Abnormal Flow Conditions Promote Endocardial Fibroelastosis Via Endothelial-to-Mesenchymal Transition, Which Is Responsive to Losartan Treatment

Nicholas A Oh; Xuechong Hong; Ilias P Doulamis; Elamaran Meibalan; Teresa Peiseler; Juan Melero-Martin; Guillermo García-Cardeña; Pedro J Del Nido; Ingeborg Friehs

doi:10.1016/j.jacbts.2021.10.002

Abnormal Flow Conditions Promote Endocardial Fibroelastosis Via Endothelial-to-Mesenchymal Transition, Which Is Responsive to Losartan Treatment

JACC Basic Transl Sci. 2021 Dec 27;6(12):984-999. doi: 10.1016/j.jacbts.2021.10.002. eCollection 2021 Dec.

Authors

Nicholas A Oh^{1

2}, Xuechong Hong¹, Ilias P Doulamis¹, Elamaran Meibalan³, Teresa Peiseler¹, Juan Melero-Martin¹, Guillermo García-Cardeña³, Pedro J Del Nido¹, Ingeborg Friehs¹

Affiliations

¹ Department of Cardiac Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
² Department of Cardiothoracic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
³ Laboratory for Systems Mechanobiology, Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Abstract

Endocardial fibroelastosis (EFE) is defined by fibrotic tissue on the endocardium and forms partly through aberrant endothelial-to-mesenchymal transition. However, the pathologic triggers are still unknown. In this study, we showed that abnormal flow induces EFE partly through endothelial-to-mesenchymal transition in a rodent model, and that losartan can abrogate EFE development. Furthermore, we translated our findings to human endocardial endothelial cells, and showed that laminar flow promotes the suppression of genes associated with mesenchymal differentiation. These findings emphasize the role of flow in promoting EFE in endocardial endothelial cells and provide a novel potential therapy to treat this highly morbid condition.

Keywords: AR, aortic regurgitation; EFE, endocardial fibroelastosis; EndoMT, endothelial-to-mesenchymal transition; GO, gene ontology; HLHS, hypoplastic left heart syndrome; HUEEC, human endocardial endothelial cells; HUVEC, human umbilical vein endothelial cells; LSS, laminar shear stress; LV, left ventricle; congenital heart disease; endocardial endothelial cells; endocardial fibroelastosis; endothelial-to-mesenchymal transition; wall shear stress; α-SMA, alpha-smooth muscle actin.