期刊
CIRCULATION
卷 120, 期 4, 页码 334-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.108.846782
关键词
echocardiography; mitral valve; valves
资金
- NHLBI NIH HHS [R01 HL38176, K24 HL67434, K24 HL067434-08, K24 HL067434, R01 HL038176, R01 HL038176-14] Funding Source: Medline
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 alpha-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. alpha-Smooth muscle actin-positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial alpha-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. (Circulation. 2009; 120:334-342.)
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