Rationale Endocardial fibroelastosis (EFE) is a unique form of fibrosis which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through establishment of staged biventricular repair surgery in HLHS infant patients, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce and specific therapeutic targets are not yet known. Objective Here we aimed to investigate the cellular origins of EFE tissue and to gain insights into underlying molecular mechanisms to ultimately develop novel therapeutic strategies. Methods and Results By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial mesenchymal transition (EndMT). We further demonstrate that such aberrant EndMT involving endocardial endothelial cells is caused by dysregulated TGFβ/BMP signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of BMP5 and BMP7. Finally, we provide evidence that supplementation of exogenous recombinant BMP7 effectively ameliorates EndMT and experimental EFE in rats. Conclusions In summary our data point to aberrant EndMT as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to BMP7 as an effective treatment for EFE and its restriction of heart growth.

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