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Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere-related genes, with MYBPC3 being the most common. Documenting potential genotype-phenotype associations may allow for more personalized genetic counselling. Observational case-control, cohort, and cross-sectional studies reporting genotype-phenotype associations and the occurrence of predefined events were selected from Cochrane and Medline databases. A random- effects meta-analysis was conducted. Twenty-four studies were included, with 3869 patients enrolled. The mean age at diagnosis of HCM associated with mutations in the MYBPC3 gene was 39.8 years (95 % CI 32.96 to 46.55), and the mean maximum left ventricular thickness was 20.4 mm (95 % CI 19.72 to 21.06). Proportion rates were 12.6 % (95 % CI 5.7 to 21.5 %) for septal reduction therapy, 20.4 % (95 % CI 11.9 to 30.2 %) for the development of heart failure New York Heart Association (NYHA) III/IV functional class, 16.1 % (95 % CI 10.3 to 22.6 %) for the occurrence of atrial fibrillation, and 26 % (95 % CI 17.0 to 36.1 %) for ventricular tachycardia. Cardioverter-defibrillators were implanted in 31.4 % (95 % CI 18.6 to 45.6 %) for secondary prevention, and sudden cardiac arrest occurred in 14.7 % (95 % CI 7.8 to 23.0 %) of patients. Cardiovascular death occurred in 8.6 % of patients over a median of 73 months of follow-up. This is the largest meta-analysis of MYBPC3 HCM patients to date. We were able to obtain data on the proportion rates of events in this population, which allows to answer some questions about the clinical course of HCM disease associated with mutations in the MYBPC3 gene more clearly. We found not only a late disease onset and low mortality risk, but importantly, a non-negligible risk of developing severe heart failure throughout life. Show less

The subchronic cardiotoxicity of 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), an unregulated disinfection byproduct with high environmental detection rates, remains poorly characterized. Using integrated multi-omics (transcriptomics, proteomics, phosphoproteomics) and histopathological analyses in zebrafish, this study systematically elucidated its dose-dependent (low-dose, 10 nM; medium-dose, 100 nM; high-dose, 1000 nM) cardiotoxicity, from adaptive remodeling to failure, over a 35-day exposure period. A reduction in atrioventricular inflow ranging from 81.4 % to 93.9 %, along with lipid droplet accumulation and Z-disc rupture, indicate a dose-dependent cardiac crisis induced by 2,6-DCBQ. Multi-omics analyses, revealed that the kinase cascade involving braf (Myhpc2_T1545), camk2a (Mybpc3_S291), and mark3b (Ttn.1_S28131) arranged dose-dependent cytoskeletal remodeling. High-dose exposure initiated an inflammation-cytoskeleton vicious cycle, wherein chemokine-driven collagen degradation exacerbated Z-disc rupture, while lipotoxic lipid droplets recruit inflammatory infiltrates, collectively escalating irreversible cardiac decompensation. These findings demonstrate that subchronic exposure to 2,6-DCBQ initiates cardiac remodeling, escalating cardiovascular susceptibility in exposed populations. Show less

Radiotherapy (RT) for breast cancer may increase atrial fibrillation (AF) risk. This study explored the association between RT and expression of AF-related genes in breast tumor tissues. A total of 1094 breast cancer patients (RT group: 1020; non-RT group: 74) were included based on inclusion criteria. Clinical data and RNA-seq profiles (TPM) were retrieved. Six AF-related genes (MYBPC3, LMNA, PKP2, FAM189A2, KDM5B, MYL4) were analyzed. Gene expression was compared using Wilcoxon rank-sum test after Log2(TPM + 1) transformation. Subgroup analyses were conducted by AJCC stage (I–III), laterality (left/right), age (< 65/≥65 years), clinical subtype (Luminal, HER2-positive, Triple-negative), and PAM50 molecular subtype (Basal, Her2, LumA, LumB, Normal). Multivariate linear regression was applied to evaluate RT’s independent effect on gene expression. In tumor tissues, expression levels of MYBPC3, LMNA, and MYL4 were significantly higher in the RT group compared to the non-RT group.Subgroup analysis revealed higher MYBPC3 expression in the RT group specifically in Stage III tumors, but lower expression in left-sided tumors and in patients < 65 years old. LMNA expression was higher in the RT group in Stage III tumors. MYL4 expression was higher in the RT group in Stage II tumors, in both left and right-sided tumors, and in both age groups (< 65 and ≥ 65 years). No significant differences were found across clinical or molecular subtypes for any gene.Multivariate regression confirmed RT as an independent predictor of increased MYL4 expression (β = 0.204), but not for MYBPC3 or LMNA expression. Sensitivity analysis in the 45–65 age subgroup supports the above findings. Based on tumor tissue analysis, breast cancer radiotherapy is associated with altered expression of AF-related genes (particularly MYL4) in tumor tissues, suggesting a potential molecular link worthy of further exploration in relation to atrial fibrillation. These findings warrant future validation in cardiac or circulatory tissues. The online version contains supplementary material available at 10.1007/s12672-026-04468-5. Show less

