Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate Effect Variants.

Background: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder primarily linked to rare variants in sarcomere genes, though recently certain non-sarcomeric genes have emerged as important contributors. Non-Mendelian genetic variants with reproducible moderate effect sizes and low penetrance-intermediate-effect variants (IEVs)-, can play a crucial role in modulating disease expression. Understanding the clinical impact of IEVs is crucial to unravel HCM's complex genetic architecture.

Echocardiographic Changes With Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy: Exploratory Insights From the ODYSSEY-HCM Trial.

Background: Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) lacks approved therapies. The ODYSSEY-HCM trial (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy; NCT05582395), the largest to date in HCM patients, evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status).

Objectives: This exploratory analysis of the phase 3, randomized, placebo-controlled trial evaluated echocardiographic changes in nHCM patients from baseline to week 48.

Effects of Mavacamten on Cardiac Biomarkers in Nonobstructive Hypertrophic Cardiomyopathy: Insights From the ODYSSEY-HCM Trial.

Background: No therapy is approved for patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM). The ODYSSEY-HCM (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy [ODYSSEY-HCM]; NCT05582395) trial, the largest to date in patients with hypertrophic cardiomyopathy (HCM), evaluating the efficacy of mavacamten in symptomatic adults with nHCM, did not demonstrate improvements in its primary endpoints (functional capacity and patient-reported health status).

Objectives: The current exploratory analysis from the ODYSSEY-HCM trial reports the associations between: 1) baseline biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity cardiac troponin I [cTnI]) with clinical, exercise, and echocardiographic characteristics; and 2) comparing changes in these biomarkers from baseline to week 48 between mavacamten and placebo groups.

Disease Penetrance in Genotype-Positive But Clinically Unaffected Relatives From Families With Dilated Cardiomyopathy.

Background: Serial clinical assessment of genotype-positive relatives from families with dilated cardiomyopathy (DCM) is recommended, but there are limited data to guide screening intervals.

Objectives: This study sought to understand the influence of age, sex, and genotype on disease expression.

Methods: Families with a DCM phenotype and a likely pathogenic or pathogenic variant in DCM-related genes were identified.

Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants.

Background: Inflammatory, myocarditis-like episodes precede and are associated with higher risk of sustained ventricular arrhythmias and heart failure in patients with pathogenic or likely pathogenic desmoplakin (DSP) variants. Whether the recurrence and treatment of myocarditis-like episodes influence the outcomes in this population is unknown. This study aimed to assess the prognostic impact of the recurrence and treatment of myocarditis-like episodes in patients with pathogenic or likely pathogenic DSP variants.

Titin-related familial dilated cardiomyopathy: factors associated with disease onset.

Background And Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM.

Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy.

Background: Desmoplakin (DSP) cardiomyopathy, caused by variants in the gene , is a unique subtype of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathies. Specific diagnostic and disease staging criteria have yet to be developed for DSP cardiomyopathy.

Objective: Utilizing a large cohort of DSP cardiomyopathy patients and their genotype-positive family members, this study aims to develop diagnostic and disease staging criteria for DSP cardiomyopathy.

Cardiac magnetic resonance markers of pre-clinical hypertrophic and dilated cardiomyopathy in genetic variant carriers.

Background: Patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) exhibit structural and functional cardiac abnormalities. We aimed to identify imaging biomarkers for pre-clinical cardiomyopathy in healthy participants carrying cardiomyopathy-associated variants (G +).

Methods: We included 40,169 UK Biobank participants free of cardiac disease at the time of cardiac magnetic resonance imaging (CMR) and with whole exome sequencing.

Tailored therapeutics for cardiomyopathies.

The term cardiomyopathy is used to describe a large family of complex heart muscle disorders of diverse aetiology and pathophysiology. For decades, the management of individual cardiomyopathy subtypes has focused primarily on the management of symptoms and the prevention of disease-related complications, such as heart failure and sudden cardiac death. Treatment of progressive myocardial dysfunction has relied on conventional evidence-based heart failure therapies, with variable success.

Myosin inhibitors for treatment of hypertrophic cardiomyopathy.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To assess the effects of myosin inhibitors compared to usual care or placebo on exercise capacity, need for septal reduction therapy, and all-cause mortality in people with hypertrophic cardiomyopathy (HCM). Secondary objectives To assess the effects of myosin inhibitors compared to usual care or placebo in people with HCM in the following population subgroups.

Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: 48-Week Results From FOREST-HCM.

Background: Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed.

Objectives: This study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study.

Methods: Obstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study.

NAXCARE: a clinical outcome registry for Naxos disease and related cardiocutaneous syndromes.

