Introduction:
Endocardial Fibroelastosis (EFE) is a condition defined by the formation of fibrotic tissue on the endocardium, stunting cardiac development. The presence of EFE restricts diastolic compliance, leading to systolic and diastolic heart failure, and contributing to higher morbidity and mortality, particularly in Hypoplastic Left Heart Syndrome. While research suggests that EFE forms through aberrant endothelial-to-mesenchymal transition (EndoMT), the trigger of its formation is still speculative. Anecdotally, however, we have observed EFE development in patients with abnormal left ventricular flow.
Objective:
Our objective is to study whether the absence of normal flow induces EndoMT in neonatal endocardium and promotes EFE development, and whether losartan treatment, which can decrease TGFβ production to impair EndoMT, can abrogate EFE formation.
Methods and Results:
Using a rodent model of EFE, we establish three flow conditions in neonatal hearts: Normal Flow (NF), Static/no flow (S), and Regurgitant Flow (RF). Histologic analysis demonstrates EFE development in S and RF conditions, but not in NF conditions. Using qPCR, Western Blot Assay, and immunohistochemistry, we demonstrate that S and RF significantly increase mRNA and protein expression of EndoMT markers (αSMA, SNAIL), and EndoMT-related signaling pathways (TGFβ, NOTCH1) whereas NF conditions do not. With losartan treatment, we observe a significant decrease in EFE in neonatal hearts documented by histology and decreased mRNA and protein expression of EndoMT markers. To determine whether our findings are translatable to humans, human endocardial endothelial cells were isolated from left ventricular tissue and subjected to two flow conditions: static and laminar shear stress (LSS). By RNAseq analysis, we demonstrate that laminar shear stress suppresses the expression of genes critical for mesenchymal differentiation and Notch signaling, which are both associated with EndoMT progression.
Conclusions:
Our data demonstrates that the absence of normal flow provides an environment that promotes EFE development through activated EndoMT. Further, we identify losartan as a potential therapy for EFE, as it is able to abrogate EFE development in our animal model.
Abnormal Flow Conditions Promote Endocardial Fibroelastosis Via Endothelial-to-Mesenchymal Transition, Which Is Responsive to Losartan Treatment
