Clinical and genetic characteristics of pediatric hypertrophic cardiomyopathy in japan: a multicenter study with validation of sudden cardiac death risk models
K Hirono, Y Hata, M Nishiyama, K Tsuboi, S Takarada, M Okabe, H Nakaoka, K Ibuki, S Ozawa, S Ichimata, N Nishida, F IchidaAbstract
Background
Sudden cardiac death (SCD) is the leading cause of mortality in pediatric hypertrophic cardiomyopathy (HCM). Risk prediction models including HCM Risk-Kids and PRiMACY have been developed predominantly in Western populations, but their applicability to Asian children remains uncertain. The clinical and genetic characteristics of Japanese pediatric HCM have not been comprehensively characterized.
Objectives
To characterize the clinical and genetic features of Japanese pediatric HCM and externally validate established SCD risk prediction models.
Methods
This retrospective multicenter study enrolled 141 Japanese children with HCM from 35 hospitals (2013–2025). Clinical characteristics were compared between infantile-onset (<1 year) and childhood-onset groups, and between genetic subgroups. The primary outcome was SCD-related major adverse cardiovascular events (SCD-MACE). External validation of four risk models (HCM Risk-Kids, AHA, PRiMACY clinical, PRiMACY genetic) was performed.
Results
Infantile-onset HCM comprised 31.2% (n=44) of the cohort, substantially higher than typically reported in Western studies. Pathogenic variants were identified in 53.9%, predominantly in MYBPC3 (20.6%), MYH7 (15.6%), and other sarcomeric genes (17.7%). Genetic yield was significantly lower in infantile-onset (27.3%) versus childhood-onset patients (65.9%, P<0.001). Genotype-specific outcomes differed significantly (P=0.046): thin filament variant carriers had the highest SCD-MACE rate (32.0%) versus MYBPC3 (10.3%), MYH7 (9.0%), and variant-negative (10.7%). Variant-positive patients showed regression of septal hypertrophy Z-scores during follow-up, while variant-negative patients demonstrated stable hypertrophy. Over median 52-month follow-up, 20 patients (14.2%) experienced SCD-MACE, with 5-year and 10-year event-free survival of 91.2% and 79.8%. All four risk models demonstrated acceptable discrimination (AUC 0.69–0.74) without significant inter-model differences. HCM Risk-Kids showed adequate calibration (Hosmer-Lemeshow P=0.252, slope 1.105), while PRiMACY clinical demonstrated miscalibration (P=0.034). Unexplained syncope (HR 25.5, P<0.001) and NSVT (HR 13.3, P=0.035) were significant predictors.
Conclusions
Japanese pediatric HCM exhibits distinctive features including high infantile-onset proportion, lower genetic yield in infants, and elevated SCD risk with thin filament gene variants. Established risk models maintain acceptable discrimination, with HCM Risk-Kids demonstrating superior calibration for clinical application.Kaplan-Meier survival analysisReceiver operating characteristic curves