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare reproductive disorders with known genetic heterogeneity. Using exome sequencing, our group previously reported the prevalence of pathogenic and likely pathogenic (P/LP) variants in genes causing IHH/KS as the primary endpoint of our study. Here, we investigate the frequency of secondary findings (SF) to determine whether individuals with IHH/KS harbor an increased burden of P/LP variants in medically actionable genes (MAGs) defined by the American College of Medical Genetics and Genomics (ACMG). We analyzed exome sequencing data from 156 individuals with clinically confirmed IHH/KS. Variants were filtered for P/LP classification using ACMG guidelines across all 84 MAGs in ACMG SF v3.3. Sanger sequencing was used for orthogonal confirmation. The prevalence of MAG variants was compared to external control datasets from the U.K. Biobank (UKB, ~ 50,000 genomes) and the NIH eMERGE Network (~ 21,000 genomes), both based on the ACMG SF v2.0 59-gene list. Among 370,000 variants, 2 individuals (1.3%) carried validated P/LP variants in two distinct MAGs: SCN5A and MYBPC3. Genes 60-84, the additional 25 genes on the ACMG SF v3.3 list, yielded no additional variants. The prevalence of MAG variants in IHH/KS (1.3%) was not significantly different from UKB (2.0%) or eMERGE (2.5%) (OR vs. UKB: OR 0.64; 95% CI, 0.16-2.61; P = 0.57). The frequency of P/LP variants in MAGs among IHH/KS patients is comparable to the general population, suggesting that MAG variants are not common in IHH/KS in contrast to some other types of infertility. Show less

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac disorder characterized by unexplained left ventricular hypertrophy and represents a leading cause of morbidity and sudden cardiac death, particularly in young adults and athletes. Early studies focused on morphological features, but advances in molecular genetics have shifted emphasis toward genetic diagnosis, mechanistic insights, and family-based management. Pathogenic variants in sarcomeric genes, especially Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, affecting 1 in 500 people. With growing access to genetic testing and incorporation of genetics in diagnosis and management of HCM, it is important to identify phenotypic predictors of HCM genotype, to improve genetic targeting and counselling as well as cascade testing for first-degree relatives. This was a retrospective analysis of consecutive probands, aged over 18 years referred to a tertiary centre for HCM gene panel testing. Demographic information was obtained from clinic data. Left ventricular hypertrophy (LVH) pattern was classified based on trans-thoracic echocardiogram (TTE). Pathogenicity of variants was classified per the American College of Medical Genetics (ACMG) criteria. 166 patients were included for analysis. Mean age was 53 years (SD 14.28). 128 (77%) were male. 59 had a history of hypertension and 19 had a family history of sudden cardiac death (SCD). The most frequent HCM pattern at baseline was concentric HCM (31.9% n = 53). 48 patients had a likely pathogenic (LP) or pathogenic (P) variant, giving a genetic testing yield of 28.9%. The most common sarcomeric genes were MYBPC3 and MYH7 accounting for 57% of cases. Younger age, female sex, and reverse curve LVH pattern were predictors of a LP or P gene variant identification. Reverse curve morphology was found to be a significant predictor for a sarcomere variant (p < 0.001). Genetic testing was appropriately offered in this cohort. Younger age, female sex, family history of SCD, normal/well controlled blood pressure and reverse pattern LVH on TTE predicted a higher yield of pathogenic variant identification. Reverse curve morphology was found to be a significant predictor for a sarcomere variant. This study has implications for supporting better phenotype-based genetic counselling and resource usage for HCM patients. Show less

