TY - JOUR
T1 - Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity
T2 - A Translational Approach
AU - Valenta, Ines
AU - Varga, Zoltan V.
AU - Valentine, Heather
AU - Cinar, Resat
AU - Horti, Andrew
AU - Mathews, William B.
AU - Dannals, Robert F.
AU - Steele, Kimberley
AU - Kunos, George
AU - Wahl, Richard L.
AU - Pomper, Martin G.
AU - Wong, Dean F.
AU - Pacher, Pal
AU - Schindler, Thomas H.
N1 - Funding Information:
This work was supported by a Departmental Fund from Johns Hopkins University (175470 to Dr. Schindler) and the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health (to Drs. Kunos and Pacher). Dr. Varga was supported by the Rosztoczy Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Valenta and Varga contributed equally to this paper and are joint first authors. Drs. Pacher and Schindler contributed equally to this work and are joint senior authors.
Publisher Copyright:
© 2018 American College of Cardiology Foundation
PY - 2018/2
Y1 - 2018/2
N2 - Objectives: 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 [11C]-OMAR and positron emission tomography (PET)/computed tomography (CT). Background: 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. Methods: Binding specificity of [11C]-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, [11C]-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 [11C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. Results: 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. Conclusions: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [11C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.
AB - Objectives: 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 [11C]-OMAR and positron emission tomography (PET)/computed tomography (CT). Background: 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. Methods: Binding specificity of [11C]-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, [11C]-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 [11C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. Results: 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. Conclusions: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [11C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.
KW - 2-arachidonoylglycerol
KW - CB1 receptor imaging
KW - PET/CT
KW - [C]-OMAR
KW - anandamide
KW - cannabinoid type 1 receptor
KW - endocannabinoids
KW - heart
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85044661768&partnerID=8YFLogxK
U2 - 10.1016/j.jcmg.2017.11.019
DO - 10.1016/j.jcmg.2017.11.019
M3 - Article
C2 - 29413441
AN - SCOPUS:85044661768
SN - 1936-878X
VL - 11
SP - 320
EP - 332
JO - JACC: Cardiovascular Imaging
JF - JACC: Cardiovascular Imaging
IS - 2P2
ER -