Myxomatous leaflet biological aberrations and potential therapeutic targets.

Abstract

Sporadic mitral valve prolapse (MVP) is one of the most common acquired cardiac valvular abnormalities in industrialized nations. It is a leading cause of isolated mitral regurgitation and is associated with various complications such as infectious endocarditis, heart failure, atrial fibrillation, stroke and death. Myxomatous degeneration involves the spongiosa of the mitral valve leaflets and is sine qua non for MVP. The primary etiology is unknown although its associated histological changes are well characterized. No specific therapy is available to slow or prevent its progression and surgery is reserved to treat its end-stage form or its complications. MVP can be classified into sporadic, familial or syndromic types. In both familial and syndromic MVP, there is evidence that dysregulation of the transforming growth factor beta (TGF-β) signaling pathway plays a role in its pathogenesis. Marfan syndrome is caused by mutation of FBN1, which codes for fibrillin-1, a principal component of extracellular matrix (ECM) microfibrils that targets latent TGF-β complexes. This results in altered matrix sequestration and dysregulation of TGF-β signaling. Although a less established phenotypic feature of Marfan syndrome, a large proportion of patients have MVP to varying degrees and FBN1 mutant mice develop MVP that can be rescued with TGF-β neutralization (1). Familial patterns of non-syndromic MVP have been recognized but with very variable penetrance even within the same family. Autosomal dominant forms have been identified on chromosomes 16, 11 and 13 and X-linked myxomatous valvular dystrophy characterized by multi-valve myxomatous degeneration is associated with mutations of filamin A, an ubiquitous phosphoprotein involved in the regulation of various cell signaling molecules. These include SMAD2, which is a primary mediator of TGF-β signaling (2). Importantly, excessive TGF-β activity can be modulated with angiotensin receptor blockers (ARBs), mediated through its idiosyncratic anti-TGF-β effects, as demonstrated by prevention of aneurysm progression in Marfan patients treated with ARBs (3). We studied the pathogenesis of sporadic MVP in patients undergoing mitral valve surgery and proposed a hypothesis that TGF-β activity is excessive in this most common form of MVP and that the pathological changes observed can be inhibited by ARB treatment in vitro (4).