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Hypertrophic cardiomyopathy can be accompanied by dynamic obstruction in the left ventricular outflow tract and acute apical ballooning, which are among the very rare causes of cardiogenic shock. This condition requires a specific treatment approach that in many ways differs from the treatment of other causes of cardiogenic shock. We present a case and our treatment strategy (including extracorporeal life support) for refractory cardiogenic shock in a patient with previously undiagnosed hypertrophic cardiomyopathy.

Historically, individuals with HCM have been restricted from vigorous competitive sports due to concerns for risk of sudden death. More recently, prospective data are emerging that individuals with HCM who participate in vigorous sports do not have increased arrhythmic risk compared to the less active, and series of athletes with HCM continuing to compete, while small, have not shown high risk. Guidelines are evolving, and while differences exist, all now recommend an individualized approach and shared decision-making for athletes with HCM wishing to return to play., Competing Interests: Declaration of competing interest Belinda Gray, None. Michael J Ackerman, consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Illumina, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. Mark Link, None. Rachel Lampert, Honoria, Research support, Medtronic, Abbott-St Jude, Boston Scientific, advisory board, Medtronic (all ended 5/22)., (Copyright © 2024. Published by Elsevier Inc.)

Aims: In clinical trials, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved symptoms in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We aimed to share our real-world experience with the efficacy and safety of mavacamten in this patient population., Methods and Results: This retrospective, single-centre study included patients with symptomatic oHCM from March 2023 to November 2023. Inclusion criteria were oHCM, age >18 years, significant LVOTO (gradient >50 mmHg at rest or with Valsalva), New York Heart Association (NYHA) class ≥II despite maximally tolerated medical therapy, and left ventricular ejection fraction (LVEF) >55%. Patients were evaluated by echocardiography, NYHA class, electrocardiography and Holter monitor on each monthly visit for 3 months. A total of 31 patients were included in this study. The mean (SD) age was 58 (16.5) years, and 14 (45%) were female. Mean provoked left ventricular outflow tract gradient (LVOTG) reduced by -49.4 mmHg (P < 0.001) at 4 weeks, -59.2 mmHg (P < 0.001) at 8 weeks, and -60.8 mmHg (P < 0.001) at 12 weeks. Twenty-six of the 31 patients (83.8%) achieved an LVOTG ≤30 mmHg at Week 12. No major side effects were reported. Sixty-seven percent experienced ≥2 NYHA class improvements, LVEF remained above 55% and no dose titration was made., Conclusions: Our real-world experience aligns with established mavacamten trial outcomes. Continuous vigilance and longitudinal investigations are needed to further assess potential long-term impacts., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hypertrophic Cardiomyopathy (HCM) presents a complex diagnostic and prognostic challenge due to its heterogeneous phenotype and clinical course. Artificial Intelligence (AI) and Machine Learning (ML) techniques hold promise in transforming the role of Electrocardiography (ECG) in HCM diagnosis, prognosis, and management. AI, including Deep Learning (DL), enables computers to learn patterns from data, allowing for the development of models capable of analyzing ECG signals. DL models, such as convolutional neural networks, have shown promise in accurately identifying HCM-related abnormalities in ECGs, surpassing traditional diagnostic methods. In diagnosing HCM, ML models have demonstrated high accuracy in distinguishing between HCM and other cardiac conditions, even in cases with normal ECG findings. Additionally, AI models have enhanced risk assessment by predicting arrhythmic events leading to sudden cardiac death and identifying patients at risk for atrial fibrillation and heart failure. These models incorporate clinical and imaging data, offering a comprehensive evaluation of patient risk profiles. Challenges remain, including the need for larger and more diverse datasets to improve model generalizability and address imbalances inherent in rare event prediction. Nevertheless, AI-driven approaches have the potential to revolutionize HCM management by providing timely and accurate diagnoses, prognoses, and personalized treatment strategies based on individual patient risk profiles. This review explores the current landscape of AI applications in ECG analysis for HCM, focusing on advancements in AI methodologies and their specific implementation in HCM care., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Chronic low-grade inflammation, often observed in hypertrophic cardiomyopathy (HCM), promotes adverse ventricular remodelling. This study aimed to investigate the relationship between inflammatory markers and myocardial fibrosis (MF) in patients with HCM., Methods and Results: This study included 102 patients with complete baseline data who underwent septal myectomy. Myocardial samples were stained with Masson's trichrome and analysed to determine myocardial collagen content and MF levels. Plasma levels of inflammatory markers were measured using standard laboratory procedures. Univariate and multivariate logistic regression analyses were performed to explore the relationship between the inflammatory markers and MF. Among the 102 participants included in the analysis, the mean age was 48.9 years, with 69 [67.6%] being men. The overall MF ranged from 2.5% to 40.7% (mean = 15.2 ± 8.1%, median = 13.0%, IQR = 9.9%-18.4%). Participants were divided into two groups based on a median MF of 13%. The high MF group had a larger left atrial diameter and left ventricular ejection fraction. Levels of interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-α were significantly higher in patients with high MF compared to those with low MF (2.3 vs. 4.0 pg/mL, 3.1 vs. 3.9 pg/mL, 4.2 vs.4.7 pg/mL, respectively; all P < 0.05). In multivariate models adjusted for age, sex and other clinical features, IL-2, IL-5 and TNF-α, were correlated with increased interstitial MF [odds ratio (OR): 1.54, 95% confidence interval (CI): 1.10-2.14; OR: 1.42, 95% CI: 1.02-1.98; OR: 1.33, 95% CI: 1.04-1.70]. After additional adjustment for imaging indicators, IL-2 and TNF-α remained significant (OR: 1.49, 95% CI: 1.06-2.09, P = 0.021; OR:1.35, 95% CI: 1.01-1.80, P = 0.044). The correlation analysis between inflammation and replacement fibrosis assessed by CMR in 97 patients revealed that 72 (74.2%) showed late gadolinium enhancement (LGE). No significant correlation was found between inflammatory markers and the presence or extent of LGE., Conclusions: Higher levels of IL-2 and TNF-α were associated with increased histopathological interstitial MF in patients with HCM. Given the gradual progression of MF in HCM, initiating anti-inflammatory treatment in the early stages may delay its progression., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: Hypertrophic cardiomyopathy (HCM) has various aetiologies, including genetic conditions like Fabry disease (FD), a lysosomal storage disorder. FD prevalence in high-risk HCM populations ranges from 0.3% to 11.8%. Early diagnosis of FD is crucial due to available treatments, but its rarity and diverse symptoms complicate identification. Heart-specific FD variants often lead to late diagnoses due to the absence of typical FD symptoms. This prospective study (NCT04943991) was conducted to identify patients with undiagnosed FD using electronic health records (EHR) at a German tertiary-care hospital., Methods: Over 20 years (2000-2020), 2824 patients with 'left ventricular hypertrophy (LVH)' or 'hypertrophic cardiomyopathy (HCM)' were identified by full-text search. Exclusion criteria were age over 85, other diagnosed cardiomyopathies, significant valvular heart disease, death, active malignancy and prior FD testing. The remaining patients received an invitation for FD genetic testing., Results: Of the 2824 identified patients, 2626 (93%) fulfilled the exclusion criteria. Among the 198 included patients, 96 responded, and 55 underwent genetic testing, yielding a response rate of 48% and a testing rate of 28%. In one patient (1.8% of tested), FD was diagnosed with the p.N215S variant. Subsequent family screening revealed six additional FD cases, with four initiating FD-specific therapies. Comprehensive clinical evaluations were conducted in five of the seven identified patients., Conclusions: Genetic testing of patients with unexplained LVH/HCM using EHR is effective for identifying FD. Subsequent family screening further identified at-risk individuals, promoting regular follow-ups and if needed FD-specific therapies. This approach highlights the potential for broader application in high-risk populations to uncover treatable genetic conditions. The next phase should focus on automating the executed search process., Trial Registration Number: NCT04943991., Competing Interests: Competing interests: KL received speaker honoraria from Takeda and travel grants from Amicus. VS received speaker honoraria from Chiesi, Takeda and travel grants from Sanofi, Amicus and Takeda. CS received speaker honoraria from Amicus. CW received institutional grants from Sanofi and speaker honoraria or consulting fees from Amgen, Amicus, Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Vifor, Chiesi, GSK, Idorsia, Eli Lilly, MSD, Novartis, Novo Nordisk and Sanofi. PN received speaker or advisory board honoraria from Amicus, Chiesi, Greenovation, Idorsia, Sanofi and Takeda. NÜ, LL and GF declare no COIs., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease's mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of "myosin inhibitors", have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF-both with preserved and reduced systolic function-has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians.

