Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

BACKGROUND 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 This study explored the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies MV adaptation. METHODS Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the PM tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered-alone). PM retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered + MI), and left ventricular (LV) remodeling was limited by external constraint in 5 additional sheep (LV constraint). Six sham-operated sheep were controls. Diastolic MV 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 + MI leaflets were markedly thicker than tethered-alone valves and sham controls. Leaflet area also increased significantly. EMT, 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 + MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered + 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.

Background-Functional mitral regurgitation (MR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about whether chronic tethering causes the mitral leaflet area to adapt to the geometric needs imposed by tethering, in part because of inability to reconstruct leaflet area in vivo. Our aim was to explore whether adaptive increases in leaflet area occur in patients with functional MR compared with normal subjects and to test the hypothesis that leaflet area influences MR severity. Methods and Results-A new method for 3-dimensional echocardiographic measurement of mitral leaflet area was developed and validated in vivo against 15 sheep heart valves, later excised. This method was then applied in 80 consecutive patients from 3 groups: patients with normal hearts by echocardiography (nϭ20), patients with functional MR caused by isolated inferior wall-motion abnormality or dilated cardiomyopathy (nϭ29), and patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (nϭ31). Leaflet area was increased by 35Ϯ20% in patients with LV dysfunction compared with normal subjects. The ratio of leaflet to annular area was 1.95Ϯ0.40 and was not different among groups, which indicates a surplus leaflet area that adapts to left-heart changes. In contrast, the ratio of total leaflet area to the area required to close the orifice in midsystole was decreased in patients with functional MR compared with those with normal hearts (1.29Ϯ0.15 versus 1.78Ϯ0.39, Pϭ0.001) and compared with patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (1.81Ϯ0.38, Pϭ0.001). After adjustment for measures of LV remodeling and tethering, a leaflet-to-closure area ratio Ͻ1.7 was associated with significant MR (odds ratio 23.2, 95% confidence interval 2.0 to 49.1, Pϭ0.02). Conclusions-Mitral leaflet area increases in response to chronic tethering in patients with inferior wall-motion abnormality and dilated cardiomyopathy, but the development of significant MR is associated with insufficient leaflet area relative to that demanded by tethering geometry. The varying adequacy of leaflet adaptation may explain in part the heterogeneity of this disease among patients. The results suggest the need to understand the mechanisms that underlie leaflet adaptation and whether leaflet area can potentially be modified as part of the therapeutic approach.