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Primary and Secondary Prevention in Mixed Dyslipidemia: What Do the Guidelines Say?


Recognizing the Importance of Extending Beyond LDL Cholesterol: Focus on Mixed Dyslipidemia

Mixed dyslipidemia is defined as elevations in LDL cholesterol and triglyceride (TG) levels that are often accompanied by low levels of HDL cholesterol. Previously, the combination of high LDL cholesterol and TG was classified under the heading of combined hyperlipidemia and was subsequently identified as the most common inherited lipoprotein phenotype in survivors of myocardial infarction (MI).[1] The predominant mechanism underlying mixed dyslipidemia is hepatic overproduction of very low density lipoprotein (VLDL) particles, leading to increases in both TG and LDL cholesterol.[2] This is in contrast to primary hypertriglyceridemic states that are characterized by reduced degradation of TG-rich lipoproteins. This is often a consequence of reduced efficiency of lipoprotein lipase, the predominant lipoprotein that hydrolyzes TG from the triglyceride-rich lipoproteins, VLDL, and chylomicrons.[3] The prevalence of mixed dyslipidemia is estimated to be between 0.5% and 8.8% in the general population[4,5] and may have its onset in childhood.[6] To gain perspective in regard to CHD risk when both cholesterol and TG are elevated, we evaluated incident CHD in 13 countries defined by populations with elevated mean cholesterol only (median TC > 200 mg/dL) or elevated mean cholesterol and TG (median TG > 150 mg/dL).[7] Figure 1 illustrates the significantly higher incidence of CHD in countries with median elevations in both total cholesterol (TC) and TG (mixed dyslipidemia) compared with TC alone,[7] supporting the concept that the combination of high TC (and LDL cholesterol) and high TG poses greater risk for CHD than elevation in TC (or LDL cholesterol) alone. This concept is further strengthened by evaluating incident CHD in the placebo arm of randomized, clinical trials. As shown in Figures 2 through 4, the highest rate of CHD events has been consistently observed in placebo-treated patients who have elevated TG and LDL cholesterol, often in association with reduced HDL cholesterol.[8-10] Therefore, epidemiological and clinical trials support mixed dyslipidemia as an important predictor of CHD event rates. However, in order to appreciate the extent to which mixed dyslipidemia promotes CHD, a review of the metabolic pathways is essential.

Figure 1. Coronary heart disease (CHD) mortality rates in 13 countries with total cholesterol (TC) > 5 mmol/L stratified by triglyceride (TG) (1.7mmol/L). From Ahmad I, Miller M. Triglycerides and coronary heart disease: a global perspective. J Cardiovasc Risk. 2000;7:303-307. Used with permission.

Figure 2. Bezafibrate infarction prevention study. Highest coronary heart disease (CHD) rates with mixed dyslipidemia. LDL = low density lipoprotein; TG = triglyceride. From No authors listed. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102:21-27. Used with permission.

Figure 3. 4S event rates based on lipid triad or isolated low-density lipoprotein (LDL) elevation in placebo and treated groups. From Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051. Used with permission.

Figure 4. Helsinki Heart Study: high triglyceride and high low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio pose highest risk for coronary heart disease (CHD). From Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85:37-45. Used with permission.

Mixed Dyslipidemia: Pathways to Atherothrombosis

The most prominent mechanism by which mixed dyslipidemia promotes atherothrombosis and CHD is via LDL particle and remnant lipoprotein-mediated cholesterol uptake by macrophages. As illustrated in Figure 5, remnant particles derived from dietary fat (chylomicron remnants) or hepatically synthesized (VLDL) may traverse across the endothelium and LDL that has been oxidized or modified may subsequently be incorporated by macrophages in an unregulated manner.[11] Increased cholesterol within macrophages promotes a proinflammatory milieu characterized by the release of cytokines such as tumor necrosis factor alpha and transcriptional regulators of inflammation such as nuclear factor kappa beta. These are involved in multiple pathways from upregulating adhesion molecule expression and transmigration and subintimal retention of leukocytes to the recruitment of macrophages and activation of other proteins involved in cellular inflammation. Although this process is accelerated when risk factors such as diabetes mellitus and cigarette smoking promote modification of LDL, an increase in remnant particles contributes to this process.[7] As a result, the combination of enhanced LDL modification coupled with remnant excess accentuates foam cell formation, atherosclerotic progression, and ultimately plaque rupture.[12]

Figure 5. Chylomicron remnant-induced development of atherosclerosis. From Yu KC-W, Cooper AD. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332-D354. Used with permission.

Triglycerides as a Marker of Increased Remnants

In the Honolulu Heart Study, an observational study of more than 1100 middle-aged Japanese-American men, an excellent correlation existed between fasting TG and the levels of remnant particles.[13] Although remnants were an independent predictor of CHD events, this association was attenuated after adjustment for TG. Therefore, TG levels serve as a useful predictor of remnant lipoproteins. That is, the higher the level of TG, the greater the likelihood of high levels of atherogenic remnant particles appearing in the circulation and subsequently in the vessel wall.[13] Taken together, if TG serves as a surrogate of atherogenic remnant particles, then the combination of high TG and high LDL-C, as defined by mixed dyslipidemia, would seemingly provide the strongest indicator of elevated CHD risk.