Effects of triglycerides on the endothelium

Sammanfattning: Hypertriglyceridaemia (HTG) is a risk factor for coronary heart disease (CHD), although the mechanisms behind the increased risk remain to be defined. It is unclear whether atherogenic or thrombogenic factors are involved, or a combination thereof The endothelium is important in maintaining normal vascular function and has a key role in atherogenesis. Endothelial dysfunction is considered to be an early marker of atherosclerosis and is associated with common risk factors for CHD and with manifest atherosclerosis. The present research programme was set up to investigate whether triglycerides have a negative effect on endothelial function and thus promote atherosclerosis, which is a proposed mechanism for how HTG acts as risk factor for CHD. In study I the effects of acute triglyceridaemia were investigated in seven healthy young men without risk factors for CHD by administration of an intravenous triglyceride-rich chylomicron-like fat emulsion. This study demonstrated that transient triglyceridaemia impaired flow-mediated endothelium-dependent vasodilation (FMD), examined by brachial artery ultrasound technique. An effect on endothelium-independent vasodilation could not be excluded in this study. In study II and study IV, 15 men with mild to moderate persistent HTG and no other risk factors for CHD and 15 age- and body mass index-matched healthy male controls were examined. Study II demonstrated that FMD of the brachial artery was impaired in chronic HTG, whereas common carotid intima media-thickness was similar in the two groups.The plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) were higher in the hypertriglyceridaemic group. There was no difference in endothelium-independent vasodilation. Study IV demonstrated that chronic HTG was associated with increased concentrations of the inflammatory marker C-reactive protein, cellular adhesion molecules (sICAM-1 and sE-selectin-1) and von Willebrand factor. Study III was performed in rat femoral arterial rings in organ baths and demonstrated that a triglyceride-rich fat emulsion and free fatty acids (FFAs) (16:0,18:1 and 18:3) impaired pharmacologically stimulated endotheliumdependent vasorelaxation, whereas no effect was seen with very low density lipoproteins. There were no effects on endothelium-independent vasoreactivity with any of the substances studied. When the antioxidant vitamin C was added to the organ baths, together with the fat emulsion or FFAs, the vasodilatory responses to the endothelial agonist improved, indicating that oxidative mechanisms are involved in the observed impairment of endotheliumdependent vasorelaxation. In study V effects of acute triglyceridaemia on myocardial ischaemia were investigated in 15 men with manifest CHD, by having the patients perform an exercise stress test before and during administration of a triglyceride-rich fat emulsion or saline, in a double-blind fashion. This study demonstrated a decreased rate pressure product and a trend towards earlier ST segment depression during infusion of triglyceride-rich fat emulsion compared with saline. Conclusions: The results demonstrate that triglycerides exert negative effects or the endothelium. Acute and chronic elevation of triglycerides, or their metabolites FFAs, is associated with impairment of endothelial function and biochemical signs of endothelial activation and inflammation. This might be caused by decreased NO bioavailability, induced by oxidative mechanisms or by increased concentrations of the NO synthase inhibitor ADMA. Taken together, this emphasises the importance of hypertriglyceridaemia as a risk factor for atherosclerosis and CHD.