The NAXCARE (NAXos disease and Cardiocutaneous Assessment and Registry for Evaluation) is a global initiative designed to collect, store, and analyze clinical outcomes data on patients with Naxos disease and related cardiocutaneous syndromes (CCS). This registry aims to fill the gaps in clinical knowledge, enhance treatment approaches, and improve patient outcomes by systematically documenting disease progression, genetic profiles, and patient care pathways. The following methodology outlines the registry's design, data collection protocols, management, security measures, and anticipated contributions to research and clinical practice.

The p.Asn271Ile Variant in the TNNT2 Gene Is Associated With Low-Risk Late-Onset Hypertrophic Cardiomyopathy.

Background: Variants in the cardiac troponin T gene (TNNT2) are a cause of hypertrophic cardiomyopathy (HCM) where mild TNNT2 structural phenotypes may be associated with sudden cardiac death.

Objectives: This study aims to demonstrate a founder effect in A Coruña (Spain) and characterize the phenotype of the TNNT2 p.Asn271Ile variant in comparison with codon 92 variants, a hotspot previously associated with high risk.

Translation of genomics into routine cardiological practice: insights from a European Society of Cardiology Cardiovascular Round Table.

Cardiovascular diseases (CVD) remain the leading cause of death globally and there is an urgent need for innovative approaches to treatment. One emerging avenue is genetic therapies, which hold particular promise for diseases with a monogenic basis. Gene silencing techniques using antisense oligonucleotides or ribonucleic acid interference strategies are currently at the forefront of genetic therapies in CVD, with several ribonucleic acid-targeted therapies already approved for the treatment of conditions such as familial hypercholesterolaemia and transthyretin amyloidosis.

Hypertrophic cardiomyopathy and atrial fibrillation: the Cardiomyopathy/Myocarditis Registry of the EURObservational Research Programme of the European Society of Cardiology.

Background: Hypertrophic cardiomyopathy (HCM) is commonly associated with atrial fibrillation (AF), but its impact on outcomes in real-world practice is uncertain. The aim of the study was to evaluate the clinical profile and prognosis of patients with HCM and AF.

Methods: Overall, 1739 adult patients with HCM (40.

Hypertrophic cardiomyopathy: prevalence of disease-specific red flags.

Background And Aims: The European Society of Cardiology guidelines recommend a systematic search for diagnostic clues or 'red flags' (RFs) in patients with hypertrophic cardiomyopathy (HCM) to better tailor disease management. To date, the prevalence and clinical significance of RF associated with HCM phenotypes in different clinical settings are unknown.

Methods: The study cohort comprised 818 patients with a clinical diagnosis of HCM [479 (62%) males, mean age 49 ± 21 years] referred to four European centres.

Naxos Disease and Related Cardio-Cutaneous Syndromes.

Naxos disease is a rare autosomal recessive condition combining arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma. The first identified causative variant was in the gene encoding the desmosomal protein plakoglobin. Naxos disease exhibits fibro-fatty myocardial replacement with immunohistological abnormalities in cardiac protein and signaling pathways, highlighting the role of inflammation and potential anti-inflammatory treatments.

Electrophysiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy.

Background: Among inherited cardiomyopathies involving the left ventricle, whether dilated or not, certain genotypes carry a well-established arrhythmic risk, notably manifested as sustained monomorphic ventricular tachycardia (SMVT). Nonetheless, the precise localization and electrophysiological profile of this substrate remain undisclosed across different genotypes.

Methods: Patients diagnosed with cardiomyopathy and left ventricle involvement due to high-risk genetic variants and SMVT treated by electrophysiological study were recruited from 18 European/US centers.

Arrhythmic risk stratification in patients with left ventricular ring-like scar.

Aims: Left ventricular (LV) ring-like scar on cardiac magnetic resonance (CMR) has been linked to malignant arrhythmias in patients with non-ischaemic cardiomyopathy. This study aimed to perform a comprehensive evaluation of this phenotype and to identify risk factors for life-threatening arrhythmic events (LAEs), a composite of sudden cardiac death (SCD), aborted SCD, and sustained ventricular tachycardia.

Methods And Results: One hundred and fifteen patients [median age 39 (interquartile range, IQR, 28-52), 42% females] were identified at 6 referral centres.

Impact of Catheter Ablation on Atrial Fibrillation Burden and Symptoms in Patients With Hypertrophic Cardiomyopathy.

Background: Atrial fibrillation (AF) is more common in patients with hypertrophic cardiomyopathy (HCM) and is often highly symptomatic. The impact of catheter ablation (CA) may be under-reported when evaluated by long-term freedom from any atrial arrhythmia.

Objectives: This study aims to evaluate whether CA of AF in patients with HCM would significantly reduce AF burden and improve symptoms.