Introduction: Nemaline myopathy (NM), also known as Nemalinosis, is a rare congenital muscle disease with an incidence of 1 in 50000. It is characterized by nemaline rods in muscle fibers, leading to muscle weakness. We reported a case of NM revealed by cardiac involvement, and we highlighted the challenges in diagnosing this condition as well as its poor prognosis., Observation: The patient is a 7.5-month-old infant from a consanguineous marriage, with a history of bronchiolitis and psychomotor retardation. The infant was admitted to the paediatric intensive care unit due to respiratory distress, which necessitated intubation and mechanical ventilation. A chest X-ray revealed cardiomegaly and bilateral bronchial syndrome, while an electrocardiogram showed left ventricle hypertrophy. Emergency echocardiography revealed biventricular hypertrophy. Laboratory tests indicated significant rhabdomyolysis, hepatic cytolysis, microcytic hypochromic anemia, negative troponins, and respiratory acidosis. The enzymatic activity of acid alpha-glucosidase was inconclusive. Genetic analysis for mutations in exon 2 associated with Pompe disease and congenital muscular dystrophy, the most common differential diagnoses, returned negative results. Given the presence of rhabdomyolysis, the emergence of tongue fasciculations, and pronounced axial and peripheral hypotonia, a muscle biopsy was performed. This revealed the presence of nemaline rods, confirming the diagnosis of NM. The patient's condition deteriorated, marked by extubating failure due to severe muscle weakness. The infant passed away after 50 days of hospitalization., Conclusion: This case underscores the severity and complexity of NM revealed by hypertrophic cardiomyopathy, emphasizing the importance of early diagnosis and prenatal genetic counseling.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Apical hypertrophic cardiomyopathy (ApHCM) represents a rare variant of hypertrophic cardiomyopathy (HCM) with distinct phenotypic characteristics. The prevalence of this variant varies according to each study's geographic region. The leading imaging modality for the diagnosis of ApHCM is echocardiography. Cardiac magnetic resonance, however, is the gold standard for ApHCM diagnosis in case of poor acoustic windows or equivocal echocardiographic findings but also in cases of suspected apical aneurysms. The prognosis of ApHCM was reported to be relatively benign, although more recent studies seem to contradict this, demonstrating similar incidence of adverse events compared with the general HCM population. The aim of this review is to summarize the available evidence for the diagnosis of ApHCM, highlight distinctions in comparison to more frequent forms of HCM with regards to its natural history, prognosis, and management strategies., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Hypertensive heart disease and hypertrophic cardiomyopathy both lead to left ventricular hypertrophy despite differing in aetiology. Elucidating the correct aetiology of the presenting hypertrophy can be a challenge for clinicians, especially in patients with overlapping risk factors. Furthermore, drugs typically used to combat hypertensive heart disease may be contraindicated for the treatment of hypertrophic cardiomyopathy, making the correct diagnosis imperative. In this review, we discuss characteristics of both hypertensive heart disease and hypertrophic cardiomyopathy that may enable clinicians to discriminate the two as causes of left ventricular hypertrophy. We summarise the current literature, which is primarily focused on adult populations, containing discriminative techniques available via diagnostic modalities such as electrocardiography, echocardiography, and cardiac MRI, noting strategies yet to be applied in paediatric populations. Finally, we review pharmacotherapy strategies for each disease with regard to pathophysiology.

Background: Sengers syndrome is an autosomal recessive mitochondrial DNA depletion syndrome characterized by hypertrophic cardiomyopathy, congenital cataracts, skeletal myopathy, exercise intolerance, and lactic acidosis. Dysfunction of acylglycerol kinase (AGK) is responsible for the disease, and several AGK gene variants have been reported., Methods: We employed a comprehensive genomic analysis approach, including whole-genome sequencing and RNA sequencing, combined with various bioinformatics tools., Results: Our analysis successfully diagnosed Sengers syndrome in a patient by detecting a known pathogenic variant and a previously unreported large deletion involving the AGK gene in a segmental duplication., Conclusion: This study demonstrates the effectiveness of combining multiple genomic analysis approaches for the accurate diagnosis of Sengers syndrome, particularly in cases involving complex genetic variations such as large deletions in segmental duplications., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Background: Patients with hypertrophic cardiomyopathy (HCM) may develop concomitant advanced heart failure (HF). However, there is limited data on the clinical outcomes of HCM patients without sarcomere gene mutations who have advanced HF., Objectives: To identify prognostic factors for advanced HF in gene-negative patients within a large HCM cohort., Methods: A total of 1529 unrelated patients with HCM were enrolled between 1999 and 2018, and followed throughout the study period. All patients underwent genotyping through whole exome or panel sequencing. From this cohort, 735 patients without mutations were studied. We assessed the effects of family history, clinical findings, and echocardiographic parameters on the development of advanced HF. Multivariable Cox proportional hazards regression analysis was conducted to identify risk factors associated with advanced HF., Results: Of the 735 gene-negative patients studied, the mean age was 52.5±13.2 years, 69.5% were male, and the mean follow-up duration was 3.2±2.3 years. During this period, 97 patients (13.2%) developed advanced HF. Using multivariable analysis, we identified significant risk factors for advanced HF: female gender (adjusted hazard ratio [HR] 2.499, 95% confidence interval [CI] 1.531-4.081, P<0.001) and older age at enrollment (adjusted HR 1.298, 95% CI 1.00-1.682, P=0.049). These findings suggest that female patients and those enrolled at an older age are at a higher risk for developing advanced HF., Conclusion: Female gender and older age may predict a higher risk of advanced HF in gene-negative patients with HCM. Early detection and proactive treatment are crucial for managing and preventing complications in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests, (Copyright © 2024. Published by Elsevier Inc.)

Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) have significant phenotypic overlap and a similar genetic background, both caused mainly by variants in sarcomeric genes. HCM is the most common cardiomyopathy, while RCM is a rare and often underdiagnosed heart condition, with a poor prognosis. This study focuses on a large family with four infants diagnosed with fatal RCM associated with biventricular hypertrophy. Affected infants were found to be homozygous for NM&#95;003280.3(TNNC1):c.23C>T(p.Ala8Val) variant. Interestingly, this variant resulted in a low penetrance and mild form of hypertrophic cardiomyopathy (HCM) in relatives carrying a single copy of the variant. Overall, this study underscores the complex nature of genetic inheritance in cardiomyopathies and the wide range of clinical presentations they can exhibit. This emphasizes the vital role of genetic testing in providing essential insights crucial for diagnosis, prognosis, early intervention, and the development of potential treatment strategies., (© 2024 Wiley Periodicals LLC.)

Background: Distinguishing hypertrophic cardiomyopathy (HCM) from other cardiomyopathies with left ventricular hypertrophy (LVH), such as hypertensive LVH, transthyretin amyloid cardiomyopathy, and aortic stenosis, is sometimes challenging. Using plasma proteomics profiling, we aimed to identify circulating biomarkers and dysregulated signaling pathways specific to HCM., Methods: In this multicenter case-control study, plasma proteomics profiling was performed in cases with HCM and controls with hypertensive LVH, transthyretin amyloid cardiomyopathy, and aortic stenosis. Two-thirds of patients enrolled earlier in each disease group were defined as the training set and the remaining one-third as the test set. Protein concentrations in HCM were compared with those in hypertensive LVH (comparison 1), transthyretin amyloid cardiomyopathy (comparison 2), and aortic stenosis (comparison 3). Candidate proteins that meet the following 2 criteria were selected: (1) higher abundance in HCM throughout all 3 comparisons or lower abundance in HCM throughout all 3 comparisons with univariable P <0.05 and |log 2 (fold change)| >0.5 in both the training and test sets and (2) independently associated with HCM with multivariable P <0.05 after adjusting for clinical parameters significantly different between HCM and controls. Using the selected candidate proteins, a logistic regression model to distinguish HCM from controls was developed in the training set and applied to the test set. Finally, pathway analysis was performed in each comparison using proteins with different abundance., Results: Overall, 4979 proteins in 1415 patients (HCM, n=879; hypertensive LVH, n=331; transthyretin amyloid cardiomyopathy, n=169; aortic stenosis, n=36) were analyzed. Of those, 5 proteins were selected as candidate proteins. The logistic regression model with these 5 proteins had an area under the receiver operating characteristic curve of 0.86 (95% CI, 0.82-0.89) in the test set. The MAPK (mitogen-activated protein kinase) and HIF-1 (hypoxia-inducible factor 1) pathways were dysregulated in HCM throughout the 3 comparisons., Conclusions: This study identified circulating biomarkers that distinguish HCM from other cardiomyopathies with LVH independently from confounders and revealed signaling pathways associated with HCM., Competing Interests: Dr Shimada has received funding from Bristol Myers Squibb and consulting income from Bristol Myers Squibb and Moderna Japan. Dr Maurer reports grant support from the National Institutes of Health (R01HL139671 and AG081582) and grants from Alnylam, BridgeBio, Intellia, and Ionis and personal fees from Alnylam, Novo-Nordisk, Roche, Prothena, AstraZeneca, Akcea, and Intellia. The other authors report no conflicts.

Background: Mavacamten is the only cardiac myosin inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy. Under the Risk Evaluation and Mitigation Strategy program for mavacamten, patients are required to be monitored for the development of systolic heart failure and reduction of left ventricular ejection fraction (LVEF) to <50%. We report results from the mavacamten Risk Evaluation and Mitigation Strategy database (April 28, 2022 to February 27, 2024)., Methods: Data on health care providers and pharmacy certification, patient monitoring (from Patient Status Forms, based partly on echocardiograms), and screening for drug interactions before each dispense were collected., Results: Of the 6299 patients who received ≥1 dose of mavacamten, 60.0% were women; 64.6% were aged >60 years. Of the 5573 patients with submitted Patient Status Forms, 256 (4.6%) developed LVEF <50%, and 71 (1.3%) experienced heart failure requiring hospitalization. On the 29 111 status forms in these patients, each representing an assessment of an echocardiogram, LVEF <50% was reported on 276 (0.9%), and heart failure requiring hospitalization was reported on 86 (0.3%). Of the 1929 patients with ≥1 year of treatment, 78 (4.0%) had an LVEF reduction to <50%, and 4 (0.2%) experienced LVEF <50% and heart failure requiring hospitalization but later resumed treatment. Of the 3228 patients initiated on 5 mg/d mavacamten and were treated for at least 6 months, 2391 (74.1%) remained at 5 or 10 mg/d. At 3 and 6 months following mavacamten treatment initiation, 57.2% and 70.3%, respectively, demonstrated post-Valsalva left ventricular outflow tract gradient <30 mm Hg., Conclusions: We describe the feasibility and experience of the first 22 months of the Risk Evaluation and Mitigation Strategy program for prescribing mavacamten in >6000 patients with symptomatic obstructive hypertrophic cardiomyopathy. The need for temporary interruption for LVEF <50% was low, including for patients on therapy ≥1 year, with even fewer LVEF reductions associated with heart failure requiring hospitalization., Competing Interests: Dr Desai is a consultant for Bristol Myers Squibb, Cytokinetics, Viz.ai, Tenaya Therapeutics, and Edgewise Therapeutics. D. Seto, M. Cheung, Dr Afsari, N. Patel, Dr Bastien, Dr Lockman, and M. Coiro are employees of Bristol Myers Squibb. Dr Martinez is an advisory board and steering committee member as well as an unbranded speaker for Bristol Myers Squibb.

