Background— In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching. Methods and Results— Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61±6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4±1.3 cm ² (17±10%) from 14.3±1.9 to 16.7±1.9 cm ² ( P =0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.14 versus 0.42±0.14 mm; P <0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31 ⁺ ) coexpressing α-smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41±19% versus 9±5%; P =0.02), indicating endothelial-mesenchymal transdifferentiation. α-Smooth muscle actin–positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial α-smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells. Conclusions— Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation.

Background —Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings. Methods and Results —We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus ( P <0.0001). To counteract these shifts, the LV was remodeled by plication of the infarct region to reduce myocardial bulging, without muscle excision or cardiopulmonary bypass. Immediately and up to 2 months after plication, MR was reduced to trace-to-mild as tethering distance was decreased ( P <0.0001). LV ejection fraction, global LV end-systolic volume, and mitral annular area were relatively unchanged. By multiple regression, the only independent predictor of MR was tethering distance ( r ² =0.81). Conclusions —Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering.

Previous studies have reported a high prevalence of mitral-valve prolapse among patients with embolic stroke (28 to 40 percent), especially among young patients (those ≤45 years old); this finding has practical implications for prophylaxis. However, diagnostic criteria for prolapse have changed and are now based on three-dimensional analysis of the shape of the valve; use of the current criteria reduces markedly the frequency of such a diagnosis and increases its specificity. Previously described complications must therefore be reconsidered.