Role of the Endocannabinoid System in Modulation of the Inflammatory Reaction in Aortic Valve Degeneration

Objectives: Calcific aortic valve disease (CAVD) is the most common indication for surgical or catheter-based valve replacement. To date, no pharmacological treatment of this common disease exists. A recent study showed enhanced cannabinoid-receptors (CB) 1 and 2 expression in human degenerated aortic valves, but no information exists on their cell-specific expression as well as their location within the degenerated valve, as multiple pathological stages can be found in one valve. Further, it has been demonstrated that the ligands of the endocannabinoid-system (ECS) modulate inflammatory response in other cardiac disease, e.g., ischemic and hypertrophic cardiomyopathy. The aim of this study is therefore to investigate the association of the ECS with the inflammatory reaction of CAVD.

Methods: A total of 36 patients undergoing surgical valve replacement at our department in 2020 were enrolled in this study, which was in accordance with the declaration of Helsinki. Ethical consent was given from the ethical review board of our institution. Aortic valve tissue was collected from patients with aortic stenosis (AS) and aortic insufficiency (AI), which served as control group. Valves were dissected according to the stage of disease in “non-diseased,” “fibrotic,” and “calcified” sections. These specimens were further processed for immunohistological, gene-expression and LC-MS/MS analysis.

Result: Immunohistochemical staining showed CB1-positive mononuclear cells predominantly located in the fibrotic areas of AS, and costainings with CD11b antibody confirm CB1 to be expressed on macrophages. This was associated with significantly higher concentration of endocannabinoids anandamide, 2-arachidonoylglycerol, and arachidonic acid in fibrotic areas. Taqman RT-qPCR analysis showed mRNA expression of CB1, but also proinflammatory chemokines CCL2 and CCL3 in fibrotic and calcified specimens. Moreover, mRNA expression of classically activated M1-macrophage marker CD80 and alternative M2a marker CD163 were significantly elevated in both disease stadiums. Of note, non-diseased specimens of AS showed no induction of inflammatory cells, chemokines or ECS-components, resembling findings from AI.

Conclusion: Cellular inflammation and expression of the ECS coincides in the fibrotic disease stadium of CAVD. Thus, the ECS may present a possible target to attenuate CAVD progression. Therapeutic approaches need to be addressed in further studies.

Publication History

Article published online:
19 February 2021