The Atherogenic Significance of an Elevated Plasma Triglyceride Level

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Abstract
The importance of hypertriglyceridemia as an independent predictor of coronary artery disease (CAD) remains unsettled. Hypertriglyceridemia, with or without associated hypercholesterolemia, occurs more frequently in premature CAD subjects than does hypercholesterolemia alone. With univariate analysis, most studies show a positive correlation between plasma triglyceride (TG) level and risk for CAD, but with multivariate analysis plasma TG level is no longer an independent risk factor except in women and diabetics. Prospective studies have shown that subjects with a high LDL/HDL cholesterol ratio and a high plasma TG level have the highest risk for CAD. Hypertriglyceridemia signifies the presence of excess triglyceride-rich lipoproteins (TRL), including chylomicrons, VLDL, and their remnants. The question then becomes one of whether TRL are directly or indirectly involved in atherogenesis. TRL were thought to be too big to infiltrate the arterial wall, and histopathological studies have shown cholesterol but not triglyceride accumulation in the atherosclerotic plaque. However, there was a recent demonstration of undegraded VLDL and IDL in atherosclerotic plaques. Larger TRL may undergo hydrolysis on the arterial surface to become smaller particles before entry into the intima. Possible cellular pathways for the uptake of TRL by macrophages have been described. The smaller TRL (Sf 20–60), including postprandial chylomicron remnants, are believed to be the most atherogenic of all TRL particles. Because large amounts of TRL are produced in the postprandial period, atherogenesis involving TRL may be primarily a postprandial phenomenon. Once in the intima, TG may undergo hydrolysis, releasing free fatty acids and mono-and diacyl glycerol, accounting for the dearth of TG in atherosclerotic lesions. Particle for particle, VLDL delivers five times as much cholesterol as LDL does to the macrophage. TRL also have an indirect influence on atherogenesis by having a profound effect on LDL and HDL. In hypertriglyceridemic states, there is an enhanced transfer of TG from TRL to LDL and HDL in exchange for cholesterol esters. The TG-enriched LDL and HDL particles become preferred substrates for hepatic lipase that converts them to smaller and denser LDL and HDL particles. Small, dense LDL particles are particularly atherogenic, and smaller HDL particles are catabolized more readily, giving rise to a low HDL cholesterol. Hypertriglyceridemia may also cause CAD through other pathological processes such as increased coagulability, impaired fibinolysis, impaired endothelial function, and activation of adhesion and chemotactic factors. Hypertriglyceridemia (HTG) should not be ignored especially in secondary prevention. HTG with a high LDL/HDL cholesterol ratio signifies the highest risk.