Myocardial Infarction Alters Adaptation of the Tethered Mitral Valve

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• 作者：Jacob P. Dal-Bianco ; MD^&lowast ; ; ^&Dagger ; ; Elena Aikawa ; MD ; PhD^&Dagger ; ; ^§ ; ; Joyce Bischoff ; PhD^&Dagger ; ; ^‖ ; ^¶ ; ; J. Luis Guerrero ; BS^&dagger ; ; Jesper Hjortnaes ; MD^§ ; ; Jonathan Beaudoin ; MD^&lowast ; ; ^&Dagger ; ; Catherine Szymanski ; MD^&lowast ; ; ^&Dagger ; ; Philipp E. Bartko ; MD ; PhD^&lowast ; ; Margo M. Seybolt ; BS^&dagger ; ; Mark D. Handschumacher ; BS^&lowast ; ; Suzanne Sullivan ; BS^&dagger ; ; Michael L. Garcia ; MA^&dagger ; ; Adam Mauskapf ; BA^&dagger ; ; James S. Titus ; BS^&dagger ; ; Jill Wylie-Sears ; MS^‖ ; Whitney S. Irvin ; MS^§ ; ; Miguel Chaput ; MD^&lowast ; ; ^&Dagger ; ; Emmanuel Messas ; MD ; PhD^&Dagger ; ; ^# ; Albert A. Hagè ; ge ; MD ; PhD^&Dagger ; ; ^# ; Alain Carpentier ; MD ; PhD^&Dagger ; ; ^# ; Robert A. Levine ; MD^&lowast ; ; ^&Dagger ; ; ^# ; ^{rlevine@partners.org" class="auth_mail" title="E-mail the corresponding author} ; for the Leducq Transatlantic Mitral Network
• 关键词：echocardiography ; endothelial-to-mesenchymal transition ; inflammation ; mitral regurgitation ; papillary muscle
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：26 January 2016
• 年：2016
• 卷：67
• 期：3
• 页码：275-287
• 全文大小：7074 K

文摘

In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition.

Objectives

The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation.

Methods

Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets.

Results

Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint.

Conclusions

MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR.