Altered expression of cannabinoid receptors 1 and 2 and activated endocannabinoid system in patients with severe chronic heart failure

Background: Animal studies suggest that endocannabinoid receptors play a role in the regulation of myocardial contractility and in the pathogenesis of chronic heart failure (CHF). The current study aimed to proof the existence of endocannabinoid receptors on human ventricular myocardium and to determine whether CHF is associated with changes in endocannabinoid receptor expression and distribution.

Methods: Expression of cannabinoid receptors 1 (CB1) and 2 (CB2) on healthy, and diseased human heart from patients undergoing heart transplantation was assessed by means of real-time PCR and immunohistochemistry; Endocannabinoid levels were assessed by high performance liquid chromatography-tandem mass spectrometry in patients with CHF.

Results: On healthy human left ventricular myocardium, mRNA transcripts of CB1 and CB2 receptors were expressed in an almost equal proportion. In patients with CHF, mRNA expression of CB1 receptors was shown to be downregulated 0.7-fold (0.7.±0.15, n=12, p<0.01), whereas expression of CB2 receptors was upregulated more than 11-fold (11.6±4.5; n=12; p<0.005). Corresponding results were obtained by immunohistochemistry. Blood levels of endocannabinoids were significantly elevated (anandamide 3.5-fold (p<0.001); 2-AG 7-fold (p=0.02)) in patients with CHF, as compared to healthy volunteers.

Conclusions: Both CB1 and CB2 receptors are present on healthy human left ventricular myocardium in a balanced distribution. Patients suffering from CHF exhibit a shift of the CB1-CB2 receptor ratio towards expression of positive inotropic CB2 receptors combined with significantly elevated peripheral blood levels of endocannabinoids. Influencing cardiac function by modulation of CB receptor signalling may offer new perspectives for the treatment of CHF.