Farbod Sedaghat-Hamedani

Background: Cardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic nonobstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM. Methods: We systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trial's primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes. Results: Three RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQ-CSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001). Conclusions: In this meta-analysis of randomized trials in symptomatic nHCM, CMIs' pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) causes substantial symptom burden and impaired functional capacity. Mavacamten has emerged as a targeted pharmacologic treatment, whereas alcohol septal ablation (ASA) is an established septal reduction therapy (SRT). Direct comparative real-world data remain limited. Methods: In this propensity-controlled observational study, longitudinal registry data from Heidelberg University Hospital were analyzed. Consecutive adults with oHCM, NYHA class ≥II symptoms, and a maximum LVOT gradient ≥50 mmHg treated with mavacamten or ASA were included. The cohort comprised 107 ASA- and 113 mavacamten-treated patients. Follow-up was performed at 6 and 12 months. The primary endpoint was a composite adverse clinical outcome including cardiovascular death, heart failure hospitalization, SRT, heart transplantation, ventricular assist device implantation, permanent pacemaker implantation for third-degree atrioventricular block, or decline in left ventricular ejection fraction to <40%. Results: Both treatments showed significant improvement in NYHA class and LVOT gradient reduction over 12 months. Mean LVOT gradient decreased from 100.3 to 44.2 mmHg after ASA and from 85.7 to 18.4 mmHg with mavacamten at 12 months (both p<0.001). Between-group differences were not significant at 6 months, whereas residual LVOT gradient was lower with mavacamten at 12 months (p=0.004). NT-proBNP declined in both groups and was lower with mavacamten at both follow-up visits (both p<0.001). Third-degree atrioventricular block occurred more frequently after ASA (6.5% vs 0%, p=0.002). The composite endpoint occurred in 13 ASA-(12.1%) and 4 mavacamten-treated patients (3.5%) (p=0.003), with higher 1-year event-free survival in the mavacamten group (HR 0.19; 95%-CI 0.06-0.60; p=0.001). Conclusions: In this real-world comparative study, both ASA and mavacamten improved symptoms and LVOT obstruction in oHCM. Mavacamten was associated with a more favorable short-term hemodynamic and safety profile at 12 months. Graphical : Study design and principal findings of a propensity-matched single-center cohort study comparing alcohol septal ablation and mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is highly sensitive to environmental influences, with physical exercise emerging as one of the most important determinants of disease expression. Growing evidence indicates that high-intensity and endurance exercise accelerate structural remodelling, promote inflammatory myocardial injury, and increase the incidence of malignant ventricular arrhythmias in genetically predisposed individuals. These effects extend beyond acute exertion, as cumulative exercise exposure contributes to the development of a persistent arrhythmogenic substrate that may sustain risk even after cessation of competitive sport. In contrast, available data suggest that low-intensity physical activity does not confer the same degree of arrhythmic burden and may support overall cardiovascular and functional health when carefully prescribed. This review integrates mechanistic insights, clinical cohort data, and current guideline recommendations to provide a balanced framework for exercise counselling in ACM. Rather than advocating complete physical inactivity, this approach differentiates high-risk endurance or competitive exercise from carefully selected low-intensity recreational activity and emphasizes individualized, shared decision-making. Thus, understanding the interaction among genetic substrate, exercise intensity, and systemic stressors is essential for optimizing personalized activity recommendations and improving long-term outcomes in this vulnerable population.

[This corrects the article DOI: 10.31083/j.rcm2506225.].

Mutations in the splice-regulator RBM20 cause heart failure with reduced ejection fraction (HFrEF), typically manifesting as dilated cardiomyopathy (DCM). Mutations at position 634 in the RS-domain cause DCM with (R634L) or without (R634W) left ventricular non-compaction (LVNC). However, the mechanisms underlying phenotype variability and personalized therapy beyond HFrEF remain unclear. We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), 3D-cardiospheres and engineered myocardial tissues from patients with RBM20 mutations R634L (LVNC) or R634W (DCM). Using CRISPR/Cas9, we created isogenic rescue and mutation-insertion lines, identifying RBM20 mis-localization, splicing errors in TTN and RYR2, and sarcomere irregularities in both. DCM-CM showed increased resting Ca²⁺ leak and reduced Ca²⁺ transient amplitude, typical of HFrEF, and spatial disorganization of sarcoplasmic reticulum and mitochondria. In contrast, LVNC-CM exhibited elevated Ca²⁺ transient amplitude with faster kinetics, driven by elevated cAMP and mis-spliced, hyperactive CAMK2D, leading to PLN-hyperphosphorylation and increased metabolic respiration. Further, LVNC showed desmosomal derangement potentially from mis-splicing of Junction plakoglobin and reduced 3D cardiosphere compaction. Despite distinct mechanisms, contractile force was reduced in both. Isogenic controls confirm mutation causality. Drug intervention with verapamil partially improved selected abnormal Ca²⁺ handling and contractile phenotypes in LVNC- and DCM-CM, whereas the CAMK2D inhibitor AIP improved systolic Ca²⁺ handling predominantly in LVNC-CM. In conclusion, different amino acid substitutions at the same RBM20-residue induce opposing Ca²⁺-handling and structural phenotypes. While DCM features impaired Ca²⁺ handling, LVNC shows defective cell-cell coupling and activated Ca²⁺ handling and metabolism, yet insufficient to compensate for organ-level dysfunction. This supports personalized pharmacological therapies in early HF, and potential CRISPR/Cas9 repair for RBM20 cardiomyopathy.

