Oxidized LDL and the Metabolic Syndrome
To the Editor:
We would like to comment on the data published by Per Sjogren and colleagues in Arteriosclerosis, Thrombosis, and Vascular Biology.1 They showed that levels of circulating oxidized LDL were not elevated in otherwise healthy men with the metabolic syndrome. Their data are in contrast with the previous findings of the Hulthe group2 and with our data from the Health, Aging, and Body Composition study, a cohort of well-functioning older adults.3 Although the authors did not refer to our previous publication, we would like to comment on the differences between the Stockholm County and the Health, Aging, and Body Composition study.
In both studies the metabolic syndrome was defined according to the Third Report of the National Cholesterol Education (ATPIII). Thus, the contrasting data cannot be attributable to differences in definition. In Health ABC, black and white men and women, age 70 to 79 years, were studied. In the Stockholm County cohort, only white men, age 62 to 64 years, were studied. The association between the metabolic syndrome and a higher prevalence of elevated levels of circulating oxidized LDL in the Health ABC cohort was independent of age, gender, and ethnicity. Although the Health ABC cohort was older, with a restricted age range, this suggests that the contrasting data are not likely to be attributable to differences in age, gender, and ethnicity.
The Health ABC cohort appeared to be representative of the U.S. population. The prevalence of the metabolic syndrome as defined by ATP III (3 or more components) in the Health ABC cohort was 38% (1147 participants with metabolic syndrome) versus 42% in a similar-aged population in the Third National Health and Nutrition Examination Survey (NHANES III). In addition, the prevalence of diabetes, smoking, and hypertension, as well as the mean BMI and waist circumference, mean LDL and HDL cholesterol, and triglyceride levels were similar between the 2 study populations. Other than functional status, there were no other exclusion criteria. Individuals with the metabolic syndrome had twice the odds of having high oxidized LDL (<1.90 mg/dL, ie, >90th percentile of distribution in individuals with no metabolic syndrome components) compared with those not having the metabolic syndrome, after adjusting for age, gender, ethnicity, smoking, and LDL cholesterol.
The prevalence of the metabolic syndrome among 62- to 64-year-old men in the subset of the Stockholm County cohort was lower (8% or 22 participants) than what could be expected (&20%) from the NHANES data. One possible explanation for the lower than expected prevalence could be the exclusion of participants with manifest diabetes, treatment with antihypertensive agents, and BMI outside the range 19 kg/m2 to 35 kg/m2. The exclusion of obese and diabetics could have affected the relation between the metabolic syndrome and circulating oxidized LDL. Previously, we have shown that both obesity and diabetes contributed to the increase in oxidized LDL independent of LDL cholesterol levels.3–5
Three other possible reasons for the observed differences, which cannot be excluded at this time are: (1) a small sample size, which limits statistical power and may have predisposed to type 2 error in the Sjogren article (n=22 for metabolic syndrome); (2) fundamental metabolic differences between the populations, possibly caused by differences in genetic architecture (we would consider this unlikely but still possible); and (3) a lack of adjustment for LDL levels in the Sjogren analyses, an adjustment we found to be critical because LDL and ox-LDL are highly correlated.
Although we do not question the merits of this study, we wanted to put some of the data in a larger perspective.
Sjogren P, Basu S, Rosell M, Silveira A, de FU, Vessby B, Hamsten A, Hellenius ML, Fisher RM. Measures of oxidized low-density lipoprotein and oxidative stress are not related and not elevated in otherwise healthy men with the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2005; 25: 2580–2586.
Holvoet P, Kritchevsky SB, Tracy RP, Mertens A, Rubin SM, Butler J, Goodpaster B, Harris TB. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort. Diabetes. 2004; 53: 1068–1073.
Holvoet P, Mertens A, Verhamme P, Bogaerts K, Beyens G, Verhaeghe R, Collen D, Muls E, Van de WF. Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2001; 21: 844–848.
Holvoet P, Harris TB, Tracy RP, Verhamme P, Newman AB, Rubin SM, Simonsick EM, Colbert LH, Kritchevsky SB. Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderly: findings from the Health, Aging, and Body Composition study. Arterioscler Thromb Vasc Biol. 2003; 23: 1444–1448.