Role of the Epicardium in the Development of the Atrioventricular Valves and Its Relevance to the Pathogenesis of Myxomatous Valve Disease.

Renélyn Wolters,Jenna Drummond,Maurice J B Van Den Hoff,Emilye Hiriart,Marie M Lockhart,Russell A Norris,Andy Wessels,Andrew B Harvey,Ray Deepe

doi:10.3390/jcdd8050054

Abstract

This paper is dedicated to the memory of Dr. Adriana “Adri” Gittenberger-de Groot and in appreciation of her work in the field of developmental cardiovascular biology and the legacy that she has left behind. During her impressive career, Dr. Gittenberger-de Groot studied many aspects of heart development, including aspects of cardiac valve formation and disease and the role of the epicardium in the formation of the heart. In this contribution, we review some of the work on the role of epicardially-derived cells (EPDCs) in the development of the atrioventricular valves and their potential involvement in the pathogenesis of myxomatous valve disease (MVD). We provide an overview of critical events in the development of the atrioventricular junction, discuss the role of the epicardium in these events, and illustrate how interfering with molecular mechanisms that are involved in the epicardial-dependent formation of the atrioventricular junction leads to a number of abnormalities. These abnormalities include defects of the AV valves that resemble those observed in humans that suffer from MVD. The studies demonstrate the importance of the epicardium for the proper formation and maturation of the AV valves and show that the possibility of epicardial-associated developmental defects should be taken into consideration when determining the genetic origin and pathogenesis of MVD.

Highlights

Myxomatous degeneration involving the leaflets of the left atrioventricular valve leads to myxomatous valve disease (MVD), a common cause of Mitral Valve Prolapse (MVP)
In 1998, she was the lead author on a paper titled “Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions” [10], a publication that, together with a few other articles that appeared around the same time [42,43,45], revolutionized our insight into the role of the epicardium in heart development
These studies truly formed the foundation for all the subsequent studies in which the contribution of epicardially-derived cells (EPDCs) to the developing mouse heart has been studied and the studies in which the molecular regulation of epicardial development is investigated

Summary

Introduction

Myxomatous degeneration involving the leaflets of the left atrioventricular valve (mitral valve) leads to myxomatous valve disease (MVD), a common cause of Mitral Valve Prolapse (MVP). Insight into the genetic etiology of familial non-syndromic MVP has been obtained from studying pedigrees of families in which multiple individuals have MVD. This approach has far led to the identification of a small number of causal genes, including FILAMIN-A (FLNA) [1,2,4] and Dachsous (DCHS1) [3]. It is interesting to note that most of the experimental in vitro studies conducted to unravel the mechanism controlling endMT of the AV cushions have historically been performed using AV explants at stages in which the major AV cushions are developing, but before the onset of development of the lateral AV cushions. Not much is known regarding the mechanisms that control endMT in this structure [31]

Contribution of the AV Cushions to the AV Valves

Consequence of Reduced Presence of AV-EPDCs in the Valve Leaflets—A Link to

Findings

10. Discussion and Reflection