Endothelial-to-Mesenchymal Transition as Underlying Mechanism for the Formation of Double-Chambered Right Ventricle

Viktoria Weixler,Peter Murin,Ingeborg Friehs,Mi-Young Cho,Joachim Photiadis,Peter Kramer,Pedro Del Nido,Judith Lindner

doi:10.1007/s00246-022-02828-w

Abstract

Double-chambered right ventricle (DCRV) is a progressive division of the right ventricular outflow tract (RVOT) often associated with a subaortic ventricular defect (VSD). The septation is caused by a mixture of hypertrophied muscle bundles and fibrous tissue, whereof the latter is of unclear pathogenesis. Our group has previously reported that flow disturbances lead to formation of fibroelastic tissue through a process called endothelial-to-mesenchymal transition (EndMT) but it is unclear whether the same mechanism exists in the RV. Tissue from patients undergoing repair of DCRV was examined to identify the histomorphological substrate of this tissue. Demographic and pre-/post-operative echocardiographic data were collected from nine patients undergoing surgery for DCRV. RVOTO tissue samples were histologically analyzed for myocardial hypertrophy, fibrosis, elastin content, and active EndMT (immunohistochemical double-staining for endothelial and mesenchymal markers and transcription factors Slug/Snail) and compared to four healthy controls. Indication for surgery were symptoms and progressive RVOT gradients. A highly turbulent flow jet through the RVOTO and VSD was observed in all patients with a preoperative median RVOT peak gradient of 77 mmHg (IQR 55.0–91.5), improved to 6 mmHg (IQR 4.5–17) postoperatively. Histological analysis revealed muscle and thick infiltratively growing fibroelastic tissue. EndMT was confirmed as underlying patho-mechanism of this fibroelastic tissue but the degree of myocardial hypertrophy was not different compared to controls (P = 0.08). This study shows for the first time that an invasive fibroelastic remodeling processes of the endocardium into the underlying myocardium through activation of EndMT contributes to the septation of the RVOT.

Highlights

Double-chambered right ventricle (DCRV) is a rare congenital heart condition, found in less than 3% of all congenital heart defects and is detected in 1:36,000 autopsies [1]
Active endothelial-to-mesenchymal transition (EndMT) was determined by immunohistochemical identification of endothelial cells double-stained with an endothelial marker, cluster of differentiation 31 (CD31; 1:100; Dako/Agilent, Santa Clara, CA, USA), and a mesenchymal marker, α-smooth muscle actin (α-SMA; 1:100; Abcam, Cambridge, MA, USA), which is indicative of active EndMT as we have described in more detail previously [8]
Diagnosis of DCRV was predominantly established in the neonatal period or shortly thereafter (90%) and only in one patient it was diagnosed at the age of fourteen

Summary

Introduction

Double-chambered right ventricle (DCRV) is a rare congenital heart condition, found in less than 3% of all congenital heart defects and is detected in 1:36,000 autopsies [1]. First described in 1858 by Peacock as a mid-cavitary right ventricular outflow tract obstruction (RVOTO), it is defined as a progressive division of the right ventricle (RV) into two chambers, a high-pressure inlet- and a low-pressure outlet chamber [1,2,3]. Case reports describing the formation of DCRV in adult unoperated patients suggest an important contribution of hypertrophied anomalous muscle bundles becoming obstructive over time which suggests an acquired obstruction with an underlying congenital substrate [2, 4]. Increasing intraventricular gradients measured over time in unoperated patients with DCRV support this hypothesis. Formation of two chambers within the RV, and the presence of a gradient across the RV cavity is indicative of DCRV

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Conclusion