Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development - Institut Pasteur Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2022

Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development

L Houyel
Sm Meilhac

Résumé

Abstract Aims In this work we investigated the embryonic origin of coronary arterio-ventricular connections, known as coronary artery fistulas (CAF), a congenital heart disease associated to postnatal and adult changes in systemic hemodynamics that may cause cardiac ischemia. Methods and results we have used different animal models (mouse and avian embryos) to experimentally model CAF morphogenesis. Conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick and quail embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Additional transcriptomics and in vitro analyses were performed to better understand how arterio-ventricular connections are originated in the embryonic heart. Our results show myocardial discontinuities in the developing heart of mutant mice presenting epicardial defects and avian embryos submitted to a physical cryodamage of the ventricle. These ventricular discontinuities promote the formation of endocardial pouch-like structures resembling human CAF. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF, showing histomorphological and immunochemical similarities. Both human and mutant mouse hearts showed similar anomalies in the compaction of the ventricular myocardium. In vitro experiments showed the abnormal contact between the epicardium and the endocardium promote the precocious differentiation of epicardial cells to smooth muscle. Conclusion Our work suggests that myocardial discontinuities in the embryonic ventricular wall are a causative of CAF. These discontinuities would promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. Translational perspective Congenital coronary artery fistulas (CAFs) lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation and failure. Unfortunately, and despite their clinical relevance, the origins these congenital anomalies remain unknown. In this work, we provide information on the developmental mechanisms involved in the formation of CAFs that is relevant for their early diagnosis and prevention.

Domaines

Morphogenèse

Dates et versions

pasteur-03851134 , version 1 (14-11-2022)

Identifiants

Citer

Paul Palmquist-Gomes, A Ruiz-Villalba, J.A. Guadix, J.P. Romero, B Bessiéres, et al.. Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development. 2022. ⟨pasteur-03851134⟩
7 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More