Department of Radiology, Division of Nuclear Medicine, Nuclear Cardiovascular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
JACC Cardiovasc Imaging. 2018 Feb;11(2 Pt 2):320-332. doi: 10.1016/j.jcmg.2017.11.019.
The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans using [C]-OMAR and positron emission tomography (PET)/computed tomography (CT).
Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy.
Binding specificity of [C]-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by γ-counter. Furthermore, [C]-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand [C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively.
Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal-weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up-regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2-arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects.
Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.
本研究旨在评估使用 [C]-OMAR 和正电子发射断层扫描（PET）/计算机断层扫描（CT）对肥胖小鼠心肌大麻素 1 型受体（CB1-R）进行靶向成像的可行性及其在人类中的潜在上调。
内源性大麻素激活心肌 CB1-R 与糖尿病小鼠的心脏功能障碍有关。肥胖可能导致心肌 CB1-R 的上调，这为肥胖与心肌病的发生和/或进展之间的机制联系提供了依据。
通过在小鼠中用利莫那班进行阻断研究，研究 [C]-OMAR 对 CB1-R 的结合特异性。从每只小鼠中取出心脏，并通过γ计数器测定其放射性。此外，还在肥胖和正常体重小鼠中进行了 [C]-OMAR 动态微 PET/CT。通过液滴数字聚合酶链反应（绝对定量）和 RNAscope 技术（一种原位核糖核酸分析平台）进行了体外验证。随后，通过静脉注射 CB1-R 配体 [C]-OMAR 和 PET/CT，分别在患有晚期肥胖症的患者和正常体重的人类对照中，对心肌 CB1-R 表达进行了非侵入性检测。
与载体相比，利莫那班显著阻断了 OMAR 在心肌中的摄取，表明 OMAR 特异性结合心肌中的 CB1-R。通过微 PET/CT 定量的小鼠心肌 OMAR 保留量在肥胖组明显高于正常体重组。液滴数字聚合酶链反应和原位杂交的绝对定量 CB1-R 基因表达证实，肥胖小鼠的所有主要心肌细胞类型（如心肌细胞、内皮细胞、血管平滑肌细胞和成纤维细胞）均存在 CB1-R 上调。肥胖小鼠的心肌内源性大麻素大麻酰胺和 2-花生四烯酸甘油也高于瘦小鼠。转化为人类发现，与正常体重受试者相比，晚期肥胖患者的心肌 OMAR 保留量更高。
应用 [C]-OMAR 和 PET/CT 对肥胖症患者的心脏 CB1-R 表达进行非侵入性成像是可行的。这些结果可能为进一步临床测试 CB1-R 靶向分子成像在心脏代谢疾病中的应用提供依据。