Heart failure (HF) with preserved (HFpEF) and reduced (HFrEF) ejection fraction may be driven by different pathophysiologies. We explored novel biomarkers, associations with clinical characteristics, discrimination between LVEF categories and associations with outcomes. In HFpEF(n=76) and HFrEF(n=36), 19 plasma biomarkers were measured including seven novel research assays for ANGPT2, BMP10, DKK3, FABP3, FGF23, IGFBP7 and MYBPC3. HFpEF patients were older (73 vs 63 years), more often female (50% vs 14%). All seven novel biomarkers except FABP3 tended to be higher in HFrEF vs HFpEF and associated with worse NYHA class and lower eGFR in both LVEF categories. MYBPC3 and FGF23 (higher in HFrEF) discriminated best between LVEF categories (AUC 85.8 and 80.0 respectively). In HFpEF, higher ANGPT2 was associated with worse right (TAPSE:β=-1.03;p=0.04) and left ventricular function (LV-GLS; β=1.29;p=0.03) and left atrial strain (LA-GLS:β=5.03;p<0.001) whereas higher IGFBP7 and MYBPC3 with diastolic dysfunction (E/e´:β=4.09;p=0.02 and β=1.36;p=0.01 respectively). All biomarkers except DKK3 were positively associated with the outcome (HFpEF:all-cause death, HF-hospitalization;HFrEF: all-cause death, LVAD or heart transplantation). Specifically (ANGPT2 (HR 1.45[95% CI 1.00-2.13]) more strongly in HFpEF and IGFBP7 (2.51[0.95-6.64]) more strongly in HFrEF (MYBPC3 (1.62[0.99-2.64]). Among seven novel biomarker assays, higher MYBPC3 (reflecting muscle injury and myopathy) and FGF23 (endothelial dysfunction, oxidative stress) distinguished HFrEF from HFpEF. Higher MYBPC3 was most prognostic in HFrEF while higher ANGPT2 and IGFBP7 (endothelial dysfunction and oxidative stress) in HFpEF. These hypothesis-generating findings support primary cardiomyocyte injury as a driver of HFrEF and systemic inflammation and oxidative stress as a driver of HFpEF. ClinicalTrials.gov NCT00774709. Show less

Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with heterogeneous clinical presentations and structural manifestations. This study aimed to assess the distribution, clinical characteristics, and diagnostic approaches in a regional cohort of patients with HCM. Patients diagnosed with HCM at a tertiary cardiomyopathy clinic between October 2021 and November 2024 were retrospectively analyzed. Patients were classified into obstructive, latent obstructive, non-obstructive, or apical phenotypes based on clinical and imaging findings. Comprehensive demographic, clinical, and imaging data were collected for detailed analysis, providing valuable insights into the phenotypic diversity of HCM. The cohort included 701 patients with a median age of 53 years of whom 68% were male. The phenotypic distribution comprised 9.3% apical, 38.1% non-obstructive, 32.5% resting obstructive, and 20.1% latent obstructive HCM. Implantable cardioverter-defibrillator implantation was more common in obstructive phenotypes, particularly in the latent obstructive group. Although late gadolinium enhancement (LGE) was more frequently observed in apical HCM, post-hoc analysis showed no significant difference in prevalence across subgroups. In contrast, LGE extent was significantly greater in the apical group. Genetic testing, performed in 32% of patients, revealed a 44% positivity rate, with MYBPC3 and MYH7 being the most commonly detected mutations. The overall mortality rate was 2.8%, with heart failure identified as the leading cause of death. In this large regional cohort of HCM patients, obstructive and non-obstructive phenotypes were predominant, with a notable burden of genetic mutations and a low overall mortality rate primarily driven by heart failure. These findings emphasize the clinical heterogeneity of HCM and highlight the importance of comprehensive diagnostic evaluation. Show less

Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented with acute heart failure and isolated cardiomyopathy or myocarditis, between 2021 and 2023 at a single tertiary care center. A total of nine patients were included; age range: 5 days-11 years (median 42 days). Eight patients (88.8%) presented in the first year of life. The turnaround time for the ES results was 5-14 days (median 9 days). The diagnostic yield was 5/9 (55.5%), confirming primary cardiomyopathy. The majority had dominant disorders (ACTC1, MYBCP3, TNNI3, and NKX2-5), with two (22.2%) occurring de novo. One patient had a recessive condition (MYBPC3). In three patients (33.3%) who rapidly deteriorated during hospitalization, ES results had a major impact on immediate medical management. In most patients, the diagnosis led to the avoidance of further metabolic workup, cardiac magnetic imaging and vitamin treatment. In two families with no prior history of cardiomyopathy, at-risk relatives were advised to initiate cardiac surveillance. Overall the results show high clinical impact due to a shorter time to diagnosis, a high diagnostic yield, an improved therapeutic approach, in addition to the facilitation of genetic counseling for family planning and cascade testing of relatives at risk. Show less

Coronary artery anomalies are rare both in coronary angiogram and computed tomography angiography. Hypertrophic cardiomyopathy (HCM) is the most frequent inherited cardiac disease. The phenotype of HCM associated with anomalous coronary origin is not commonly seen especially in children. We describe a case series of two children with HCM combined right coronary artery (RCA) originated from left coronary sinus. Case 1 was a 9-month-old female with HCM coexisted with anomalous origin of RCA has different clinical presentation, and it maybe due to different gene mutation. Show less

Increased levels of α-tubulin and its post-translational modifications (PTMs) are found in human heart failure and could initiate diastolic dysfunction by modulating cardiomyocyte stiffness. How these modifications occur and how they may underlie cardiac dysfunction remains unknown. Upstream kinases may play a critical role, but this has not been explored. Here we address this question by, for the first time ever, determining levels of the enzymes involved in microtubule (MT) detyrosination and acetylation (αTAT1, HDAC6) in a well-characterized cohort of patients with hypertrophic cardiomyopathy (HCM). In HCM patients (N=10-11), protein levels of detyrosination enzymes remain unaltered, whilst levels of αTAT1 and HDAC6 were decreased and increased, respectively. Phosphoproteomics in HCM (N=24) and control (N=8) myocardium identified significant differences in over 1900 serine/threonine and 160 tyrosine phosphosites, in addition to increased EGFR/IGF1R-MAPK signaling in HCM. We subsequently showed that MT repolymerization was increased in HCM We show that the altered HCM MT code cannot be attributed to levels of key MT-modifying enzymes. By combining kinome analyses in human HCM hearts with hiPSC-CM studies on MT dynamics, PTMs and contractility we unveiled a regulatory role for MTs in the cardiomyocyte response to beta-adrenergic receptor stimulation. Disease-mediated changes in the MT code thereby exert both a direct, and indirect effect on cardiac function via mediating the response to adrenergic activation. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease. In 20% to 30% of patients, a disease-causing variant can be identified and may also be present in relatives. Individuals carrying a pathogenic variant (G+) without left ventricular hypertrophy (LVH) are classified as genotype-positive/phenotype-negative (G+/P-). Their risk of developing LVH or HCM-related events remains uncertain. The aim of the article is to describe the clinical course of G+/P- individuals during long-term follow-up. G+/P- individuals were recruited from relatives of HCM patients at a tertiary center. All underwent clinical assessment, electrocardiography (ECG), and transthoracic echocardiography (TTE). Phenotype-negative status was defined as maximal left ventricular wall thickness (MLVWT) <13 mm. HCM was diagnosed when MLVWT ≥13 mm was observed without hypertension or other hemodynamic causes. Genetic testing used targeted Sanger sequencing, with variants classified per ACMG/AMP criteria. Thirty-four individuals were classified as G+/P-; the mean age was 31.7 ± 14.8 years, and 27% were men. Variants occurred in MYBPC3 (76%) and MYH7 (24%). Most were asymptomatic (85%), and 71% had a normal ECG. Mean follow-up was 6.6 ± 3.7 years, with complete ECG and TTE data in 88%. MLVWT increased from 9.6 ± 1.6 mm to 10.7 ± 3.3 mm (p = 0.01), while other echocardiographic parameters and ECG findings remained stable. Nine individuals (26%) developed LVH after a mean of 5.1 ± 4.1 years. One patient developed nonsustained ventricular tachycardia and received a primary prevention implantable cardioverter-defibrillator. In conclusion, G+/P- individuals were young and largely asymptomatic, yet 26% progressed to HCM. These results support regular TTE and ECG surveillance to enable early identification of disease progression and guide risk stratification. Show less

