Role of NPPB for recovery post ventricular assist device in paediatric dilated cardiomyopathy: Single-cell multiomics

Paediatric heart transplantation requires lifelong immunosuppression, highlighting the need for recovery-oriented strategies. A subset of children with dilated cardiomyopathy (DCM) recovers left ventricular (LV) function after LV assist device (LVAD) implantation, allowing for device explantation. We aimed to identify factors associated with LV functional recovery using single-nucleus multiomics analysis of LV tissue collected at LVAD implantation.

We included children with idiopathic DCM who underwent LVAD implantation between 2013 and 2023. Patients who achieved device explantation and medical stabilization were classified as the recovery group while those who required transplantation or died were classified as the non-recovery group. Single-nucleus RNA and ATAC sequencing were performed in six representative cases. Differential gene expression, chromatin accessibility and gene ontology (GO) enrichment analyses were conducted. Candidate markers were validated histologically and serologically in the full cohort.

Twenty-five cases were included (non-recovery, n = 15; recovery, n = 10). Age at LVAD implantation [median (range)] was 0.9 (0.1-4.6) versus 0.8 (0.3-5.6) years (P = 0.8), sex 27% versus 30% male (P > 0.9) and body weight 5.9 (3.8-14.0) versus 7.5 (5.0-26.0) kg (P = 0.049). LV ejection fraction at implantation was similar (24 (10-44) % vs. 15 (10-25) %, P = 0.2). RNA sequencing showed elevated NPPB, MYL7 and PCDH9 in recovery-group cardiomyocytes, with NPPB highest expression [baseMean = 16 305; log₂Fold Change (FC) = 2.698; P < 0.001] and an accessible chromatin peak at its locus (log₂FC = 1.17; P < 0.01). GO analysis indicated enrichment in apoptosis-related pathways (coefficient = 1.77, P = 0.023). Serum brain natriuretic peptide (BNP), the protein product of NPPB, was significantly higher in the recovery group at implantation [732 (372-4179) vs. 3048 (642-6032) pg/mL, P = 0.04] as was the proportion of non-apoptotic cardiomyocytes [0.21 (0.02-0.37) vs. 0.37 (0.19-0.48), P = 0.03].

Elevated NPPB expression and BNP levels at LVAD implantation are associated with LV recovery in paediatric DCM. These findings support an anti-apoptotic role of BNP in successful bridge-to-recovery outcomes.