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In children with hypertrophic cardiomyopathy (HCM), the genotype–phenotype association of abnormal electrocardiographic (ECG) features in the backdrop of gene positivity has not been well described. This study aimed to describe the abnormal ECG findings in children with HCM harboring who have genetic variants and determine the association with major adverse cardiac events (MACE). We retrospectively analyzed 81 variants-positive, phenotype-positive (V+P+), 66 variant-positive, phenotype-negative (V+P−), and 85 non-sarcomeric subjects. We analyzed ECG findings and clinical outcomes in the three groups of subjects. Repolarization abnormalities (ST and T wave changes) and pathologic Q waves were the most common abnormalities in variant and non-sarcomeric subjects. The V+P+ group showed higher occurrence of ST segment changes and T wave abnormalities compared to V+P− group. Independent predictors of MACE included ST segment changes (OR 3.54, CI 1.20–10.47, p  = 0.022). T wave changes alone did not predict outcome (OR 2.13, CI 0.75–6.07, p  = 0.157), but combined repolarization abnormalities (ST+T changes) were strong predictors of MACE (OR 5.84, CI 1.43–23.7, p  = 0.014) than ST segment changes alone. Maximal wall z score by echocardiography was a predictor of MACE (OR 1.21, CI 1.07–1.37, p  = 0.002). Despite the presence of significant myocardial hypertrophy (z score > 4.7), voltage criteria for LVH were much less predictive. In the non-sarcomeric group, RVH was significantly associated with MACE (OR 3.85, CI 1.08–13.73, p  = 0.038). These abnormal ECG findings described on the platform of known genetic status and known myocardial hypertrophy may add incremental value to the diagnosis and surveillance of disease progression in children with HCM. Select ECG findings, particularly repolarization abnormalities, may serve as predictors of MACE in children.

Purpose Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels. Methods We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting. Results Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics. Conclusion The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed.

Partitional clustering is the most used in cluster analysis. In partitional clustering, hard c -means (HCM) (or called k -means) and fuzzy c -means (FCM) are the most known clustering algorithms. However, these HCM and FCM algorithms work worse for data sets in a noisy environment and get inaccuracy when the data set has different shape clusters. For solving these drawbacks in HCM and FCM, Wu and Yang (Pattern Recognit 35:2267–2278, 2002) proposed the alternative c -means clustering with an exponential-type distance that extends HCM and FCM into alternative HCM (AHCM) and alternative FCM (AFCM). In this paper, we construct a more generalization of AHCM and AFCM with Gaussian-kernel c -means clustering, called GK-HCM and GK-FCM. For theoretical behaviors of GK-FCM, we analyze the bordered Hessian matrix and then give the theoretical properties of the GK-FCM algorithm. Some numerical and real data sets are used to compare the proposed GK-HCM and GK-FCM with AHCM and AFCM methods. Experimental results and comparisons actually demonstrate these good aspects of the proposed GK-HCM and GK-FCM algorithms with its effectiveness and usefulness. Finally, we apply the GK-FCM algorithm to MRI segmentation.

Purpose Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7 , a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Methods Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Results Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants ( n  = 12), highlighting the critical importance of data sharing. Conclusion These adapted rules provide increased specificity for use in MYH7 -associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.

