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

Background: Double-chambered right ventricle (DCRV) is a progressive division of the right ventricular outflow tract (RVOT), however the exact genesis of this pathological septation is still unknown. Our group has previously reported that flow disturbances within the left ventricle lead to formation of fibroelastic tissue through endothelial-to-mesenchymal transition (EndMT) but it is unclear whether the same mechanism exists in the RV.

Method: Tissue from nine patients undergoing DCRV repair was examined to identify the histomorphological substrate. Demographic and pre-/postoperative echocardiographic data were collected. RVOTO samples were analyzed for myocardial hypertrophy, fibrosis and elastin content, and active EndMT (immunohistochemical double-staining for endothelial and mesenchymal markers CD31/α-SMA and transcription factors Slug/Snail) and compared with non-RVOTO control samples using t-test. p-Value ≤ 0.05 was considered statistically significant.

Results: Median age was 0.8 years (IQR: 0.5–5.2). Indication for surgery was symptoms and progressive RVOTO. A highly turbulent flow jet through the RVOTO and the subaortic ventricular defect (VSD) was observed in all patients with a preoperative median RVOT peak gradient of 77 mm Hg (IQR: 55.0–91.5) which improved to 6 mm Hg (IQR: 4.5–17) postoperatively. Histological analysis revealed muscle and thick infiltratively growing fibroelastic tissue. EndMT was confirmed as underlying pathomechanism; however, the degree of myocardial hypertrophy was not different compared with controls (p = 0.08).

Conclusion: This study shows for the first time that an invasive fibroelastic remodeling of the endocardium through activation of EndMT most likely caused by flow disturbances contributes to the septation of the RVOT.

Publication History

Article published online:
03 February 2022