Tetrahydrocannabinol as Potential Drug for Modulation of the Post-ischemic Inflammation and Restoration of Myocardial Function in Patients with Coronary Artery Disease

Background: Previous studies showed an involvement of the endocannabinoid system (ECS) in the inflammatory response to myocardial ischemia and reperfusion (I/R). Here, we investigated whether ischemia caused by coronary artery disease (CAD) results in ECS modification and inflammatory reaction, and whether a potential modulation is selective for the heart. In a translational approach, we aimed to restore potential I/R-induced left ventricular (LV) dysfunction in mice by treatment with selective (HU308) and non-selective, specific cannabinoid receptor-2 (Cnr2) agonist tetrahydrocannabinol (THC) after temporary occlusion of the left anterior descending artery (LAD).

Methods: In 26 patients undergoing myocardial revascularization via coronary artery bypass graft (CABG) surgery (CAD-group), and in 6 patients undergoing myxoma extirpation (control group), we evaluated the expression of endocannabinoids in human coronary sinus (CS) and peripheral venous (PV) blood samples using quantitative targeted mass spectrometry (LC-MS/MS). Moreover, we measured pro- and anti-inflammatory cytokines using Luminex protein assay. In C57/Bl6 mice, we performed repetitive, short I/R mimicking CAD for 7days and assessed LV function with M-mode echocardiography.

Results: The concentration of the endocannabinoid anandamide (AEA) was significantly higher in CS compared with PV blood in CAD group, suggesting cardio-selective induction of the ECS in response to ischemia. Further, AEA levels increased after 6 hours, possibly indicating a perpetuated effect through ischemia caused by cardioplegia-induced cardiac arrest. Interestingly, the precursor of AEA, arachidonic acid, showed a comparable trend, being in line with previously published data from I/R in mice. Interestingly, while, compared with control group, IL-1β protein levels were increased in CAD patients already before surgery in PV and CS blood, TNF-α was only elevated in CS blood of CAD group before cardioplegic arrest, suggesting cardio-selective, CAD-induced inflammation. Most importantly, only specific Cnr2 activation with THC was able to significantly ameliorate fractional shortening as a parameter for global LV function in mice.

Conclusion: This study confirms the relevance of the ECS in mediating inflammatory responses upon myocardial I/R, thus providing a new perspective for anti-inflammatory therapy. Unexpectedly, our mouse experiments point to a potential therapeutic role for THC in the post-ischemic treatment of CAD.

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Artikel online veröffentlicht:
11. Februar 2025