Role of endocannabinoid system in development of cardiac dysfunction in cirrhosis

Baseline cardiac function is normal in cirrhosis but its responsiveness to stressful stimuli is blunted. This condition is known as cirrhotic cardiomyopathy. Interest in cirrhotic cardiomyopathy has recently increased significantly because of the possible role of cardiac dysfunction in morbidity and mortality in cirrhotic patients, specially after major surgical procedures including orthotopic liver transplantation. Prior to this project, there were two reports of increased activity of endocannabinoid system in cirrhotic subjects and animals and this alteration was shown to play a role in peripheral vasodilatation but not in cardiac dysfunction in cirrhosis. We systematically investigated possible roles of the endocannabinoid system in the development of cirrhotic cardiomyopathy.;Experiments were performed in a rat model of bile duct ligation-induced cirrhosis (BDL). Blockade of cannabinoid receptor 1 (CB1) but not cannabinoid receptor 2 (CB2) or the vanilloid receptor (TRPV1) significantly improved cardiac contractile function in the in vitro studies. This finding could be explained by upregulation of cardiac CB1 receptors, but expression and efficacy of these receptors were unchanged. We hypothesized that local cardiac production of endocannabinoids were increased in the cirrhotic heart. This hypothesis was supported by force-frequency experiments on isolated left ventricular papillary muscles. This hypothesis was further confirmed by quantification of cardiac concentrations of endocannabinoids that showed increased levels of both anandamide and 2-arachidonoylglycerol (2-AG) at resting state and further increase in levels of anandamide after hemorrhagic stress in BDL rats. The pathophysiological relevance of these findings was tested by evaluating the effects of CB1 receptor blockade on cardiovascular response to hemorrhage and also the development of pulmonary congestion in cirrhotic animals. These conditions showed significant improvement after CB1 receptor blockade. This project describes, for the first time, an increase in local production of endocannabinoids in the cirrhotic heart and provides evidence that the endocannabinoid system is involved in the pathophysiology of cirrhotic cardiomyopathy. Further investigation is required to identify the biochemical pathways of endocannabinoid synthesis and degradation in the cirrhotic heart.