PO56 Presence of cardiomyopathy-associated genetic variants reduces the likelihood of weaning from ventricular assist devices in children with severe heart failure

Background In children with severe heart failure, ventricular assist devices (VADs) serve as a bridge to transplantation or, ideally, to myocardial recovery, allowing VAD explantation and avoidance of life-long transplant-related morbidity. Paediatric recovery rates reach around 8.7%, independent of aetiology and markedly higher than in adults, with myocarditis-caused heart failure showing the strongest recovery potential. Recent genetic studies have identified likely pathogenic or pathogenic (LP/P) variants in cardiomyopathy (CMP)-associated genes in up to 44.5% of children with complicated acute myocarditis, underscoring the concept of overlapping disease entities. Purpose This study aimed to investigate the impact of CMP-associated genetic variants on the likelihood of myocardial recovery and successful VAD weaning in children with severe heart failure. Methods We retrospectively analysed 57 paediatric patients with biopsy-confirmed myocarditis requiring VAD support, enrolled in the multicentre MYKKE registry. Outcomes were classified as recovery vs non-recovery. Genetic testing included whole-exome sequencing (WES, n=49), cardiovascular panel sequencing (n=6), or whole-genome sequencing (WGS, n=2). LP/P variants were classified according to ACMG guidelines and ClinGen recommendations. Gene-based burden and rare variant enrichment analyses were performed. Results Median age at symptom onset was 1.3 years, and 31 patients (54%) were male. Thirty-three patients (58%) were bridged to transplant, whereas 24 patients (42%) recovered and were successfully weaned from VAD after a median time of 96 days (IQR 65; 157). Rare deleterious variants in 97 CMP genes were significantly enriched in the study cohort compared to healthy controls (p<0.001). Twelve patients (21%) carried LP/P variants. Of the identified LP/P variants, seven (64%) were found in sarcomere-related genes, including TNNI3, TTN, MYH7 and TNNT2, whereas five (36%) were found in the non-sarcomere CMP-associated genes FLNC, BAG3 and LMNA. Age and sex did not differ between patients with LP/P variants and those without. LP/P variants were more frequent in the non-recovery group (10/33; 30%) than in the recovery group (2/24; 8%) (p=0.045). Interestingly, both recovery cases carrying LP/P variants had TTN truncating variants (TTN-tv). Gene burden analysis showed significant enrichment of TNNI3 variants in the non-recovery cohort, whereas TTN-tv was enriched in patients who recovered. Conclusions In this cohort of paediatric myocarditis patients with severe heart failure requiring VAD support, CMP-associated genetic variants were significantly enriched, highlighting the disease overlap of cardiomyopathies and myocarditis. Myocardial recovery was strongly associated with the absence of CMP-associated variants. Integrating genetic data into the diagnostic workflow of patients with severe heart failure may improve prediction of recovery potential and guide personalized treatment strategies.