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the primary indication for heart transplantation. The intricate and poorly elucidated pathogenesis of genetic DCM, coupled with the paucity of effective therapeutic options, imposes a substantial burden on both patients and their families. In this study, we identified a novel MYBPC3 mutation (c.194C > T) in a patient diagnosed with DCM and established a patient-specific human induced pluripotent stem cell (hiPSC) model. Cardiomyocytes derived from these patient-specific hiPSCs (hiPSC-CMs) exhibited hallmark features of DCM, including cell enlargement, aberrant distribution of sarcomeric α-actinin, and dysregulated calcium ion homeostasis, as compared to control hiPSC-CMs derived from a healthy individual. RNA sequencing analysis revealed a significant upregulation of CASQ2, which encodes calsequestrin, a protein that binds to Ryanodine receptor 2 (RyR2). Notably, treatment with the RyR2 inhibitor ryanodine effectively restored the abnormal calcium transients observed in DCM-hiPSC-CMs. In summary, our findings provide compelling evidence that the c.194 C > T mutation of MYBPC3 plays a definitive pathogenic role in DCM, and that modulation of the RyR2 receptor may alleviate calcium dysregulation in affected cardiomyocytes. These insights enhance our understanding of the molecular mechanisms underlying DCM and offer a promising therapeutic strategy for patients with calcium ion dysregulation associated with this condition. Show less

Heart function depends on cardiomyocyte contractile apparatus and proper sarcomere protein expression. Variants in sarcomere genes cause inherited forms of cardiomyopathy and arrhythmias, including atrial fibrillation. Recently, a sarcomere component, myosin-binding protein-H like (MyBP-HL), was identified. MyBP-HL is mainly expressed in cardiac atria and is homologous to the last three C-terminal domains of cardiac myosin-binding protein-C (cMyBP-C). The MYBPHL R255X nonsense variant has been linked to atrial enlargement, dilated cardiomyopathy, and arrhythmias. Similar nonsense mutations in MYBPC3 are linked to hypertrophic cardiomyopathy, with these mutations preventing myofilament incorporation and the degradation of the truncated protein. However, the allele frequency of the MYBPHL R255X variant is too high in the human population to be pathogenic. We sought to determine whether MYBPHL nonsense variants impact on MyBP-HL sarcomere integration and degradation of the truncated protein, and whether the MyBPHL nonsense variants lead to changes in cardiomyocyte calcium dynamics and contractility. We mimicked human MYBPHL nonsense variants in the mouse Mybphl cDNA sequence and tested their sarcomere incorporation. We demonstrated that full-length MyBP-HL overexpression showed the expected C-zone sarcomere incorporation. Nonsense variants showed defective sarcomere incorporation. We demonstrated that full-length MyBP-HL and MyBP-HL nonsense variants were degraded by both proteasome and calpain mechanisms. We did not observe changes in calcium transients. In addition, we observed changes in contraction kinetics, including sarcomere shortening. Together, these data support the hypothesis that MYBPHL nonsense variants are functionally similar. Show less

Left ventricular non-compaction (LVNC) can be observed as a phenotypic trait in patients with dilated cardiomyopathy. Familial cases have been increasingly recognized, with sarcomeric gene mutations-particularly in We report a 7-year-old girl with a clinical diagnosis of dilated cardiomyopathy with LVNC since infancy. Genetic analysis revealed two heterozygous missense variants in sarcomeric genes associated with inherited cardiomyopathies: This report highlights the clinical relevance of identifying digenic sarcomeric variants in paediatric cardiomyopathy, particularly when associated with a positive maternal history of PPCM. Familial evaluation and recognition of genotypic overlap may aid in risk stratification and management. Show less

