Author + information
- Kenneth M. Fish, PhD∗ ( and )
- Roger J. Hajjar, MD
- ↵∗Address for correspondence:
Dr. Kenneth M. Fish, Icahn School of Medicine at Mount Sinai, Cardiovascular Research Center, 1 Gustave Levy Place, New York, New York 10029.
The incidence of obesity has increased rapidly over several decades and continues at an alarming rate. Some estimates suggest that the incidence will reach >80% in the coming decade (1,2). Being overweight or obese predisposes the global population to most major risk factors for morbidity and mortality, including hypertension, hyperlipidemia, and diabetes mellitus and heart failure. Being overweight is among the leading causes of death and disability (3). Taken together, these concerns highlight the unmet need to understand the mechanisms of obesity-driven cardiovascular disease and related comorbidities. Known mechanistic components contributing to cardiovascular disease in obesity and obesity-driven diabetes include elevation of circulating endocannabinoid metabolites derived from excess long-chain polyunsaturated fatty acid processing and oxidation. This results in up-regulation of cannabinoid type 1 receptor (CB1-R) in the heart and elsewhere. With the established link between endocannabinoids and cardiac dysfunction, a clear pathway from obesity, the metabolic syndrome, and diabetes to heart failure (4,5) has been established via CB1-R (5). It is notable that CB1-R and cannabinoid type 2 receptor can elicit opposing effects in the cardiovascular system, but their precise involvement in cardiac pathophysiology is not well understood. Key pathophysiological endpoints as downstream effects of CB1-R signaling in the myocardium have been established, including metabolic dysregulation, oxidative stress, inflammation, and fibrosis.
With the complexity of obesity-induced cardiometabolic disorders, novel research approaches are required to understand the underlying detailed mechanisms and evaluate potential therapeutic targets, including CB1-R. Imaging agents facilitating in vivo determination of altered endocannabinoid signaling via the cannabinoid receptors (Figure 1) could facilitate a more complete mechanistic understanding of obesity, diabetes, and substance abuse–driven cardiovascular disease.
In this issue of iJACC, Valenta et al. (6) evaluate the feasibility of imaging obesity-driven myocardial CB1-R up-regulation. This study was conducted in obese and control mice using [11C]-OMAR positron emission tomography/computed tomography, originally developed for neuroimaging of CB1-R. The results were translated to a small cohort including normal-weight and obese but otherwise healthy human volunteers.
Using the mouse model of obesity, Valenta et al. (6) documented the dysregulation of endocannabinoid levels in the myocardium compared with normal-weight control animals. Anandamide was 2 times that in the lean control mice examined, while 2-aracidonoylglycerol increased by about 1.25 times and arachidonic acid by at least 10 times. Concomitantly, the abundance of cyclooxygenase 2, the arachidonic acid–metabolizing enzyme, doubled in response to elevated levels of these endocannabinoids. Other endpoints indicating cardiac pathophysiology known to be up regulated by endocannabinoid binding to CB1-R are not reported.
[11C]-OMAR is 1 of many biarylpyrazole analogues developed as CB1-R imaging agents. This family of agents includes incorporation of either 11C or 18F radionuclides. Rimonabant is also a member of the biarylpyrazole family that was developed as an inverse antagonist of CB1-R to treat obesity, but it was removed from the European market in 2009, and in June 2007, the U.S. Food and Drug Administration’s Endocrine and Metabolic Drugs Advisory Committee recommended against its approval because of concerns about dangerous psychological side effects and cardiac adverse events in patients (7).
In their report, Valenta et al. (6) show enhanced cardiac uptake in the hearts of obese mice and obese, but otherwise healthy, volunteers compared with nonobese control subjects. In the mouse experiments, cardiac uptake was similar to brain cerebellar uptake. Although high radiotracer levels in the liver are mentioned, more comprehensive biodistribution remains an unmet need. Pre-treatment with rimonabant resulted in decreased radiotracer uptake as measured in collected tissues by γ-counter. Although this was taken as evidence for specific binding, it should be noted that both [11C]-OMAR and rimonabant are very similar biarylpyrazole analogues that as a group are known to be selective, not specific, for CB1-R. This is particularly important because the work presented here is a result of doses reaching 103 times the binding constant for CB1-R, thus similar and lower affinity targets including the opioid receptors (8,9) may have come into play. Valenta et al. (6) present compelling evidence that CB1-R expression at the transcription level is elevated in obese mice, as evidenced by both polymerase chain reaction analysis and CB1-R messenger ribonucleic acid. Despite extensive attempts to detect and quantify the CB1-R protein, antibodies available to the research team were not specific enough to conduct definitive experiments. From an elegant series of in situ hybridization experiments, there is a clear up-regulation of CB1-R messenger ribonucleic acid in cardiac vascular smooth muscle cells, cardiomyocytes, and cardiac fibroblasts from obese animals compared with lean control subjects. Therefore, the increased [11C]-OMAR uptake in obese animal models corresponds to increased expression of CB1-R at the transcriptional level.
There are now several imaging agents targeting CB1-R on the basis of the rimonabant structural platform that have been developed. For example, Nojiri et al. (10) have developed an 18F positron emission tomographic active analogue of rimonabant that partially detargets the brain. It would be beneficial to have side-by-side comparisons of these agents to assess their relative utility as CB1-R and cannabinoid type 2 receptor imaging agents. Some of the other CB1-R positron emission tomographic imaging agents developed for neuroimaging have higher binding affinity than OMAR, further supporting the need for comparisons for cardiac CB1-R imaging to differentiate them from one another.
Although Valenta et al. (6) present biodistribution focusing on brain, blood, and heart, other studies have clearly shown significant if not dominant uptake levels in other peripheral organs (11). Indeed, the images in Figure 7A clearly show very high uptake in the liver partially obscuring the target organ. Therefore, a more detailed biodistribution study, correlated with messenger ribonucleic acid and CB1-R protein levels, remains an unmet need for establishing the utility of [11C]-OMAR over other potentially diagnostic imaging agents.
Although Valenta et al. (6) showed that there was reduced uptake of [11C]-OMAR in the presence of rimonabant, this is not clear evidence for specific CB1-R, because both ligands are similar biarylpyrazoles and act as allosteric modulators of CB1-R. Results with CB1-R-knockout mice revealed lower [11C]-OMAR with decreased CB1-R messenger ribonucleic acid, but without a specific antibody targeting CB1-R direct binding to the putative target, direct comparative quantitation of OMAR uptake correlations to cardiac receptor levels remains an unmet need. Furthermore, the levels of additional receptors known to bind rimonabant and OMAR remain an unmet data gap in these imaging and biodistribution studies. This a concern, as there are growing reports that the parent rimonabant compound binds to other targets, including G protein–coupled receptors (12). Examples of off-target receptors include cannabinoid type 2 receptor and the μ-opioid receptor, with binding affinities within that of the delivered molecular doses. Complementary approaches to showing specificity to the target receptor could include the intraindividual linear correlation between candidate binding partners and the levels of receptor transcripts across multiple organs.
In conclusion, Valenta et al. (6) have taken initial innovative steps in demonstrating proof of concept for imaging cardiac endocannabinoid system up-regulation in response to obesity. Specifically, the ability to monitor CB1-R levels in the heart will facilitate mechanistic discovery of obesity-driven endocannabinoid dysregulation and cardiac pathophysiology.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
This work is supported by grants R01 HL0135013, R01 HL112324, and R01 HL119046 from the National Heart, Lung, and Blood Institute and grant 13CVD01 from Foundation Leduq. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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