Background and Aim: Dilated cardiomyopathy is a major cause of heart failure, and hypertrophic cardiomyopathy is a common cause of sudden cardiac death in young adults. Epidemiological studies reporting the association between these cardiomyopathies and common cardiovascular risk factors, including smoking, alcohol, and obesity, are limited, and the published studies are mostly observational, making them vulnerable to bias., Methods and Results: We performed a two-sample Mendelian randomization analysis to assess whether cardiovascular risk factors were causally associated with dilated and hypertrophic cardiomyopathies. Independent genetic variants associated with body mass index, smoking, and alcohol were selected as instrumental variables, with two sets of instrumental variables utilized for alcohol. Dilated cardiomyopathy data on 355,318 samples and hypertrophic cardiomyopathy data on 489,727 samples were obtained from a European population-based genome-wide association study (GWAS) meta-analysis. The large GWAS data sample size improved the statistical power. Our results showed significant associations between a genetic predisposition for smoking and the risk of dilated cardiomyopathy (odds ratio (OR) = 1.33; 95 % confidence level (CI): 1.07-1.67; p = 0.012) and between a genetic predisposition for obesity and the risk of dilated cardiomyopathy (OR = 1.62; 95 % CI, 1.30-2.02; p = 1.51 × 10 -5 ). The results of the other associations were not significant., Conclusions: This study suggests that smoking and obesity are causally associated with an increased risk of dilated cardiomyopathy., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Over the past decade, knowledge about the risk of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) has advanced significantly. A standard well-recognized approach to risk stratification is based on the fundamental risk factors and SCD risk models that should be incorporated into the shared decision-making process. More detailed analysis including additional indicators, such as reduced left ventricular systolic function, the presence of late gadolinium enhancement, or in some cases genetic variants, may provide valuable insights for intermediate-risk patients, enabling more personalized diagnosis and treatment. Risk stratification remains challenging in specific groups, such as patients who have undergone septal reduction therapy, those taking mavacamten, or those with phenocopies of HCM. The advancement of modern methodologies, including multifactorial approaches supported by artificial intelligence algorithms, offers hope for more precise and individualized SCD risk assessment in HCM patients.

Background: Danon disease (DD) is a rare X-linked dominant lysosomal storage disorder. Studies on DD pediatric patients are limited owing to the small number of cases and challenges in early detection., Methods: We retrospectively analysed clinical and genetic data of 29 pediatric patients who visited our hospital for treatment or genetic counselling for DD from July 2014 to December 2023., Results: The mean age at diagnosis was 7.2 ± 5.9 years for boys (n = 21) and 9.4 ± 5.0 years for girls (n = 8). Asymptomatic elevated liver transaminase or creatine kinase (CK) levels were initial manifestations detected in 10 male patients (48%) and absent in female patients. Hypertrophic cardiomyopathy (HCM) was observed in 20 male patients (95%) and 7 female patients (88%), whereas dilated cardiomyopathy (DCM) was not detected. Ventricular preexcitation (VP) was observed initially in 10 patients (36%) and in 15 (54%) at latest evaluation. Patients with VP had higher left ventricular posterior wall thickness in end-diastole z-scores than those without VP (5.6 ± 2.2 vs 3.5 ± 2.1; P = 0.029). During a median 2.7 years of follow-up, 2 male patients received heart transplants. One boy and 1 girl died of heart failure and sudden cardiac arrest, respectively. Twenty-three pathogenic LAMP2 variants were identified, including 7 novel variants., Conclusions: A retrospective review of 29 DD cases suggests an underrecognised asymptomatic period in male DD patients, characterised by elevations in serum CK and transaminases. HCM appears to be the only cardiac manifestation in pediatric female patients, unlike a high incidence of DCM in adult female patients. The incidence of VP may increase with disease progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on causal variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JI receives research grant support from Bristol Myers Squibb. All other authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) needs careful differentiation from other cardiomyopathies. Current guidelines recommend genetic testing, but genetic data on differential diagnoses and their relation with clinical outcomes in HCM are still lacking. This study aimed to investigate the prevalence of genetic variants and the proportion of other cardiomyopathies in patients with suspected HCM in Korea and compare the outcomes of HCM according to the presence of sarcomere gene mutation., Methods: We enrolled 1,554 patients with suspected HCM having left ventricular hypertrophy on transthoracic echocardiography between April 2012 and February 2023. Patients who declined genetic testing or who had pure apical HCM without a familial history were excluded. Genetic testing was performed using a next-generation sequencing panel or whole-exome sequencing for cardiomyopathies. We performed cardiovascular magnetic resonance if the diagnosis was inconclusive. Genotype-positive HCM was defined as sarcomere gene mutations of pathogenic or likely pathogenic variants. Adverse clinical outcomes were defined as a composite of all-cause death, resuscitated cardiac arrest, heart failure-related admission, appropriate implantable cardioverter defibrillator shocks, and stroke., Results: Of 492 patients (mean age 49.6 ± 14.7 years, 29.4% women) who underwent genetic testing, 214 (43.5%) had disease-causing gene mutations. After combining gene tests, multi-imaging modality, and clinical information, 447 (90.9%) had HCM, and 27 (5.5%) had Fabry disease. Among the HCM patients, 182 (40.7%) were genotype-positive, and 265 (59.3%) were genotype-negative. Kaplan-Meier curve analysis showed that genotype-positive HCM patients experienced more composite outcomes (log-rank, P < 0.001). In multivariable Cox analysis, non-sustained ventricular tachycardia (NSVT) (hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.17-3.12; P = 0.010), left ventricular ejection fraction (LVEF) < 50% (HR, 5.50; 95% CI, 2.68-11.27; P < 0.001), LA reservoir strain (HR, 0.96; 95% CI, 0.93-0.99; P = 0.037), and positive sarcomere gene mutation (HR, 1.70; 95% CI, 1.04-2.78; P = 0.034) were significantly association with composite outcomes. Sarcomere gene mutation had incremental value for predicting adverse outcomes added on NSVT and LVEF < 50%., Conclusion: Genetic testing is helpful in diagnosing HCM, and sarcomere gene mutations in HCM are significantly associated with clinical outcomes., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder associated with an increased risk of arrhythmias, heart failure, and sudden cardiac death. Current imaging and clinical markers are not fully sufficient in accurate diagnosis and patient risk stratification. Although known cardiac biomarkers in blood are used, they lack specificity for HCM and primarily stratify for death due to heart failure in overt cases. Non-coding RNAs, particularly microRNAs, have emerged as promising biomarkers due to their role in regulating gene expression in both healthy and pathological hearts. Circulating microRNA signatures may dynamically reflect the progression of HCM, offering potential utility in diagnosis and disease monitoring as well as inform biologic pathways for innovative therapeutic strategies. However, studying microRNAs in cardiovascular diseases is still in its early stages and poses many challenges. This review focuses on emerging research perspectives using advanced cardiac magnetic resonance techniques. We presume, that the search for circulating miR signatures associated with specific adverse myocardial features observed on cardiac magnetic resonance imaging - such as fibrosis, disarray, and microvascular disease - represents a promising direction in HCM research., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Chumakova and Mershina.)