Childhood-onset cardiomyopathies are rare and not well characterised. This study aimed to describe the clinical features of a paediatric cohort with primary cardiomyopathies, with a particular focus on aetiology and both short- and long-term outcomes. A retrospective descriptive study was conducted, including patients diagnosed with primary cardiomyopathies before the age of 18. Clinical presentation, aetiology, and outcomes were analysed for each morphological subtype of cardiomyopathy. A total of 76 patients met the inclusion criteria. Dilated cardiomyopathy was the most common subtype (48.6%), followed by hypertrophic (31.5%), left ventricular non-compaction (10.5%), restrictive (5.2%), and arrhythmogenic cardiomyopathy (3.9%). The mean age at diagnosis was 6.3 ± 5.6 years, with a slight female predominance (56.6%). The rate of genetic diagnosis was 25.6%; the most commonly identified pathogenic or likely pathogenic variants were in These findings highlight the heterogeneous aetiology of paediatric cardiomyopathies and the variability in outcomes according to morphological, genetic, and clinical subtypes. The results underscore the importance of individualised evaluation and management for affected patients. Show less

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease characterized by left ventricular (LV) hypertrophy that cannot be fully explained by abnormal loading conditions. To describe the clinical spectrum, morphological variants and sarcomere gene mutations in patients with HCM from northwestern Mexico. We conducted a prospective, cross-sectional study of patients diagnosed with HCM by echocardiography. Morphological variants were classified as: asymmetric septal, concentric, mid-cavity, lateral, and apical according to the location of the greatest LV thickening. Next-generation sequencing was performed with a predesigned panel of 19 genes associated with HCM. A total of 110 patients (47.3% women; median age 58) were enrolled. Apical HCM was the most frequent morphological variant (42%), followed by asymmetric septal HCM (35%). Patients with apical HCM were older than those with other variants (p = 0.002). Patients with asymmetric septal hypertrophy had a higher septal/posterior wall thickness ratio (1.85 ± 0.6, p = 0.0001) and a larger left atrial anteroposterior diameter (48 ± 9, p = 0.0001). LV outflow obstruction, systolic anterior motion, and severe mitral regurgitation were more prevalent in patients with asymmetric septal HCM (p = 0.0001). Patients with concentric HCM had the greatest E/e' ratio (16.3 ± 8, p = 0.01). Among genotyped patients, 44% had a sarcomeric gene mutation, most commonly MYBPC3 (24%) and MYH7 (7%), with no significant differences across morphological variants. Apical HCM was the most frequent morphological variant of HCM in the studied population. Consistent with global reports, MYBPC3 and MYH7 were the most commonly identified gene mutations. Show less

Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims. This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models. A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation. Show less

Sports participation in patients with inherited cardiac conditions remains a major challenge, particularly when balancing arrhythmic risk against quality of life. A case of a 38-year-old recreational athlete diagnosed with hypertrophic cardiomyopathy (HCM) is described. A comprehensive assessment was performed, including electrocardiogram, echocardiography, exercise stress testing, Holter monitoring, and cardiac magnetic resonance, which revealed asymmetric non-obstructive HCM with extensive late gadolinium enhancement. Genetic testing identified two missense variants in This case highlights the value of multimodal imaging, genetic testing, and guideline-based SCD risk stratification in guiding individualized management of athletes with HCM. Show less

Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7 First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM. Show less

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder characterized by left ventricular hypertrophy and contractile dysfunction. Mutations in sarcomeric genes, particularly cardiac myosin-binding protein C (MYBPC3), are a leading cause of HCM. Here, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of patients carrying distinct MYBPC3 mutations (c.2490dupT and c.1800delA). Both lines displayed normal morphology, stable karyotypes, robust expression of pluripotency markers, and trilineage differentiation potential. These patient-specific iPSC lines provide a valuable platform for modeling MYBPC3-associated HCM and enable mechanistic and therapeutic studies of inherited cardiac disease. Show less

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, represents a paradigmatic condition for precision cardiovascular medicine. Once regarded as a monogenic autosomal dominant disorder driven by rare sarcomeric variants, HCM is now recognized as a genetically complex disease characterized by incomplete penetrance, variable expressivity, and heterogeneous clinical trajectories. This review summarizes current evidence on the evolving genetic architecture of HCM, emphasizing the predominant role of definitively validated sarcomeric genes, particularly Show less

