Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.
Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.
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DOI：
10.1161/circulationaha.108.846782
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发表时间：
2009-07-28
期刊：
影响因子：
37.8
通讯作者：
Carpentier A
中科院分区：
文献类型：
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作者：
Dal-Bianco JP;Aikawa E;Bischoff J;Guerrero JL;Handschumacher MD;Sullivan S;Johnson B;Titus JS;Iwamoto Y;Wylie-Sears J;Levine RA;Carpentier A
在左心室梗死或扩张的患者中，移位的乳头肌（PM）导致的瓣叶栓系经常引起二尖瓣返流（MR），导致死亡率加倍。关于二尖瓣（MV）补偿心室重构的生物学潜力知之甚少。我们检验了以下假设：二尖瓣瓣叶表面积随着时间的推移而增加，其中PM位移通过细胞活化产生机械拉伸，而不是被动拉伸。在体外循环下，6只成年绵羊的PM尖端在顶部缩回，未产生MR，以复制栓系，而无混淆MI或湍流。在61±6天内，通过3D超声心动图定量舒张期瓣叶面积，并与6个未拉伸的绵羊MV进行比较。舒张期瓣叶总面积增加2.4±1.3cm2（17±10%），从14.3±1.9cm2增加到16.7±1.9cm2（p=0.006），尽管进行了假心内直视手术，未伸展瓣膜没有变化。处死时，拉伸的MV比正常的厚2.8倍（1.18±0.14 vs 0.42± 0.14 mm，p<0.0001），海绵层增加。通过荧光细胞分选，共表达α-平滑肌肌动蛋白（α-SMA）的内皮细胞（CD 31+）在栓系瓣叶中比在正常瓣叶中明显更常见（41±19% vs 9± 5%，p=0.02），表明内皮-间充质转分化（EMT）; α-SMA阳性细胞出现在心房内皮中，渗透到心房，胶原沉积增加。增厚的腱索显示内皮和内皮下α-SMA。在培养的内皮细胞中也证明了EMT能力。PM栓系施加的机械应力增加MV瓣叶面积和厚度，细胞变化表明重新激活的胚胎发育途径。了解这种主动适应机制可能为增加MV面积和减少缺血性MR提供治疗机会。
In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles (PMs) frequently induces mitral regurgitation (MR), which doubles mortality. Little is known about mitral valve (MV) biological potential to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by PM displacement through cell activation, not passive stretching. 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 leaflet area was quantified by 3D-echo over 61±6 days, compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4±1.3cm2 (17±10%) from 14.3±1.9cm2 to 16.7±1.9cm2 (p=0.006) with stretch, without change in unstretched valves despite sham open-heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.14 vs 0.42±0.14mm, p<0.0001) at sacrifice, with increased spongiosa layer. Endothelial cells (CD31+) co-expressing α-smooth muscle actin (α-SMA) were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41±19% vs 9±5%, p=0.02), indicating endothelial-mesenchymal transdifferentiation (EMT); α-SMA-positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial α-SMA. EMT capacity was also demonstrated in cultured endothelial cells. Mechanical stresses imposed by PM tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic development pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic MR.