Response of Endocardial Fibroelastosis-Derived Cells to Flow Alterations and Statins: Hypoplastic Left Ventricle versus Normal Size Left Ventricle

Background: Endocardial fibroelastosis (EFE) is primarily associated with hypoplastic left heart syndrome but also with congenital heart defects with normal sized ventricles, the former having worse outcome. As we have recently shown, the communality of these congenital diseases irrespective of ventricular size is flow disturbances. Moreover, we have identified endothelial-to-mesenchymal transition (EndMT) as the underlying mechanism for EFE development. EndMT is attributed to atherosclerosis in the vascular system as a consequence of flow disturbances, and has been shown to be amenable to treatment with atorvastatin via KLF2 (i.e., EndMT inhibition). We sought to determine whether physiological flow and atorvastatin protected healthy endocardial endothelial cells (EECs) and EFE-derived EECs from EndMT.

Method: EFE-derived EECs and healthy EECs were exposed to either flow stagnation (0 dyn/cm²) or physiological flow (10 dyn/cm²) with and without atorvastatin (0.5 μmol) for 72 hours, using a flow pump system (ibidi). EndMT was evaluated through qRT-PCR (endothelial, mesenchymal markers, Snai2) and induction of regulatory pathways through KLF2 (upregulation indicative of endothelial cell protection) and SMAD2 (upregulation indicative of EndMT).

Results: Physiological flow protected healthy EECs (n = 5) from EndMT (mean ± SEM, *p < 0.05) with an added benefit of atorvastatin (mean ± SEM, #p < 0.05) through KLF2 upregulation. In contrast, EFE-derived cells responded to physiological flow with KLF2 induction, but without inhibition of EndMT or collagen production. Atorvastatin under flow was protective against EndMT only in normal sized ventricles (n = 8) but not in small sized ventricles (n = 4).

Conclusion: We conclude that EFE-derived EECs have an altered response to flow compared to healthy EECs. Furthermore, EECs from small sized ventricles are more severely affected by flow alterations, and only EECs from normal sized ventricles are responsive to treatment with atorvastatin. Overall, this study identified atorvastatin as a potential medication against EndMT-mediated EFE formation in patients with normal sized ventricles and points toward an underlying predisposition to EndMT in patients with small ventricles which requires further investigation.

Publikationsverlauf

Artikel online veröffentlicht:
28. Januar 2023