Abstract 1134: Active Adaptation of the Tethered Mitral Valve: Insights into a Compensatory Mechanism for Ischemic Mitral Regurgitation
Background: In patients with myocardial infarction (MI) or left ventricular (LV) dilatation, mitral regurgitation (MR) is frequently induced by leaflet tethering imposed by displaced papillary muscles (PMs), and doubles mortality. Despite this, little is known about mitral valve (MV) tissue biology and its potential to compensate for LV remodeling, which has not yet been studied prospectively. We tested the hypothesis that MV area increases over time with mechanical stretch induced by PM displacement, and as a consequence of cell activation and matrix production as opposed to passive stretching.
Methods: Under cardiopulmonary bypass, the PM tips in 6 adult sheep were retracted apically short of producing MR to replicate tethering without confounding MI or turbulence. Diastolic MV leaflet area (without systolic stretch) was quantified by a new validated 3D echo algorithm at baseline and after 61±6 days, and MV tissue collected for histology (H&E, Masson) and fluorescent cell sorting at sacrifice. Data were compared with 6 unstretched sheep MVs.
Results: Total diastolic MV leaflet area increased by 2.4±1.3cm2 (17±10%) from 14.3±1.9cm2 to 16.7±1.9cm2 (p<0.01) with maintained stretch, without significant change in unstretched valves despite sham open-heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.43 vs 0.42±0.14mm, p<0.01) due to increased spongiosa layer. Endothelial cells (CD31+) also expressing alpha-smooth muscle actin (α-SMA) were significantly more common by cell sorting in tethered versus normal leaflets (41±19% vs 9±5%, p=0.02), indicating endothelial-mesenchymal transdifferentiation (EMT); α-SMA+ positive cells indicating activation/EMT appeared in the high-stress atrial layer, penetrating into the valve interstitium, with increased collagen deposition, all absent normally.
Conclusion: Mechanical stresses imposed by PM tethering increase MV leaflet area and matrix thickness, with cellular changes suggestive of reactivated embryonic valve development pathways. These findings support the concept of an actively adapting MV; understanding adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic MR.