Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease.
Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease.
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DOI：
10.2967/jnumed.114.152355
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发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Sadeghi MM
中科院分区：
文献类型：
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作者：
Jung JJ;Razavian M;Challa AA;Nie L;Golestani R;Zhang J;Ye Y;Russell KS;Robinson SP;Heistad DD;Sadeghi MM
钙化性主动脉瓣疾病（CAVD）是主动脉瓣狭窄最常见的原因。基质金属蛋白酶（MMP）在CAVD中上调，并促进瓣膜重塑和钙化。我们研究了MMP靶向分子成像检测CAVD瓣膜生物学的可行性和相关性。将ApoE−/−小鼠喂食西方饮食（WD）3、6和9个月（n= 108）以诱导CAVD。野生型小鼠作为对照组（n=24）。通过CT、超声心动图、使用RP 805（一种99 mTc标记的示踪剂）的MMP靶向microSPECT成像和组织学分析跟踪CAVD的发展。在WD 6个月后观察到CAVD的关键特征，瓣叶增厚和瓣膜钙化，并在9个月后更加明显。这与主动脉瓣叶分离显著减少和经主动脉瓣流速增加相关。在体内microSPECT/CT图像上，与对照动物相比，WD 6个月的小鼠主动脉瓣面积MMP信号显著增加，此后降低。信号的特异性通过使用过量的未标记的前体阻断来证明。与MMP信号相似，原位酶谱法检测的MMP活性和CD 68染色的瓣膜炎症在6个月时达到最大。在CAVD中，RP 805的体内摄取与MMP活性（R2=0.94，p<0.05）或CD 68表达（R2=0.98，p<0.01）之间存在显著相关性。MMP靶向成像检测CAVD中的瓣膜炎症和重塑。如果在人类中得到证实，这可能为跟踪新兴医学治疗干预的效果和预测CAVD的结局提供工具。
Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMP) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD. ApoE−/− mice were fed a Western diet (WD) for 3, 6 and 9 months (n= 108) to induce CAVD. Wild-type mice served as the control group (n=24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted microSPECT imaging using RP805, a 99mTc-labeled tracer, and histological analysis. Key features of CAVD, leaflet thickening and valvular calcification were noted after 6 months of WD, and were more pronounced after 9 months. This was associated with a significant reduction in aortic valve leaflet separation and increase in trans-aortic valve flow velocity. On in vivo microSPECT/CT images, aortic valve area MMP signal was significantly increased in mice on WD for 6 months compared to control animals and decreased thereafter. The specificity of the signal was demonstrated by blocking using excess non-labeled precursor. Similar to MMP signal, MMP activity by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 months. There was a significant correlation between RP805 uptake in vivo, and MMP activity (R2=0.94, p<0.05) or CD68 expression (R2=0.98, p<0.01) in CAVD. MMP-targeted imaging detects valvular inflammation and remodeling in CAVD. If confirmed in humans, this may provide a tool for tracking the effect of emerging medical therapeutic interventions and predicting outcome in CAVD.