Lipid Mediators of the Endocannabinoid and Lipoxygenase Pathways Are Enhanced after Cardioplegic Arrest in CABG Patients

Objectives: Endogenous cannabinoids and the cannabinoid receptor 2 (CB2) are activated during myocardial ischemia and reperfusion and play an important role in modulation of the inflammatory response. Therefore, we investigated the role of endocannabinoids and of selected inflammation-lipid mediators in patients undergoing open-heart surgery using cardioplegic arrest on cardiopulmonary bypass (CPB).

Methods: Twenty-five patients undergoing coronary artery bypass surgery (CABG) were included in this study. Blood was obtained from a peripheral vein (PV) before surgery, before aortic cross-clamp, at the beginning of cardiac reperfusion and 6 hours after surgery. Blood from the heart itself was obtained from the coronary sinus (CS) before cross-clamp and at the start of reperfusion. Lipid mediators including endocannabinoids, prostaglandins (COX-2 pathway) and mediators of the lipoxygenase-pathway were measured using quantitative targeted mass spectrometry via liquid chromatography-multiple reaction monitoring (LC-MRM).

Results: LC-MRM revealed induced production of the endocannabinoid anandamide (AEA) at 6 hours after surgery and of its precursor arachidonic acid (AA). Thses data are in accordance with our previous findings in infarcted mouse hearts, showing enhanced AEA and AA production 3 days after reperfusion of the infarcted hearts. Evaluation of prostaglandins (PG) revealed no production at that time, indicating that AA is not substrate to COX-2-pathway but substrate to the endocannabinoid pathway at that time. Further, PGE-2 and 6-keto-prostaglandin F1 (6kPGF1)-alpha concentration were highest in CS-blood before and after cardiac arrest, but during CPB, suggesting a cardiac-specific inflammation in response to the heart–lung machine (HLM), or surgical trauma. 12(S)-hydroxyeicosatetraen acid (12(S)-HETE), a mediator of the lipoxygenase pathway, was induced after reperfusion of the ischemic heart, and the blood concentration in PV and CS was equal, indicating involvement of these regulators of macrophage and neutrophil activity in the ischemic human heart.

Conclusion: Our study suggests a role for the endocannabinoid and the lipoxygenase pathways in ischemic myocardium. Further, similar concentrations of 12(S)-HETE in PV and CS blood as well as induced AEA and AA levels 6 hours after surgery in PV suggest a potential value as inflammatory biomarkers after myocardial ischemia.