as well as the multiple etiologies involved, we reviewed metabolomic studies employing high-throughput platforms to understand how metabolic pathways shift across CM subtypes and how these perturbations may inform clinical translation. Several recurring disruptions emerge across CM with alterations in amino acid metabolism (valine, leucine, methionine, tryptophan, tyrosine); mitochondrial redox imbalance (NAD/NADH shifts, niacinamide, acylcarnitines); and oxidative stress as central hallmarks. Each subtype, however, displays a different emphasis. For instance, hypertrophic CM is characterized by nucleotide remodeling, particularly in cases involving Show less

We present multimodality imaging of ventricular septal calcification. A 38-year-old man with asymptomatic gene-positive hypertrophic cardiomyopathy was found to have extensive dystrophic calcification of the ventricular septum. We hypothesized that the extensive ventricular septal calcification would represent an area of severe myocardial fibrosis, resulting in calcification secondary to postsurgical (septal myectomy) changes. Calcification of the ventricular septum is a rare finding, not previously described following septal myectomy, that should prompt a comprehensive evaluation and follow-up with multimodality imaging and testing. Show less

A woman in her 50s with known MYBPC3-associated obstructive hypertrophic cardiomyopathy was evaluated for septal reduction therapy. The electrocardiogram, echocardiogram, and cardiac magnetic resonance found several features inconsistent with the diagnosis. Targeted screening confirmed adult-onset Fabry disease. Enzyme replacement therapy was started. Show less

Many emerging service delivery models triage genetic counselor time with patients to postgenetic testing, including population genomic screening followed by genetic counseling (GC). To prime patients and help genetic counselors tailor such visits, a previsit (PV) chatbot was created to assess patient understanding, emotional response to, and family communication about genetic results. This study explored patients' perceptions of the PV chatbot and how they would use it. User testing was conducted via videoconference with patients who had completed GC. A codebook thematic analysis informed by Proctor's Conceptual Model of Implementation Research in a postpositivist paradigm was conducted. In total, 16 participants completed user testing, of whom 12 were women and 4 were men with a mean age of 55.4 (range 32-69). Participants had a variety of genetic results out of 78 genes among cancer (PMS2 n = 2; PALB2 n = 4; BRCA2 n = 1) and cardiovascular (LDLR n = 1; MYBPC3 n = 1; DSP n = 1; TTN n = 5; MYH7 n = 1) conditions. Participants reported high acceptability (M = 4.53/5, SD = 0.45) and feasibility (M = 4.43/5, SD = 1.04) of the chatbot. Participants reported liking the chatbot because of its ease of use and anticipated benefit to GC. Participants viewed the chatbot as complementary to GC and shared that the chatbot would have helped prepare them for GC in ways they may not have considered, including inviting a family member to join the appointment. Participants desired more personalization within the chatbot, including responsiveness to their personal/family history, optional supplementary education, and more emotionally supportive language. Some participants described challenges with certain aspects of the chatbot, including the repetitiveness and phrasing of validated scaled measures. Overall, participants perceived the PV chatbot to be of value in educating and preparing them for GC and reflected on how the PV chatbot may have enhanced GC. Many of the perceived benefits of this chatbot are applicable across GC settings. Show less

Sudden cardiac arrest (SCA) is a leading cause of death in pediatric hypertrophic cardiomyopathy (HCM). The study sought to analyze the clinical and genetic characteristics of pediatric HCM and assess the applicability of current SCA risk prediction models. We enrolled individuals diagnosed as HCM before 20 years of age, between 2000 and 2020, excluding those secondary to hemodynamic causes and those associated with genetic syndromes other than RASopathies. Among 91 patients (31 female, 60 male), SCA occurred in 13 (14.3%) patients, with 6 (46%) cases presenting as the initial symptom. These 6 patients were older and had lower left ventricular mass In pediatric HCM, SCA is notably associated with sarcomere gene pathogenic variants. While newer risk scoring systems, if incorporated with genetic information, effectively predict SCA in this Asia cohort, a challenge remains: nearly half of SCA cases present as the initial clinical manifestation. Show less

Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, the role of PDK4 (pyruvate dehydrogenase kinase 4), a key regulator of cardiac glucose and fatty acid oxidation, in HCM-related heart failure remains unknown. Single-nucleus RNA sequencing was performed to analyze gene expression in patients with HCM (n=12), categorized into the following groups: normal, reduced, and heart failure. We validated our findings in additional cohorts of patients undergoing septal resection or heart transplantation. Cardiac-specific Single-nucleus RNA sequencing identified distinct cardiomyocyte clusters, with cardiomyocyte cluster 4 ( Our findings highlight metabolic disturbance, specifically PDK4-driven suppression of glucose oxidation, as crucial in HCM progression to heart failure. PDK4 represents a promising therapeutic target for preventing or treating heart failure in patients with HCM. Show less

