Triglycerides and heart disease: still a hypothesis?

Abstract

The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport, and its tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride-rich lipoproteins, their influence on high-density lipoprotein and low-density lipoprotein, or the underlying diseases that lead to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate very-low-density lipoprotein and their remnants and chylomicron remnants in atherosclerosis development, but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease.

Figure 1. Atherogenicity of triglyceride-rich lipoproteins

Two hypotheses for pathways by which triglyceride-rich lipoproteins (TGRL) might increase atherosclerosis are illustrated. Left panel shows the remnant infiltration hypothesis. Conversion of TGRLs to remnants produces particles that then enter the arterial wall, carrying both triglyceride and cholesterol. Arterial LpL may be important to increase the local concentration of these particles. Remnants can be internalized by macrophages and convert these cells into foam cells. Right panel illustrates the toxic lipolysis product hypothesis. During lipolysis of TGRLs a number of inflammatory lipids are released that alter endothelial biology. These lipids - including fatty acids lysolecithin and oxidized lipids - increase expression of adhesion molecules and cytokines, and promote coagulation.