Abstract Body (Do not enter title and authors here):
Background: Endocardial fibroelastosis (EFE) is marked by a thickened fibro-elastic layer derived by endothelial-to-mesenchymal transition (EndMT), leading to restrictive myocardial function and poor cardiac growth, complicating biventricular repair in hypoplastic left heart complex (HLHC) patients. Neuregulin (NRG) signaling, crucial in EndMT and myocardial development, is implicated in various cardiomyopathies and heart failure, and its dysregulation may drive EFE pathogenesis.
Hypothesis: NRG signaling dysregulation influences the cellular and molecular mechanisms of EFE.
Methods: Single nucleus RNA sequencing (snRNA-seq) was conducted on human left ventricular (LV) tissue resected from 7 EFE patients (0.4-15 years) and 4 non-congenital heart disease (CHD) postmortem human controls (0.02-16 years). Differential gene expression was analyzed using the Wilcoxon Rank Sum test. We used CellChat, a computational tool for analyzing intercellular communication networks, to identify signaling changes via quantitative contrasts and joint manifold learning.
Results: We identified 11 cell types in 64,963 nuclei. In EFE samples compared to non-CHD samples, NRG1-expressing fibroblasts increased from 3.4% to 21.2% (P<0.0001), and NRG2-expressing cardiomyocytes from 11.9% to 45.9% (P<0.001). CellChat analysis revealed a denser NRG signaling network in EFE, with enhanced interactions among cardiomyocytes, endocardial cells, fibroblasts, mast cells, and smooth muscle cells (Fig. 1A-B). Cardiomyocytes emerged as significant senders of NRG signaling in EFE, while endocardial cells, though still key senders, showed reduced influence. Fibroblasts became strong mediators, receivers, and influencers, smooth muscle cells emerged as prominent receivers, and mast cells gained roles as mediators and influencers (Fig. 1 C-D). These changes indicate a complex NRG signaling network in EFE, highlighting altered cellular interactions driving disease progression.
Conclusion: Dysregulated NRG signaling in EFE contributes to pathological cellular crosstalk, fibrosis, and myocardial dysfunction, potentially hindering successful biventricular repair in HLHC patients. Targeting NRG pathways could represent a novel therapeutic approach. These findings offer promising implications for affected patients, potentially improving outcomes. Future research should explore additional molecular pathways involved in EFE and assess the therapeutic efficacy of targeting NRG signaling.