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SUPPLEMENT II: Contents | Introduction | Faculty

Triglycerides as a Risk Factor in Cardiac Heart Disease

MICHAEL MILLER, M.D., F.A.C.C., Guest Editor

This supplement is based on the Triglycerides as a Risk Factor in Cardiac Heart Disease meeting held September 25–27, 1998, in Washington, D.C. The meeting and publication of the proceedings were developed under the auspices of the University of Florida, College of Medicine, Gainesville, and supported by unrestricted grants from Parke-Davis, Division of Warner-Lambert Company, and Pfizer Laboratories.

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Introduction [HTML]
M. Miller, M.D., F.A.C.C.

The Epidemiology of Triglyceride as a Coronary Artery Disease Risk Factor [PDF]
M. Miller, M.D., F.A.C.C.  II-1

Triglyceride (TG) has long been associated as a risk factor for coronary artery disease. A recent meta-analysis of various epidemiologic studies has confirmed this link. An important issue is to assess further the appropriate cutpoints to classify desirable TG because recent data indicate that levels <200 mg/dl confer elevated risk. The dietary habits of present hunter-gatherer populations reveal the impact of a Westernized diet on both TG and cholesterol and suggest that a desirable TG is <100 mg/dl. The epidemiologic and observational data in support of this concept are explored.

Pathophysiology of Triglyceride-Rich Lipoproteins in Atherothrombosis: Cellular Aspects [PDF]
S. H. Gianturco, Ph.D. and W. A. Bradley , Ph.D.  II-7

Elevated plasma levels of triglyceride-rich lipoproteins (TGRLP), including very-low density lipoproteins (VLDL), chylomicrons, and their remnants, are now acknowledged as risk factors for cardiovascular disease. Interactions of TGRLP with lipoprotein receptors on monocytes, macrophages, and endothelial cells may be mechanistically linked to this risk. Triglyceride-rich lipoproteins from hypertriglyceridemic (HTG) subjects have the abnormal ability to bind to low-density lipoprotein receptors via apoE, and plasma chylomicrons from all subjects bind to a new, distinct receptor for apoB48 that is expressed specifically by monocytes, macrophages, and endothelial cells. Receptor binding and uptake of TGRLP by these cells are likely mechanisms involved in the formation of lipid-filled, macrophage-derived "foam cells" of atherosclerotic lesions and for defective fibrinolysis due to endothelial dysfunction. Recognition of the atherothrombogenic potential of TGRLP may lead to improved interventions to lessen or prevent the often fatal sequelae of coronary atherosclerosis and thrombosis associated with elevated plasma triglyceride levels.

Pathophysiology of Triglyceride-Rich Lipoproteins in Atherothrombosis: Clinical Aspects [PDF]
H. N. Hodis, M.D., W. J. Mack, Ph.D., R. M. Krauss, M.D., P. Alaupovic, Ph.D.  II-15

Invasive and noninvasive arterial imaging are important techniques used to study atherosclerosis and, specifically, to evaluate the atherogenecity of triglyceride-rich lipoproteins (TRL). Serial coronary angiography trials show significant benefit from lowering low-density lipoprotein cholesterol (LDL-C) which serves to retard lesion progression. Even with aggressive LDL-C reduction, however, up to half of patients demonstrate continued progression of atherosclerosis. Angiographic studies reveal that lowering LDL-C has the most impact on severe lesions, those >=50% diameter stenosis, whereas TRL (and their apolipoprotein markers) have been identified as a driving factor behind progression of mild-to-moderate lesions <50% diameter stenosis. Quantitative coronary angiography (QCA) has demonstrated that progression of mild-to-moderate lesions are among the most significant predictors of clinical coronary events, and that lowering TRL reduces progression of CAD to the same degree as the lowering of LDL-C.

