Genetics and pathophysiology of mitral valve prolapse

Abstract

Mitral valve prolapse (MVP) is a common condition affecting 2–3% of the general population, and the most complex form of valve pathology, with a complication rate up to 10–15% per year in advanced stages. Complications include mitral regurgitation which can lead to heart failure and atrial fibrillation, but also life-threatening ventricular arrhythmia and cardiovascular death. Sudden death has been recently brought to the forefront of MVP disease, increasing the complexity of management and suggesting that MVP condition is not properly understood. MVP can occur as part of syndromic conditions such as Marfan syndrome, but the most common form is non-syndromic, isolated or familial. Although a specific X-linked form of MVP was initially identified, autosomal dominant inheritance appears to be the primary mode of transmission. MVP can be stratified into myxomatous degeneration (Barlow), fibroelastic deficiency, and Filamin A-related MVP. While FED is still considered a degenerative disease associated with aging, myxomatous MVP and FlnA-MVP are recognized as familial pathologies. Deciphering genetic defects associated to MVP is still a work in progress; although FLNA, DCHS1, and DZIP1 have been identified as causative genes in myxomatous forms of MVP thanks to familial approaches, they explain only a small proportion of MVP. In addition, genome-wide association studies have revealed the important role of common variants in the development of MVP, in agreement with the high prevalence of this condition in the population. Furthermore, a potential genetic link between MVP and ventricular arrhythmia or a specific type of cardiomyopathy is considered. Animal models that allow to advance in the genetic and pathophysiological knowledge of MVP, and in particular those that can be easily manipulated to express a genetic defect identified in humans are detailed. Corroborated by genetic data and animal models, the main pathophysiological pathways of MVP are briefly addressed. Finally, genetic counseling is considered in the context of MVP.

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium

“…In MAC participants with HTAD, we found that the prevalence of MVP was five times higher than in the general population and was frequently accompanied by MAD [23, 24]. Our data is consistent with other studies showing that PV in TGF-β pathway genes, primarily TGFBR1 (22%, 11/50), TGFBR2 (20%, 17/83), TGFB3 (25%, 5/20), and SMAD3 (20%, 16/80, are most strongly associated with these mitral phenotypes [4,25,26,31]. The overall rates of MVP and MAD were 7-8 times higher in MAC participants with PV in TGF-β pathway genes than in the rest of the MAC cohort.…”

Spatial Dynamics of the Developing Human Heart

“…Cardiac valves are often affected in congenital and acquired heart diseases, however, the cellular culprits in these pathologies are often unclear. Thus, we explored the expression pattern of genes implicated in syndromic and non-syndromic forms of two major cardiac valve anomalies, bicuspid aortic valve disease (BAV) and mitral valve prolapse (MVP) [69][70][71] , across the valvular cell states (Fig. 7e).…”

Integrated Pathogenesis of Vascular and Cardiac Valve Disease

“…Although there is limited data, the identified hereditary variants of nonsyndromic mitral regurgitation (MR) have not implicated PROX1 or FOXC2. 21 It is important to highlight that aortic valve pathology is entirely different, and patients rarely present with simultaneous and severe defects of both valves.…”