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease, characterized by genetic and phenotypic heterogeneity. Although extensively studied in North American and European populations, data from Brazil remain limited. To characterize the genetic and clinical profiles of a Southern Brazilian cohort of HCM patients and their relatives using massive parallel sequencing. In this observational study, HCM patients and first-degree relatives were recruited from outpatient cardiology clinics. Clinical and imaging data were collected, and genetic analysis used a 100-gene panel. Variant pathogenicity was assessed according to American College of Medical Genetics and Genomics criteria, and statistical analyses were performed using R software. Eighty individuals were included in the final analysis (mean age: 49.2 ±18.5); 60% male; 40 index cases and 40 affected relatives). MYH7 and MYBPC3 were the most frequently related genes, with pathogenic / likely pathogenic variants (P/LP) identified in 33% and 16% of participants, respectively. No pathogenic TNNT2 variants were detected. Ninety percent of participants carried an identified variant (including variants of uncertain significance), with 68% harboring P/LP variants. MYH7 carriers exhibited a higher proportion of left ventricular outflow tract obstruction, whereas MYBPC3 carriers had a higher proportion of arrhythmic events and earlier diagnosis; however, these differences did not reach statistical significance and should be interpreted as exploratory. Clinical comparisons revealed regional differences, suggesting the potential impact of genetic diversity on the presentation of HCM in this part of Brazil. This study offers the first detailed genetic and clinical characterization of a Brazilian HCM cohort using massive parallel sequencing. Our findings underscore the importance of genetic testing for diagnosis, risk stratification, and management. Show less

Sevoflurane, a widely used volatile anesthetic, has raised concerns regarding its potential developmental toxicity, particularly due to its extensive application in non-obstetric surgeries and fetal intervention procedures during pregnancy. However, its effects on heart development and function remain unclear. Using zebrafish larvae as a model, we investigated the effects of prolonged sevoflurane exposure (0.04-0.08%) from 10 to 72 h post-fertilization (hpf). Under these conditions, treated larvae exhibited dose-dependent developmental abnormalities, including reduced body length, pericardial edema, and impaired heart tube looping. Cardiac function analysis revealed significant decreases in ejection fraction, stroke volume, heart rate, and cardiac output, indicating impaired cardiac contractility and pumping efficiency. These functional impairments were accompanied by structural changes including ventricular wall thinning and chamber dilation, along with upregulation of cardiac stress markers (nppa, nppb) - characteristic features of dilated cardiomyopathy (DCM). Molecular analysis demonstrated downregulation of sarcomeric (tnnt2a, mybpc3) and calcium-handling (atp2a2a, slc8a1a) genes, suggesting disruption of sarcomere integrity and calcium homeostasis. Additionally, sevoflurane exposure elevated inflammatory cytokines (il-6, tnf-α, il-1β) and promoted leukocyte infiltration into cardiac tissue. RNA sequencing analysis implicated dysregulation of Apelin signaling pathway, with reduced prkaa2 (AMPKα2) expression and phosphorylation observed in both zebrafish and H9C2 cardiomyocytes. Critically, pharmacological activation of AMPK using A-769662 effectively mitigated sevoflurane-induced cardiotoxicity, identifying AMPKα2 as a potential therapeutic target. Collectively, these findings delineate the molecular mechanisms underlying sevoflurane-induced developmental cardiotoxicity following prolonged exposure in zebrafish and suggest that targeting AMPKα2 signaling merits investigation as a potential strategy to mitigate anesthetic-related cardiac developmental risks. Show less

MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). MYBPC3-deleted hiPSC-CMs revealed the characteristics of heart failure, which exhibited increased contractility at 30 days but decreased at 40 days. Furthermore, at 40 days, it also shows abnormal calcium handling, increased ROS levels, and mitochondrial damage. Further RNA sequencing revealed that the oxidative stress pathway was aberrant, in addition to alterations linked to hypertrophic cardiomyopathy. Moreover, after adding melatonin to hiPSC-CMs at 30 days, MYBPC3-deleted hiPSC-CMs showed restored calcium handling capacity, decreased ROS levels, and improved myocardial contractility. In summary, reducing ROS can improve the phenotype of hypertrophic cardiomyopathy. Show less