Background: Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended., Aims: The performance of this approach was tested in GEREMY, a HCM prospective observational French register., Methods: Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used., Results: A 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis., Conclusions: Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach., Competing Interests: Declaration of competing interest Pr. Hagege has served as an advisor to Alnylam, Amicus, Bristol Myers Squibb, Cytokinetics, Gilead, Myokardia, Pfizer, Sanofi Genzyme, Tenaya., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: The diagnosis of hypertrophic cardiomyopathy (HCM) with moderate hypertrophy is challenging. Hypertensive heart disease (HHD) is the most common differential diagnosis that mimics the LVH of HCM. The aim of this study was to compare the QRS duration in HCM and HHD to create a novel diagnostic tool to identify primary HCM., Methods and Results: We conducted an international retrospective multicentre study enrolling patients with true HCM and HHD. A total of 547 individuals with HCM and 139 with HHD were included. The median QRS duration was significantly shorter in HCM than in HHD (88 ms [80-94] vs. 98 ms [88-108]; P < 0.01). Multivariable logistic regression identified for the novel diagnostic HCM (D-HCM) score: absence of antihypertensive drugs (+2); family history of unexplained sudden death (+2); QRS duration [<95 ms] = +1; maximum wall thickness (mm) [≥17] = +1. A cumulative QRS-HCM score ≥2 supports the diagnostic certainty of true HCM with a sensitivity of 79%, specificity of 99%, negative predictive value (NPV) of 55%, and positive predictive value (PPV) of 99%., Conclusion: The QRS duration in patient with HCM is significantly shorter compared with patients with HHD-related LVH. QRS duration can be used as a diagnosis marker to distinguish between HCM and HHD. The D-HCM score is a novel, simple, and accurate diagnosis tool for HCM patients with mild to moderate phenotypes., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Recognition of transthyretin amyloid cardiomyopathy is increasing due to advances in cardiac imaging and diagnostic strategies, but questions remain regarding disease frequency and characteristics. We examined the prevalence and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy of unascertained aetiology., Methods and Results: TTRACK was a multicentre, non-interventional, cross-sectional epidemiologic study funded by Pfizer and conducted in 20 hospitals and medical centres in 11 countries (NCT03842163). Eligible patients were aged ≥50 years, had hypertrophic cardiomyopathy (maximal end-diastolic left ventricular wall thickness ≥15 mm on echocardiogram) without an identified genetic or alternative origin at study enrolment, and underwent 99m Technetium bone scintigraphy, with or without single photon emission computed tomography (SPECT). Cardiac-versus-bone uptake on scans was visually scored from 0 to 3 (Perugini scoring). Patients with grades 1-3 underwent monoclonal protein and laboratory testing and transthyretin (TTR) gene sequencing. Of 766 eligible patients, 691 (90.2%) had scintigraphy alone and 75 (9.8%) scintigraphy plus SPECT. Two hundred and eight patients (27.2%) had grade 2 or 3 cardiac uptake on scintigraphy; 144 (18.8%) had grade 2 or 3 cardiac uptake and no evidence of plasma cell dyscrasia and were diagnosed with transthyretin amyloid cardiomyopathy. Of patients with transthyretin amyloid cardiomyopathy, 11 (7.6%) had a pathogenic TTR gene variant and 34 (23.8%), 74 (51.7%), and 35 (24.5%) had New York Heart Association class I, II, and III/IV heart failure (HF) symptoms, respectively. Clinical and laboratory diagnostic characteristics were observed in ≥90% of patients with transthyretin amyloid cardiomyopathy. The characteristics most strongly associated with transthyretin amyloid cardiomyopathy on multivariable analysis were carpal tunnel syndrome (odds ratio [OR] 54.3; P < 0.0001) and male sex (OR 7.9; P < 0.0001)., Conclusions: In the TTRACK study, almost one in five patients ≥50 years of age with hypertrophic cardiomyopathy had transthyretin amyloid cardiomyopathy. Greater awareness of the frequency and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy are needed to help improve early detection of this debilitating but treatable disease., (© 2024 Pfizer Inc. and The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: End-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM., Methods and Results: A total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF) < 50% were defined as having ES-HCM, and a control group (LVEF ≥ 50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF ≥ 50%. The mean age of the patients at enrolment was 62.5 ± 10.3 years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF ≥ 50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P < 0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR] = 0.95, 95% CI [0.90, 1.00], P = 0.042), New York Heart Association (NYHA) class (OR = 7.73, 95% CI [2.93, 20.41], P < 0.001), heart rate (OR = 1.07, 95% CI [1.02, 1.12], P = 0.003), QRS duration (OR = 1.03, 95% CI [1.00, 1.05], P = 0.020), left ventricular end-diastolic diameter (LVEDD) (OR = 1.15, 95% CI [1.04, 1.28], P = 0.006), left atrial anteroposterior diameter (LAD) (OR = 1.13, 95% CI [1.03, 1.24], P = 0.012), and maximum left ventricular wall thickness (MLVWT) (OR = 0.80, 95% CI [0.68, 0.93], P = 0.005). Among the 50 patients with ES-HCM, NYHA class (P < 0.001) and heart rate (P = 0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses., Conclusions: The influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM-Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM-Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan-Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF > 50%) compared with mildly reduced (LVEF 41%-50%) and reduced (LVEF ≤ 40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0 mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric-onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM-Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult-onset and other sarcomeric variant counterparts. HCM-Thin seems to have a distinct phenotype, which may require a different management approach., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

A two-year-old, 3.9-kg, male castrated, domestic shorthair cat presented to The Ohio State University Veterinary Medical Center for acute onset neurological signs. During hospitalization, he was diagnosed with an American College of Veterinary Internal Medicine (ACVIM) stage B1 hypertrophic cardiomyopathy phenotype on echocardiogram. His clinical signs acutely worsened, including seizure activity and panting, and he was euthanized. Necropsy revealed the histopathologic diagnosis of systemic reactive angioendotheliomatosis, which notably severely affected the myocardium. In this case report, we present the antemortem diagnostic results and postmortem necropsy results of this rare condition in cats. This case demonstrates that echocardiographic assessment of the heart in cats affected by systemic reactive angioendotheliomatosis may lead to the false diagnosis of hypertrophic cardiomyopathy and thus should be considered as a differential diagnosis in cats with symmetrical left ventricularl wall thickening on echocardiography., Competing Interests: Conflict of Interest Statement The authors do not have any conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM., Methods: The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation., Results: We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1])., Conclusions: Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM., Competing Interests: None.