Measurement of Triglyceride-Rich Lipoproteins by Nuclear Magnetic Resonance Spectroscopy [PDF]
J. Otvos, M.D.  II-21

Nuclear magnetic resonance (NMR) spectroscopy is being used to determine the concentrations of very-low density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein subclasses of different size. These subclasses have unequal associations with coronary heart disease. Nuclear magnetic resonance distinguishes among the subclasses on the basis of slight differences in the spectral properties of the lipids carried within the particles, which vary according to the diameter of the phospholipid shell. Studies using NMR spectroscopy have shown that individuals with elevated triglycerides are likely to have higher-risk lipoprotein subclass profiles. Triglyceride-rich lipoproteins drive the metabolic reactions that produce LDL of abnormal size and cholesterol content. The quantities of these abnormal LDL particles and the associated risk of coronary heart disease are underestimated by conventional cholesterol measurements. Nuclear magnetic resonance spectroscopy measures lipoprotein subclasses directly and efficiently and produces information that may improve the assessment and management of cardiovascular disease risk.

Postprandial Triglyceride Metabolism in Diabetes Mellitus [PDF]
A. Georgopoulous, M.D.  II-28

Individuals with diabetes have a two-to-four times higher risk of cardiovascular morbidity and mortality compared with nondiabetics. Patients with both type 1 and type 2 diabetes share a similar risk. Studies in individuals with type 1 diabetes have shown a decreased clearance of postprandial triglyceride-rich lipoprotein particles of abnormal composition. Particles isolated from diabetic individuals show abnormal composition and an increased tendency to cause cholesteryl ester accumulation in macrophages and therefore are potentially atherogenic. Various interventions may alter these abnormalities and improve the atherosclerotic risk. These include adopting a high-carbohydrate diet over a high monounsaturated diet, improving glycemic control, infusing insulin intraperitoneally, and using pharmacologic therapies such as the statins.

Brachial Artery Ultrasound: A Noninvasive Tool in the Assessment of Triglyceride-Rich Lipoproteins [PDF]
R. A. Vogel, M.D., F.A.C.C.  II-34

In recent years, endothelial dysfunction has been identified as an early feature of atherosclerosis. Endothelial function can be measured noninvasively by using brachial artery ultrasound. A variety of factors associated with atherosclerosis also impair endothelial function. Some of these factors are lipoproteins such as various forms of low-density lipoprotein, postprandial chylomicron remnants, fasting triglyceride-rich particles, and free fatty acids. A high-fat diet also has an adverse effect on endothelial function. Several interventions can improve endothelial function and, at the same time, reduce cardiovascular events. Measuring endothelial function may eventually serve as a useful index to determine an individual's risk for coronary artery disease.

Nonpharmacologic Treatment of Hypertriglyceridemia: Focus on Fish Oils [PDF]
W. S. Harris, Ph.D.  II-40

Early studies in Greenland Eskimos stimulated further interest in evaluating the effect of Omega-3 fatty acids on coronary artery disease. Later, subsequent studies showed a significant decrease in triglyceride levels in patients receiving high doses of fish oil containing DHA and EPA. Slight increases in low-density lipoprotein were also observed in patients receiving fish oil supplements. These studies have also shown a dose–response effect which persists as long as supplementation continues. Later trials, specifically the Diet and Reinfarction Trial and the Indian Experiment of Infarct Survival, have demonstrated a reduction in cardiac death rates and in the incidence of cardiac symptoms in patients receiving fish oil.

Pharmacologic Management of Triglycerides [PDF]
D. B. Hunninghake, M.D.  II-44

Currently available, cholesterol-lowering pharmacologic agents have been studied for their effect on reducing triglyceride levels. The fibrates increase lipoprotein activity, thereby decreasing the size of triglyceride-rich particles. High doses of niacin can produce decreases in very low-density lipoprotein levels, triglyceride-rich particles, and low-density lipoprotein (LDL) by inhibiting lipoprotein synthesis. By increasing LDL-receptor activity, the statins increase the removal rate of triglyceride-rich particles. Each class of agents produces various degrees of triglyceride lowering, depending on the existing baseline level and other factors. Patients with elevated LDL and who are hypertriglyceridemic should receive statins as first-line therapy. Niacin may be used as an alternative first-line agent in patients with small LDL elevations. Combination therapy, using other agents, may be indicated depending on the patient's levels of triglycerides and LDL.

The opinions expressed in this presentation are those of the panelists and are not attributable to the sponsor or the publisher, editor, or editorial board of Clinical Cardiology. Clinical judgment must guide each physician in weighing the benefits of treatment against the risk of toxicity. References made in the articles may indicate uses of drugs at dosages, for periods of time, and in combinations not included in the current prescribing information.

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