👤 Dominic J Abrams

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]; 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. Show less

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 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]; 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. Show less

Implantable cardioverter defibrillators (ICDs) used to prevent sudden cardiac arrest in children not only provide appropriate therapy in 25% of patients but also result in a significant incidence of inappropriate shocks and other device complications. ICDs placed for secondary prevention have higher rates of appropriate therapy than those placed for primary prevention. Pediatric patients with primary prevention ICDs were studied to determine time-dependent incidence of appropriate use and adverse events. A total of 140 patients aged <21 years (median age, 15 years) at first ICD implantation at Boston Children's Hospital (2000-2009) in whom devices were placed for primary prevention were retrospectively identified. Demographics and times to first appropriate shock; adverse events (including inappropriate shock, lead failure, reintervention, and complication); generator replacement and follow-up were noted. During mean follow-up of 4 years, appropriate shock occurred in 19% patients and first adverse event (excluding death/transplant) occurred in 36%. Risk of death or transplant was ≈1% per year and was not related to receiving appropriate therapy. Conditional survival analysis showed rates of appropriate therapy and adverse events decrease soon after implantation, but adverse events are more frequent than appropriate therapy throughout follow-up. Primary prevention ICDs were associated with appropriate therapy in 19% and adverse event in 36% in this cohort. The incidence of both first appropriate therapy and device-related adverse events decreased during longer periods of follow-up after implantation. This suggests that indications for continued device therapy in pediatric primary prevention ICD patients might be reconsidered after a period of nonuse. Show less