Metabolic Syndrome and Cardiovascular Disease: The Need for LDL Particle Measurements

Robert S. Rosenson, M.D.

The long-term risk of major coronary events (MCEs) associated with the metabolic syndrome was evaluated retrospectively in placebo-treated patients enrolled in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).1 At baseline, the metabolic syndrome was present in 411 or 1,991 (20.6%) subjects in 4S, and 1,467 of 3,188 (46%) in AFCAPS/TexCAPS. The metabolic syndrome identified subjects enrolled in 4S with a 1.5-fold (95% CI 1.2 to 1.8) higher risk of MCEs (31.1% versus 23.5% of subjects with and without the metabolic syndrome), and 1.4-fold (95% CI 1.04 to 1.9) higher risk of MCEs (6.4% versus 4.7% of subjects with and without the metabolic syndrome) enrolled in AFCAPS/TexCAPS. Analysis of individual metabolic risk factors indicated that low HDL cholesterol and high triglyceride levels were associated with an increased risk of MCEs in 4S, whereas hypertension was associated with a high risk of MCEs in AFCAPS/TexCAPS. The increased risk of MCEs associated with the metabolic syndrome remained significant after adjusting for the Framingham risk score.

What may account for the residual risk of MCEs in metabolic syndrome subjects? The Framingham risk equation includes lipid measures of total cholesterol and HDL cholesterol, whereas the metabolic syndrome is defined by lipid criteria that include not only low HDL cholesterol levels (< 40 mg/dL in men and < 50 mg/dL in women), but also high triglycerides (³ 150 mg/dL). Low HDL cholesterol and high triglycerides are commonly accompanied by small LDL particles and high LDL particle concentrations.2 In the Framingham Offspring Study, the number of components of the metabolic syndrome was strongly related to the concentration of total and small LDL particles.3 In the Women’s Health Study4 and Cardiovascular Health Study,5 LDL particle concentration was the most important lipoprotein risk factor for cardiovascular disease in multivariate analysis.

This report by Girman and colleagues demonstrates that metabolic syndrome patients have a higher CHD risk than ascertained from the Framingham risk score. Future analyses should incorporate LDL subclass particle measurements that more accurately describe the dyslipoproteinemia in these high-risk patients.

References:

1. Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR, Beere PA, Gotto AM, Clearfield M. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol. 2004;93:136-41.
2. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002;90:22i-29i.
3. Otvos JD, Cromwell WC, Shalaurova I, Schaefer EJ. LDL particles, not LDL cholesterol, are highly elevated in the metabolic syndrome: results from the Framingham Offspring Study. Circulation. 2003;108(Suppl):IV-740.
4. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-7.
5. Kuller L, Arnold A, Tracy R, Otvos J, Burke G, Psaty B, Siscovick D, Freedman DS, Kronmal R. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2002;22:1175-80.