Proinflammatory Matrix Metalloproteinase-1 Associates With Mitral Valve Leaflet Disruption Following Percutaneous Mitral Valvuloplasty.

Robert A Levine,Masanori Aikawa,Elena Aikawa,William A M Esteves,Thanh-Dat Le,Cláudio L Gelape,Jacob P Dal-Bianco,Dakota Becker-Greene,Luís Felipe R De Almeida,Luiz G Passaglia,Walderez O Dutra,Livia S A Passos,Divino Pedro A Rocha,Renato Braulio,Maria Carmo P Nunes,Judy Hung,Carlos Augusto P Gomes

doi:10.3389/fcvm.2021.804111

Abstract

Mitral regurgitation (MR) is a major complication of the percutaneous mitral valvuloplasty (PMV). Despite high technical expertise and cumulative experience with the procedure, the incidence rate of severe MR has not decreased. Although some of MR can be anticipated by echocardiographic analysis; leaflet tearing, which leads to the most dreaded type of MR, remains unpredictable. Irregular valvular collagen remodeling is likely to compromise tissue architecture and increase the tearing risk during PMV balloon inflation. In this study, we evaluated histological and molecular characteristics of excised mitral valves from patients with rheumatic mitral stenosis (MS) who underwent emergency surgery after PMV due to severe MR caused by leaflet tear. Those findings were compared with patients who underwent elective mitral valve replacement surgery owing to severe MS, in whom PMV was not indicated. In vitro assay using peripheral blood mononuclear cells was performed to better understand the impact of the cellular and molecular alterations identified in leaflet tear mitral valve specimens. Our analysis showed that focal infiltration of inflammatory cells contributes to accumulation of MMP-1 and IFN-γ in valve leaflets. Moreover, we showed that IFN-γ increase the expression of MMP-1 in CD14+ cells (monocytes) in vitro. Thus, inflammatory cells contribute to unevenly remodel collagen resulting in variable thickening causing abnormalities in leaflet architecture making them more susceptible to laceration.

Highlights

Significant mitral regurgitation (MR) can be a major complication when treating rheumatic mitral stenosis (MS) with percutaneous mitral valvuloplasty (PMV) [1]
Our study reports on histopathological, cellular, and molecular changes that potentially contribute to mitral valve (MV) tearing during PMV
We provide insights into a synergistic mechanism between MMP-1 and IFN-γ generating an active inflammatory leaflet tissue response contributing to the localized degradation of collagen predisposing to leaflet tear (Figure 6)

Summary

Introduction

Significant mitral regurgitation (MR) can be a major complication when treating rheumatic mitral stenosis (MS) with percutaneous mitral valvuloplasty (PMV) [1]. Over the last several decades, the incidence of severe MR owing to leaflet rupture remains unchanged and up to 2% of patients may require urgent mitral valve (MV) replacement [1, 6]. As patients with rheumatic MS are usually young, mechanical prostheses are favored over tissue prostheses as they only have limited durability requiring repeated surgeries. It is essential to determine the underlying mechanisms that are potentially responsible for valve/leaflet integrity disruption after PMV. In this context, comprehensive histological evaluation of the excised MVs from patients who developed post-PMV severe MR due to leaflet tearing may provide novel insights into such mechanisms

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