Christopher Semsarian

Description:In the article by Meisner et al, “Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy,” which published online on December 5, 2024, and appears in the March 18, 2025, issue of the journal (Circulation. 2025;151:783–798. DOI: 10.1161/CIRCULATIONAHA.124.069398), a correction to the author list is needed. The authors notified the Editorial office that an author was mistakenly omitted from the author list. Iacopo Olivotto, MD has been added as an author. Dr Olivotto is a consultant for Bristol Myers Squibb, Amicus, Sanofi, Cytokinetics, Bayer, Tenaya, Rocket Pharma, and Lexeo. All authors were notified of the updated author list.

Description:This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group. Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the proportion of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% of the overall population and 0.8%, 0.8%, 0.5%, and 1.2% of European, African, East Asian, and South Asian ancestry individuals, respectively. Over the lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (HRadj, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (HRadj, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (HRadj, 2.12 [95% CI, 1.78-2.53]). Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.

Description:Bystander cardiopulmonary resuscitation (CPR) and defibrillation improve out-of-hospital cardiac arrest survival. However, basic life support (BLS) skills are low. The FirstCPR cluster randomised controlled trial aimed to test the effectiveness of a community organisation-targeted BLS education and training approach. Clusters (community organisations with 50+ members) were randomly allocated to intervention (12-month period of opportunities to access BLS education and training) or control (no intervention). Outcomes were assessed via surveys at 12 months and pre-specified analysis involved hierarchical mixed-models. Of 165 randomised clusters (82 intervention), 58% were sports and 42% were social/faith-based. Most of the intervention clusters (74/82) participated in at least one intervention activity (15 in all activities). Factors such as the COVID-19 pandemic and organisation support impacted intervention uptake. Overall 924 members, across 93 clusters (407 from 57 intervention clusters; 517 from 36 control clusters), completed surveys. At 12-months, intervention organisation surveyed members reported higher rates of: being trained and willing to perform CPR on a stranger (primary outcome: 63.8% vs 46.9 %; Adjusted Odds Ratio (AOR) 2.22, 95% confidence interval (CI):1.50-3.30), confidence to use an automated external defibrillator (AED) (48.4% vs 26.4%; AOR:3.23, 95%CI:2.22-4.71) and willingness to use AEDs on a stranger (73.9% vs 62.9%; AOR:1.84, 95%CI:1.22-2.80). The results should be interpreted cautiously as the survey response rates were very low. However, survey respondents showed desired outcomes and key learnings for future research were gained.

Description:Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry. Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR). After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; P=0.0003) but a lower risk of atrial fibrillation (HR, 0.74 [95% CI, 0.59-0.93]; P<0.0001) and ventricular arrhythmia (HR, 0.60 [95% CI, 0.38-0.94]; P=0.027) than males. No sex difference was observed for death (P=0.84). Sarcomere-positive males had higher heart failure (HR, 1.34 [95% CI, 1.06-1.69]) and death risks (HR, 1.48 [95% CI, 1.08-2.04]) not seen in females (HR, 0.85 [95% CI, 0.66-1.08] versus HR, 0.86 [95% CI, 0.71-1.21]). MYBPC3 variants lowered heart failure risk in females (HR, 0.56 [95% CI, 0.41-0.77]) but not in males (HR, 1.29 [95% CI, 0.99-1.67]). A sex difference appeared in moderate (4% to <6%) versus low risk (<4%) European Society of Cardiology hypertrophic cardiomyopathy risk score, with females at moderate risk more prone to ventricular arrhythmia (HR, 3.57 [95% CI, 1.70-7.49]), unobserved in males (HR, 1.13 [95% CI, 0.63-2.03]). We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes.

Description:Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.