Aims: The fibrosis-4 index (FIB-4) is a non-invasive tool to assess fibrosis risk in chronic liver disease. We aimed to explore the relationship between the FIB-4 index and long-term major adverse cardiovascular events (MACE) in HCM patients., Methods and Results: Consecutive patients diagnosed with HCM were included. Patients were divided into two groups using a defined cutoff value established through a ROC analysis for predicting MACE (FIB-4 ≥ 2.37 and FIB-4 < 2.37). The final analysis comprised 187 HCM patients (34.8% females, 66.49 ± 11.43 years of age), with 47 (25.1%) in the FIB-4 ≥ 2.37 group and 140 (74.9%) in the FIB-4 < 2.37 group. Among these, 147 (78.6%) individuals had complete follow-up data. Patients with FIB-4 ≥ 2.37 demonstrated a higher prevalence of co-morbidities such as atrial fibrillation (27.7% vs. 7.9%; P < 0.001), heart failure (55.3% vs. 24.3%; P < 0.001), elevated NT-proBNP levels (3.03 ± 4.74 vs. 0.66 ± 1.08; P < 0.001), and lower LVEF (58.51 ± 7.86 vs. 61.84 ± 5.04; P = 0.001). Over a median of 41 (IQR 16-63) months follow-up, MACE occurred in 49 (33.3%), with a significantly higher incidence in the FIB-4 ≥ 2.37 group (58.8% vs. 25.7%, P < 0.001). Cardiac death rates were also elevated in the FIB-4 ≥ 2.37 group (20.6% vs. 2.7%, P = 0.001). Cox regression analysis revealed an independent association between FIB-4 ≥ 2.37 and a higher risk of MACE (adjusted HR: 1.919, 95% CI 1.015-3.630; P = 0.045) and cardiac death (adjusted HR: 9.518, 95% CI 1.718-52.732; P = 0.010). Furthermore, the FIB-4 index shows positive correlations with left atrium diameter (r = 0.229; P = 0.003), septal thickness (r = 0.231; P = 0.002), posterior wall thickness (r = 0.235; P = 0.001), and NT-proBNP (r = 0.271; P < 0.001). Conversely, a negative correlation was observed between the FIB-4 index and left ventricular ejection fraction (r = -0.185; P = 0.011)., Conclusion: Elevated FIB-4 index, indicative of liver fibrosis, is independently associated with an increased risk of long-term MACE in HCM patients. This emphasizes the potential influence of liver function abnormalities on HCM prognosis, underscoring the need for comprehensive risk assessment in clinical management., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Hypertrophic cardiomyopathy (HCM) with or without left ventricular outflow tract (LVOT) obstruction is a common primary myocardial disease, with a prevalence of 1:500. It is characterized by thickening of the myocardium. Its diagnostic evaluation includes history-taking and physical examination, genetic studies, transthoracic echocardiography, and cardiac MRI. When optimally treated, it carries a mortality of less than 1% per year., Methods: This review is based on pertinent publications retrieved by a selective literature search, including the current guidelines., Results: In symptomatic patients with high LVOT gradients (≥ 50 mm Hg), the treatment of first choice is pharmacotherapy with nonvasodilating beta-blockers or non-dihydropyridine-type calcium channel antagonists. Common side effects include bradycardia and hypotension, and there is a risk of AV nodal blockade. Both substance classes lower the LVOT gradient. Beta-blockers alleviate dyspnea and improve patients' quality of life. Verapamil can increase physical resilience. A further option is mavacamten, a myosin inhibitor that gained approval in Germany in mid-2023: it, too, lowers the LVOT gradient and improves quality of life. In 7-10% of patients, there is a reversible reduction of the left ventricular ejection fraction to less than 50%. Septal reduction treatments can be considered if drug therapy fails. Attention must also be paid to the management of sequelae such as atrial fibrillation, malignant arrhythmias, and mitral valve insufficiency., Conclusion: Patients with HCM have a near-normal life expectancy if the disease is diagnosed early and treated according to the guidelines. The treatment of HCM and HOCM (hypertrophic obstructive cardiomyopathy) have been studied in no more than a few clinical trials, and randomized studies with clinical endpoints are needed.

Analysis of heart sound signals plays an essential role in preventing and diagnosing cardiac diseases. This study proposes a multi-level feature encoding algorithm based on frequency-balanced power spectral intensity for heart sound signal classification. Firstly, a wavelet threshold function is employed to denoise the heart sound signals. Then, the frequency-balanced power spectral intensity envelope is calculated, and an encoder is utilized to extract multi-level features based on the envelope. Finally, an ensemble bagging tree classifier is selected for classification. The experimental data includes binary classification data from the 2016 PhysioNet/CinC Challenge and ternary classification data from the self-collected hypertrophic cardiomyopathy dataset. Results demonstrate that the proposed algorithm performs well, achieving an average classification accuracy of 98.73% for normal and abnormal heart sounds, and 98.12% for normal and two types of hypertrophic cardiomyopathy heart sounds. The proposed method holds significant reference value for the early diagnosis of heart diseases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Hypertrophic cardiomyopathy (HCM) is an inherited disorder whose causal variants involve sarcomeric protein genes. One of these is myosin-binding protein C (MYBPC3), being previously associated with a favourable prognosis. Our objective is to describe the clinical characteristics and events of a molecularly homogeneous HCM cohort associated with truncating MYBPC3 variants., Methods and Results: A cohort of patients and relatives with HCM diagnosis and carrying a truncating MYBPC3 variant were retrospectively recruited. Subjects had an average follow-up of 7.77 years, with an incident HCM phenotype of 10%. They were middle-aged adult patients (47±16.8 years) without significant comorbidities or symptoms. Hypertrophy was discrete with a significative difference between probands and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001). Ejection fraction was predominantly preserved (65%±10%). Despite it being the most common clinical event, relevant heart failure (observed in 8.1% of patients) was infrequent and commonly found in the presence of a second environmental precipitating agent. ESC-HCM risk calculator and modifier factors did not correlate with the risk of major events predicting events, which were low (1.51 per 100 patients/year) and associated with the severity of HCM, abnormal QRS in the ECG and age. Genetic factors and sex were not associated with major events., Conclusions: This is the first molecularly homogeneous, contemporary cohort, including HCM patients secondary to MYBPC3 truncating variants. Patients showed a good prognosis with a low event rate. In our cohort, major arrhythmic events were not related to measured environmental or genetic factors., Competing Interests: Competing interests: RB has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Alnaylam; and research grants from Sanofi and Bristol Myers Squibb. JAPD received advisory fees from Bristol Myers Squibb. There are no other relevant relationships with the industry., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This patient was a septuagenarian female with a past medical history of hypertrophic cardiomyopathy with systolic anterior motion and moderate mitral regurgitation. Preprocedural transoesophageal echocardiography did not show any abnormal papillary muscle. An elective alcohol septal ablation was performed. During alcohol septal ablation at the catheterization laboratory, the patient developed acute cardiogenic shock with pulmonary oedema that required intubation. Transoesophageal echocardiography showed worsening obstruction of the left ventricular outflow tract due to swelling of the septum with severe mitral regurgitation. Emergency surgery via a median sternotomy revealed anomalous papillary muscles with direct insertion into the body of the leaflet and attachment to the free edge of the anterior leaflet (Mayo classification type II). The anterior leaflet and abnormal papillary muscles were resected, followed by septal myectomy through the same exposure. The mitral valve was replaced with a 29-mm tissue valve. Postoperative transoesophageal echocardiography confirmed the release of the left ventricular outflow tract obstruction. The patient's postoperative course was uneventful. This case highlights a rare but serious complication after alcohol septal ablation. Whereas anomalous papillary muscle is one of the important mechanisms of left ventricular outflow tract obstruction, its diagnosis can be challenging in a subset of patients prior to surgical repair., (© The Author 2024. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Alcohol septal ablation (ASA) is recommended for moderate to severe symptomatic patients with hypertrophic obstructive cardiomyopathy. The current guidelines don not recommend particular alcohol doses and the amount of alcohol injected into the septal artery is based more on the interventionalist's decision rather than on systematic evidence. Our objective is to execute a comprehensive assessment of the efficacy and safety of low alcohol doses (1-2 ml)) in comparison to large ones (2-4 ml)., Methods: Multiple databases, encompassing PubMed, WOS, Scopus, Embase, and Cochrane library were systemically assessed from inception to October 2023. Randomized controlled trials (RCTs) and observational studies comparing low-alcohol and high-alcohol dose in patients with HOCM was included. The main outcome was creatine kinase-MB (CK-MB). The secondary ones are septal thickness, left ventricular outflow pressure gradient, and atrioventricular (AV) block., Results: Eight studies, with a total of 1446 individuals, were finally involved in our investigation. low alcohol doses showed lower CK-MB levels relative to high ones (MD=-0.93, 95% CI [-1.15 to -0.72], P = 0.00001). Furthermore, in terms of septal thickness, left ventricular outflow pressure gradient, and AV block, neither of the two doses was preferred., Conclusion: We propose that the low alcohol dose is equally effective as the high dose. moreover, the low alcohol dose was associated with a lower CK-MB levels in comparison to the high one., Prospero Registration: CRD42024511537., (© 2024. The Author(s).)

