Sarcomere gene variants did not improve cardiac function in pediatric patients with dilated cardiomyopathy

Background Dilated cardiomyopathy (DCM) is a progressive myocardial disorder with significant morbidity in children. Although pathogenic gene variants are detected in approximately 30–40% of DCM cases, the impact of sarcomere gene variants on cardiac function and left ventricular reverse remodeling (LVRR) in pediatric DCM remains unclear. Purpose This study aimed to investigate the association between sarcomere gene variants and clinical outcomes—including LVRR—in a nationwide cohort of Japanese pediatric DCM patients, thereby determining whether these variants confer a favorable response to standard heart failure therapies. Methods A total of 123 pediatric patients with primary DCM (median age: 8 months; range, 1–51 months) were enrolled from 45 Japanese hospitals between October 2014 and March 2023. Comprehensive clinical evaluations, serial echocardiography, and next-generation sequencing targeting 203 cardiomyopathy-related genes were performed. Patients were stratified based on the presence or absence of pathogenic variants, with a particular focus on those in sarcomere genes. LVRR was defined as either an improvement of left ventricular ejection fraction (LVEF) to ≥50% or an absolute increase in LVEF by ≥10% at 1 year. Statistical analyses included non-parametric tests for paired data and Kaplan–Meier survival analysis. Results Pathogenic variants were identified in 35% (45/123) of the cohort, with the most common being MYH7 (14%), RYR2 (12%), and TPM1 (8%). LVRR was achieved in 47.5% of all patients. Notably, patients harboring sarcomere gene variants showed no significant improvement in LVEF (from 31.4% to 39.8%, P = 0.1913), whereas those with non-sarcomere variants and variant-negative patients exhibited significant LVEF increases (33.6% to 54.1%, P = 0.0522; and 33.6% to 54.1%, P < 0.0001, respectively). Serial echocardiographic assessments revealed that reductions in left ventricular dimensions were less pronounced among patients with sarcomere gene variants. Although there was no statistically significant difference in the incidence of major adverse cardiac events (MACE) between the groups, a trend toward reduced reverse remodeling in the sarcomere variant group was observed. Conclusion In this large Japanese pediatric DCM cohort, sarcomere gene variants were detected in 35% of patients but did not improve cardiac reverse remodeling, as evidenced by a lack of significant LVEF improvement. In contrast, patients without these variants experienced notable functional recovery. These findings suggest that the presence of sarcomere gene variants may predict a less favorable response to conventional heart failure therapies, highlighting the need for individualized, genotype-guided management strategies in pediatric DCM.