Background: Obstructive hypertrophic cardiomyopathy (HCM) is defined by left ventricular hypertrophy with outflow tract obstruction. Despite clear guideline-directed medical therapy recommendations from the European Society of Cardiology (ESC), it remains unclear whether real-world treatment aligns with these guidelines. This study evaluates adherence to ESC guidance in Germany, focusing on pharmacological and invasive therapies and identifying gaps in real-world care for patients with obstructive HCM. Methods: A retrospective cohort analysis was conducted using the WIG2 Benchmark database, containing administrative claims data from German statutory health insurers. Patients aged ≥18 years who received an International Classification of Diseases (ICD)-coded diagnosis of HCM between 2012 and 2018 were included. Treatment alignment was assessed against ESC guidelines on HCM. Results: Of 6793 patients with an HCM diagnosis, 1141 had obstructive HCM. Mean age was 59.7 years and 62% were male. Following initial HCM consultation, 18% received beta-blocker (BB) monotherapy and 12% received calcium channel blocker (CCB) monotherapy, in accordance with ESC guidelines. However, 43% of treatment combinations were not aligned with the ESC guidelines, including use of contraindicated dihydropyridine CCBs and vasodilating BBs, and 22% of patients did not receive any HCM-related pharmacological treatment. Overall, only 57% of the prescribed treatments were consistent with ESC guidelines for obstructive HCM management. Conclusions: This study reveals substantial gaps in alignment with the ESC guidelines for obstructive HCM management in Germany, underscoring the need for enhanced clinician education on existing therapies. Greater uptake of guideline-directed medical therapy is critical to improving patient well-being, functional status and outcomes.

To collect sensitive patient data during clinical trials, the Informed Consent (IC) of the participants must be obtained beforehand. If the IC is not correct and complete, the document cannot be used to represent the will of the participant and will not be considered a legally valid document. However, few studies have examined the quality of the IC and the IC-quality found is unfortunately not satisfactory. The aim of this article is to describe the development of an IC quality assurance concept and to report the results of an evaluation using the example of a German Centre for Cardiovascular Research (DZHK) registry. All quality issues identified during the study were documented. These were aggregated into the quality indicators “Completeness”, “Consistency of Data”, “Correctness” and “Validity”. Of 2,453 ICs, 1,588 had at least one quality issue; 99.8% of them were resolved. In addition, training sessions were conducted with study staff to raise awareness of the importance of correct IC collection, including documentation, and to minimize quality issues. Our data exemplify that improvements in the recording of ICs by the study staff can be achieved. This evaluation shows the value and importance of continuous IC quality control.

Hypertrophic cardiomyopathy (HCM) represents the most common inherited cardiac disease and a leading cause of heart failure, arrhythmias, and sudden cardiac death in young individuals. For decades, management of HCM has relied on symptom control with β-blockers, calcium channel blockers, disopyramide, or invasive septal reduction in advanced cases. The identification of pathogenic sarcomere variants and the recognition of hypercontractility as a central disease mechanism have paved the way for cardiac myosin inhibitors (CMIs), the first truly disease-specific pharmacological therapy for HCM. Indeed, CMIs represent a revolutionary therapeutic paradigm that redefines the standard of care by translating molecular discovery into clinical application. This review provides a guide to the mechanistic basis of sarcomere modulation, summarizes the clinical evidence for mavacamten and aficamten, and critically evaluates the evolving roles of both medications in obstructive and non-obstructive HCM.

Background: The clinical and economic burden of obstructive hypertrophic cardiomyopathy (HCM) in Germany for symptomatic versus asymptomatic patients has not been comprehensively assessed. Methods: This retrospective observational study analyzed nationally representative WIG2 Benchmark Database data, identifying adults diagnosed with obstructive HCM from 2012 to 2018. Study index was the first date when a participant met eligibility criteria. An algorithm based on coded symptoms and pharmacological treatments was used to divide patients into symptomatic and asymptomatic subgroups. Annual prevalence, patient characteristics, outcomes, resource utilization, and costs were assessed during follow-up. Results: Overall, 1141 patients were included (649 symptomatic patients and 492 asymptomatic patients during the 1-year pre-index period [baseline]). In total, 1042 patients had symptomatic disease at some point during follow-up. Annual obstructive HCM prevalence increased between 2011 and 2019 and was higher for symptomatic than asymptomatic patients. Compared with asymptomatic patients, symptomatic patients: were older (mean age: 62.8 vs. 55.5 years), were less likely to be male (59% vs. 67%), and had higher Charlson Comorbidity Index (mean: 2.82 vs. 1.69) at baseline; had higher rates of all-cause mortality (0.05 vs. 0.02 per 100 patient-years) and cardiovascular events (mean follow-up: 4.7 years); had more outpatient visits (13.3 vs. 10.8 per patient-year [PPY]), inpatient visits (0.7 vs. 0.5 PPY), and longer mean length of stay (8.7 vs. 7.4 days); and had higher mean costs PPY for outpatient, inpatient, and pharmacy services (total: €5975 vs. €4399). Conclusions: Patients with symptomatic obstructive HCM experienced greater clinical and economic burden than asymptomatic patients in Germany. Graphical

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. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.