Background: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease, and clinical and genetic family screening is recommended by guidelines., Objectives: This study sought to investigate the diagnostic yield of screening relatives of HCM patients and identify predictive factors for HCM development during long-term follow-up in relatives from gene-elusive families., Methods: This was a retrospective cohort study of families screened at clinics for inherited cardiomyopathies in Eastern Denmark, from 2006 to 2023., Results: We included 1,230 relatives (55% female; age: 42 ± 17 years) from 531 families. The combined clinical and genetic yield at baseline was 26% (n = 321). After 7 years (mean) of follow-up (6,762 person-years), 43 (4%) additional relatives developed HCM. The strongest predictors of developing HCM were carrying a likely pathogenic/pathogenic variant (HR: 4.58; 95% CI: 2.50-8.40; P < 0.001) and larger left ventricular maximum wall thickness (MWT) (HR: 2.21 per mm; 95% CI: 1.76-2.77 per mm; P < 0.001). In gene-elusive families, we found that an MWT of ≥10 mm represented the optimal classification threshold for developing HCM (area under the curve: 0.80), with only 2 (0.4%) relatives from gene-elusive families with an MWT of <10 mm developing HCM during follow-up., Conclusions: In HCM, the diagnostic yield of a single screening visit was 1 in 4, and the additional yield during 7 years of follow-up was 4%. Gene carriers and relatives from gene-elusive families with a baseline MWT of ≥10 mm were at the highest risk of developing HCM during follow-up. These findings may inform future recommendations on the management of relatives of HCM patients., Competing Interests: Funding Support and Author Disclosures The study was supported by Rigshospitalet Research Council. The funder had no part in the design of the study, the collection, analysis, or interpretation of data or publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia among patients with hypertrophic cardiomyopathy (HCM), increasing symptom burden and stroke risk. We aimed to construct a plasma proteomics-based model to predict new-onset AF in patients with HCM and determine dysregulated signalling pathways., Methods and Results: In this prospective, multi-centre cohort study, we conducted plasma proteomics profiling of 4986 proteins at enrolment. We developed a proteomics-based machine learning model to predict new-onset AF using samples from one institution (training set) and tested its predictive ability using independent samples from another institution (test set). We performed a survival analysis to compare the risk of new-onset AF among high- and low-risk groups in the test set. We performed pathway analysis of proteins significantly (univariable P < 0.05) associated with new-onset AF using a false discovery rate (FDR) threshold of 0.001. The study included 284 patients with HCM (training set: 193, test set: 91). Thirty-seven (13%) patients developed AF during median follow-up of 3.2 years [25-75 percentile: 1.8-5.2]. Using the proteomics-based prediction model developed in the training set, the area under the receiver operating characteristic curve was 0.89 (95% confidence interval 0.78-0.99) in the test set. In the test set, patients categorized as high risk had a higher rate of developing new-onset AF (log-rank P = 0.002). The Ras-MAPK pathway was dysregulated in patients who developed incident AF during follow-up (FDR < 1.0 × 10-6)., Conclusion: This is the first study to demonstrate the ability of plasma proteomics to predict new-onset AF in HCM and identify dysregulated signalling pathways., Competing Interests: Conflict of interest: Y.J.S. has received research funding from Bristol Myers Squibb and consulting income from Bristol Myers Squibb and Moderna Japan. M.S.M. has received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy in cats. The diagnosis can be difficult, requiring advanced echocardiographic skills. Additionally, circulating biomarkers (N-terminal pro-B type natriuretic peptide and cardiac troponin I) have several limitations when used for HCM screening. In previous work, we identified interleukin 18 (IL-18), insulin-like growth factor binding protein 2 (IGFBP-2), brain-type glycogen phosphorylase B (PYGB), and WNT Family Member 5 A (WNT5A) as myocardial genes that show significant differential expression between cats with HCM and healthy cats. The products of these genes are released into the circulation, and we hypothesized that IL-18, IGFBP-2, PYGB, and WNT5A serum RNA and protein concentrations differ between healthy cats, cats with subclinical HCM, and those with HCM and congestive heart failure (HCM + CHF). Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) and enzyme-linked immunosorbent assay (ELISA) were applied to evaluate gene and protein expression, respectively, in the serum of eight healthy controls, eight cats with subclinical HCM, and six cats with HCM + CHF. Serum IGFBP-2 RNA concentrations were significantly different among groups and were highest in cats with subclinical HCM. Compared to healthy controls, serum IL-18 and WNT5A gene expression were significantly higher in cats with HCM + CHF, and WNT5A was higher in cats with subclinical HCM. No differences were observed for PYGB. These results indicate that further investigation via large scale clinical studies for IGFBP-2, WNT5A, and IL-18 may be valuable in diagnosing and staging feline HCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) patients with sarcomere mutations have an increased risk of heart failure and left ventricular (LV) systolic dysfunction. We hypothesize that sarcomere mutation carriers have abnormal myocardial contractility before LV dysfunction. Therefore, we aimed to associate myocardial contractility with identified sarcomere mutations and predict genotyped HCM patients with sarcomere mutation by three-dimensional speckle tracking imaging (3D-STI). A retrospective analysis of 117 HCM patients identified 32 genotype-positive (G +) and 85 genotype-negative (G-) patients. Genotype-positive patients had higher globe circumferential strain (GCS), globe longitudinal strain (GLS), and globe radial strain (GRS) (p < 0.05), and multivariate logistic regression revealed that these variables were associated with a positive genetic status (p < 0.05). After the propensity matches other possible influencing factors, we developed three models, named Model GCS, Model GLS, and Model GRS, which could identified genotype-positive HCM patients with excellent performance (AUC of 0.855, 0.833, and 0.870 respectively, all p < 0.001). Genotype-positive HCM patients show a higher myocardial hyper-contractility status than patients without sarcomere mutations. When combined with clinical and echocardiographic markers, the 3D-STI parameters can effectively identify the likelihood of genotype-positive HCM., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiovascular disease characterized by asymmetric thickening of the left ventricular wall, frequently occurring in families predisposed genetically. While HCM in twins is rare, it presents a unique opportunity to explore the disease's genetic and epigenetic underpinnings due to the phenotypic heterogeneity observed even among genetically identical individuals. This review collates and analyzes global clinical studies that focus on the twin phenomena in HCM. It explores the genetic foundations of HCM, examines the influence of environmental and epigenetic factors on disease expression, and emphasizes the crucial role of genetic screening in the early and differential diagnosis of HCM. By focusing on twin cases in HCM, this review aims to enhance our understanding of HCM's complex genetic background, which could lead to more personalized approaches in the management and treatment of this condition, thus drawing significant interest from researchers and clinicians alike.