Alpha-actinin 2 (ACTN2) is a key protein at the Z-disk of the sarcomere. It is critical for stabilizing the contractile muscle apparatus and organizing actin filaments. Genetic missense variants of ACTN2 are associated with hypertrophic cardiomyopathy (HCM), a disease characterized by sudden cardiac death. In 2014, a study identified an ACTN2 missense variant, M228T, in a family of 11 patients with HCM. In addition, our previous in vivo study showed that mice homozygous for M228T were embryonically lethal, whereas mice heterozygous for M228T exhibited little to no cardiac phenotype.The mechanism by which the M228T variant impacts ACTN2 is poorly understood. Herein, we examine the changes occurring at the structural level of the mutant protein using structural modelling and biophysical characterization techniques. Molecular changes were assessed using an induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model incorporating the M228T variant.Structural predictions showed that the M228T variant may destabilize the interface between the two calponin homology domains (CH1 and CH2) of ACTN2, thus impacting its binding to actin. Purification of mutant ACTN2 from E. coli showed a significant decrease in protein solubility. Further biophysical characterization techniques, including size-exclusion chromatography SAXS, mass photometry, and dynamic light scattering, were used. Furthermore, protein aggregates were identified in the iPSC-CM model homozygous for the M228T variant. Mutant cardiomyocytes showed upregulation in the fetal gene programme, as well as in markers of hypertrophy and fibrosis. Molecular analysis revealed significant degradation of ACTN2 protein. This was further analyzed using biochemical fractionation techniques. The role of the ubiquitin-proteasome system in protein degradation was assessed using a proteasome inhibitor, MG-132. Mutant cardiomyocytes also showed upregulation of autophagy markers, indicating a potential role for the autophagy-lysosomal pathway in protein degradation.Collectively, this study provides a better understanding of the impact of M228T missense variant on ACTN2 structure and function. Therefore, this may be the first step towards understanding disease pathways for Z-disc-associated HCM.Conflict of InterestNone

Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family’s causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity.

Hypertrophic cardiomyopathy (HCM) is a complex, heterogeneous disorder that affects approximately 1 in every 500 persons worldwide and about 750,000 Americans. It is characterized by left ventricular hypertrophy that is usually asymmetric, with enlarged myocytes in disarray, unexplained by loading conditions. Obstruction to left ventricular outflow occurs in approximately 60% of patients. The natural history and cardiac morphology of HCM are quite heterogeneous. Although most patients with HCM are asymptomatic or mildly symptomatic, a minority are disabled by dyspnea, angina, or syncope, develop advanced heart failure, or die suddenly.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease worldwide and may present with or without dynamic left ventricular outflow tract obstruction (LVOTO). Significant advances have been made in the management of obstructive HCM. On the other hand, despite their significant symptomatic burden, patients with non-obstructive HCM (nHCM) (i.e., without LVOTO) still do not have evidence-based therapeutical options. The recent IMPROVE-HCM study, a phase 2 randomized, double-blinded trial, aims to place a first step in filling this gap in knowledge. The study assessed the safety (primary endpoint) and efficacy (secondary endpoint) of ninerafaxstat, a novel cardiac mitotrope drug that increases adenosine triphosphate production. We highlighted the main findings of the trial, contextualizing these results within the larger landscape of completed and ongoing trials in nHCM.

Background Cats with hypertrophic cardiomyopathy (HCM) and congestive heart failure (CHF) can have resolution of both left ventricular hypertrophy and CHF. Objectives To describe the clinical characteristics of cats with transient myocardial thickening (TMT) and CHF compared with a control population of cats without resolution of HCM. Animals A total of 21 cats with TMT, 21 cats with HCM. Methods Retrospective study. Clinical records at 4 veterinary centers were searched for TMT cases and a control group of cats with HCM and CHF. TMT was defined as initial maximal left ventricular wall thickness (LVWT) ≥6 mm with left‐sided CHF, with subsequent resolution of CHF, reduction in left atrium/aorta (LA/Ao), and LVWT<5.5 mm. HCM was defined as persistent LVWT ≥6 mm. Results Cats with TMT were younger (2 [0.4–11.4] years) than cats with HCM (8 [1.6–14] years) (P < 0.0001), and antecedent events were more common (15/21 versus 6/21, respectively) (P = 0.01). In cats with TMT, LVWT normalized from 6.8 [6.0–9.7] mm to 4.8 [2.8–5.3] mm and LA/Ao decreased from 1.8 [1.6–2.3] to 1.45 [1.2–1.7] after a mean interval of 3.3 (95% CI: 1.8–4.7) months. CHF recurred in 1 of 21 TMT and 15 of 21 cats with HCM. Cardiac treatment was discontinued in 20 of 21 cats with TMT and 0 of 21 HCM cats. All cats with TMT survived, whereas 8 of 19 cats with HCM died during the study period. Conclusions and Clinical Importance TMT occurs in younger cats, and antecedent events are common. The prognosis is better in cats with CHF associated with TMT than HCM.