Comparative pathology of human and canine myxomatous mitral valve degeneration: 5HT and TGF-β mechanisms

Abstract

Myxomatous mitral valve degeneration (MMVD) is a leading cause of valve repair or replacement secondary to the production of mitral regurgitation, cardiac enlargement, systolic dysfunction, and heart failure. The pathophysiology of myxomatous mitral valve degeneration is complex and incompletely understood, but key features include activation and transformation of mitral valve (MV) valvular interstitial cells (VICs) into an active phenotype leading to remodeling of the extracellular matrix and compromise of the structural components of the mitral valve leaflets. Uncovering the mechanisms behind these events offers the potential for therapies to prevent, delay, or reverse myxomatous mitral valve degeneration. One such mechanism involves the neurotransmitter serotonin (5HT), which has been linked to development of valvulopathy in a variety of settings, including valvulopathy induced by serotonergic drugs, Serotonin-producing carcinoid tumors, and development of valvulopathy in laboratory animals exposed to high levels of serotonin. Similar to humans, the domestic dog also experiences naturally occurring myxomatous mitral valve degeneration, and in some breeds of dogs, the lifetime prevalence of myxomatous mitral valve degeneration reaches 100%. In dogs, myxomatous mitral valve degeneration has been associated with high serum serotonin, increased expression of serotonin-receptors, autocrine production of serotonin within the mitral valve leaflets, and downregulation of serotonin clearance mechanisms. One pathway closely associated with serotonin involves transforming growth factor beta (TGF-β) and the two pathways share a common ability to activate mitral valve valvular interstitial cells in both humans and dogs. Understanding the role of serotonin and transforming growth factor beta in myxomatous mitral valve degeneration gives rise to potential therapies, such as 5HT receptor (5HT-R) antagonists. The main purposes of this review are to highlight the commonalities between myxomatous mitral valve degeneration in humans and dogs, with specific regards to serotonin and transforming growth factor beta, and to champion the dog as a relevant and particularly valuable model of human disease that can accelerate development of novel therapies.

Keywords: Mitral valve disease; Mitral valve repair; Mitral valve replacement; Myxomatous mitral valve degeneration; Serotonin.

Figure 1.

Normal mitral valve structure (A) and mechanism of myxomatous mitral valve disease (MMVD) (B). The normal valve is made up of a layer of endothelial cells surrounding the atrialis layer, which is made up of elastic and collagen fibers, the spongiosa layer, which consists of extracellular matrix (ECM) rich in proteoglycans and the occasional valvular interstitial cell, and the fibrosa, which consists of tightly packed collagen fibers. In valves affected by MMVD, the interstitial cells are activated into a myofibroblast-like phenotype, which is accompanied by excessive deposition of ECM, dissolution and fragmentation of the elastic and collagen fibers of the atrialis and fibrosa, endothelial to mesenchymal cell transformation and migration of endothelial cells into the spongiosa, and denudation of the endothelial cell lining and exposure of the subendothelial collagen.

Figure 2.

Proposed mechanism of serotonin (5HT) and transforming growth factor beta (TGF-β) in myxomatous mitral valve disease (MMVD).

Figure 3.

Isolated canine mitral valve valvular interstitial cells (VICs) treated with serotonin (5HT) and vehicle or 5HT and the specific 5HT-receptor subtype 2B antagonist LV272015 (LY) reveals LY reduced phosphorylation of ERK1/2, which is a marker of VIC activation. Adapted from Driesbaugh et al [59].

Figure 4.

Blockade of mitral valve changes by antagonism of the serotonin 2B receptor (5HT-2BR) in a mouse model of myxomatous mitral valve disease (MMVD) created by angiotensin II (AngII). Representative H&E (A) and modified Movat pentachrome (B) staining of cross sections of the mitral valve from mice treated for 28 days with saline or AngII with or without treatment with the 5HT-R_2B antagonist LY272015 (LY). Quantitative analysis of average valve leaflet area for each treatment group indicated a reduction of valve area in AngII mice treated with LY as compared to positive control (C). Representative H&E staining of mitral valve from mice exposed to nordexfenfluramine for 28 days showing myxomatous leaflet nodules (D) and prevention of valve lesions in 5HT-R_2B KO mice (D). (A-C) from Driesbaugh et al [59]; (D-E) from Ayme-Dietrich et al [121].