Hypertrophic obstructive cardiomyopathy (HOCM) is an autosomal dominant condition that still remains significantly under-diagnosed worldwide. Early detection through clinical evaluation, imaging, and familial history is crucial to prevent severe complications such as heart failure and sudden cardiac death. While cuddsnt management strategies primarily offer symptomatic relief through pharmacotherapy or invasive procedures, their effectiveness and accessibility are limited, revealing substantial gaps in care. The emergence of Mavacamten, a recently FDA-approved drug, could potentially revolutionize HOCM management as it addresses the underlying pathophysiology by inhibiting cardiac myosin ATPase, showing promise in reducing obstruction and improving cardiac function. Our review aims to assess mavacamten's efficacy, emphasizing the pivotal role of genetic testing in identifying at-risk individuals and guiding precise diagnoses for personalized treatments. Additionally, we aim to highlight disparities in access to advanced diagnostics and therapies, particularly affecting underserved populations globally and within communities, as well as explore the potential of artificial intelligence (AI) in enhancing early detection and monitoring treatment responses in HOCM. This review thus offers valuable insights to inform future research directions and clinical practices aimed at optimizing outcomes for individuals with HOCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: We sought the cardiopulmonary exercise testing (CPET) parameter that most accurately reflected therapeutic efficacy in patients with hypertrophic cardiomyopathy (HCM)., Methods: Well-being questionnaire, N-terminal brain natriuretic peptide measurements, echocardiography, and CPET were performed in patients with symptomatic non-obstructive HCM during phase II, randomized, open-label multicentre study, before and after 16 weeks of traditional or sacubitril/valsartan treatment. Patients were followed 36 months after the initial CPET. Primary endpoints were changes in: 1) peak oxygen consumption (VO 2 ); 2) VO 2 at anaerobic threshold (AT); 3) oxygen pulse; 4) minute ventilation (VE)/carbon-dioxide (CO 2 ) production slope; 5) VE/VCO 2 at AT (VE/VCO 2 &#95;AT); 6) VE/VCO 2 nadir; 7) VE/VCO 2 intercept; and 8) partial end-tidal pressure of carbon-dioxide (P ET CO 2 ) change during CPET., Results: Of 115 screened patients, 61 (52 ± 14 years, 43 % women) were included. Within subject therapy effects were detected only by the VE/VCO 2 intercept and P ET CO 2 change, whereas the differences between medical regimens were detected by differences in VE/VCO 2 nadir and VE/VCO 2 &#95;AT changes after the treatment. The best predictors of the change in well-being were left ventricular outflow tract maximal gradient and VE/VCO 2 intercept (B = 0.41,0.36; SE = 0.16,0.30; CI = 0.14-0.79, 0.15-1.14; p = 0.006,0.016, respectively). Adverse cardiac events were best predicted by the initial VE/VCO 2 nadir., Conclusion: Ventilatory efficiency parameters outperform peak VO 2 in gauging therapy effects in patients with HCM., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Infantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and middle-income nations. This study attempts to characterise the phenotypic expression, genetic architecture and short-term clinical outcomes of infantile HCM from a South Asian tertiary referral centre., Methods: This study includes all infants from the Amrita HCM cohort between January 2011 and July 2021. Clinical history, ECG, echocardiographic data, and genetic analyses were evaluated., Results: 34 patients with infantile HCM were diagnosed at a median age of 3.7 months (IQR 1-6 months). Underlying aetiologies were RASopathy (n=13; 38%), non-syndromic (n=12; 35%) and inborn errors of metabolism (n=9; 27%). Genetic analysis was done in 20 patients (59%) with a yield of 90%. Clinical presentation included failure to thrive (n=29; 85%), dyspnoea on exertion (n=23; 68%) and clinical heart failure (n=24; 71%). Echo showed concentric left ventricular hypertrophy in 22 patients (65%), obstructive HCM in 11 patients (32%) and left ventricular systolic dysfunction in 6 patients (18%). The mortality rate was 10.0 deaths per 100 patient years over a median follow-up period of 3.1 years. The main risk markers for mortality were the age at diagnosis, gender and concentric Left ventricular hypertrophy., Conclusions: This cohort demonstrates the morphological, functional and genetical heterogeneity of infantile HCM, enunciating the need for integration of cardiology, metabolic and genetic services to achieve optimum outcomes in these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes., Methods and Results: This retrospective study analyzed 1231 consecutive patients with HCM from 2 tertiary hospitals. We performed latent class analysis to categorize patients into phenotypic groups. Three distinct phenotypic groups were identified using latent class analysis. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular events, 133 all-cause mortality events, and 70 noncardiovascular mortality events were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 versus 2 versus 3: 0.8% versus 8.2% versus 4.0%, respectively, P <0.001), and cardiovascular events were more frequent in Groups 2 and 3 compared with Group 1. All-cause and noncardiovascular mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance., Conclusions: This study identified 3 distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.