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as Show less

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder characterized by left ventricular hypertrophy and variable clinical manifestations, including asymptomatic states and sudden cardiac death (SCD). Data on its phenotype and genotype in the Indian population remain limited. We studied 113 patients diagnosed with HCM. All underwent clinical assessment, 24-h Holter monitoring, echocardiography, and cardiac MRI. Genetic testing was performed in 80 patients. Clinical and imaging features were compared between genotype-positive and genotype-negative groups. The mean age was 47 ± 10.8 years, with 82.6 % being males. Dyspnoea and chest pain were the most frequent symptoms. Obstructive HCM was seen in 70 (61.9 %) patients. Cardiac MRI showed late gadolinium enhancement >15 % in 13 (23.2 %) and apical aneurysms in 2 (3.5 %). Genetic mutations were detected in 40 (50 %) patients, with MYBPC3 (33 %) and MYH7 (26.8 %) being most common. Genotype-positive individuals more frequently had chest pain, a family history of SCD, and more severe hypertrophy. In this Indian HCM cohort, the condition predominantly affected males. Genotype-positive patients exhibited more severe hypertrophy and adverse clinical profiles, underscoring the importance of genetic screening in risk stratification. Show less

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 GS identified the 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. Show less

Hydroxychloroquine cardiotoxicity is a rare cause of dilated or restrictive cardiomyopathy. A 50-year-old male with a prior clinical diagnosis of hypertrophic cardiomyopathy presented with monomorphic ventricular tachycardia. Cardiac magnetic resonance imaging (CMR) revealed biventricular hypertrophy and systolic dysfunction, with diffuse nonischemic fibrosis. Endomyocardial biopsy (EMB) revealed myocyte hypertrophy and interstitial fibrosis, consistent with hypertrophic cardiomyopathy, and vacuolated myocytes and myeloid bodies, consistent with hydroxychloroquine cardiotoxicity. Genetic testing found a heterozygous pathogenic MYBPC3 intronic variant, confirming the diagnosis of sarcomeric hypertrophic cardiomyopathy. Hydroxychloroquine is an underrecognized cause of cardiotoxicity, particularly in patients with a preexisting cardiomyopathy. In the setting of preexisting cardiomyopathy with clinical deterioration and suspicion of a superimposed process, CMR, EMB, and genetic testing can provide diagnostic clarity and facilitate cascade screening. Show less

Asian populations are underrepresented in the hypertrophic cardiomyopathy (HCM) genomic databases, which are currently largely dominated by Caucasian population. We aim to characterize the genetic landscape of HCM in patients from Hong Kong Chinese population. From March 2023 to March 2024, fifty-three unrelated patients with an unequivocal clinical diagnosis of HCM were enrolled at a single tertiary center in Hong Kong and underwent genetic testing using a standardized 19-gene panel. In this cohort study, we identified 13 patients (24.5%) with a predominant pathogenic or likely pathogenic (P/LP) variant and 12 patients (22.6%) with a predominant variant of unknown significance (VUS). Most of the P/LP variants identified were in Our study provided insight into the genetic landscape of HCM in Hong Kong Chinese population. We identified several recurrent variants and novel variants in our HCM cohort. Patients with P/LP variants were associated with an increased risk of developing left ventricular dysfunction. Future studies on the potential founder effects of these recurrent variants, cumulative effects of multiple variants, and longitudinal follow up of HCM patients would be useful. Show less

A variety of techniques for DNA sequencing, such as specific gene sequencing, whole genome sequencing, or exome sequencing, are currently used to detect single nucleotide variations (SNVs). Although RNA-seq can be used to identify SNVs, studies that employ this approach are uncommon, and those that do often rely on outdated mapping methods or methods that are more suitable for genomic and exomic alignment. In this work, our aim is to apply modern RNA-seq specific alignment method in order to identify SNV in a cohort of HCMP patients, and characterize those SNV to gain insight into possible mechanisms of HCMP pathogenesis. The algorithm of identification of SNV based on transcriptomic sequencing data has been developed and evaluated. The algorithm was evaluated and the optimal quality threshold was determined based on allelic discrimination for the rs397516037 mutation (MYBPC3 c.3697 C > T) among patients. A total of 42,809 SNVs with a quality of 75 or higher were identified in 48 transcriptomes of hypertrophic cardiomyopathy (HCMP) myocardial tissue. Verification of missense and nonsense variants in key HCMP genes using Sanger sequencing confirmed the accuracy of the pipeline results. To identify variants potentially associated with HCMP pathogenesis, a filtration process was conducted based on minor allele frequency, substitution prediction score and ClinVar outcome. 214 missense mutations and 6 nonsense mutations were selected. Together with nonsense mutations, 19 mutations meeting the strictest SIFT and PolypPhen criteria were identified as potential factors influencing HCMP pathogenesis. We have developed and validated a method for identifying SNVs based on transcriptomic data, which can be used to identify putative pathogenic variants. We identified mutations in key HCMP genes MYBPC3 and MYH7 in a cohort of patients. We also found potentially pathologic mutations in genes ANXA6 and FEM1 A and obtained data supporting the role of NEBL in myocardial diseases. This method would be useful in analyzing transcriptomic data available in the Gene Expression Omnibus, but should be used with caution as we have tested it on a specific disease. Show less