COMMENTARIES

Small Dense LDL Particles and Metabolic Syndrome in a Sample of Middle-Aged Women. Findings from Progetto Atena

Marco Gentile, Ph.D., Salvatore Panico, M.D., Fabrizio Jossa, M.D., Amalia Mattiello, M.D., Stefania Ubaldi, M.D., Gennaro Marotta, M.D., Paolo Pauciullo, M.D., and Paolo Rubba, M.D., Department of Clinical and Experimental Medicine, University "Federico II" Medical School, Naples, Italy

Please address correspondence to:
Dr. Marco Gentile
Department of Clinical and Experimental Medicine,
University "Federico II"
Via Pansini 5 - 80131 - Naples, Italy
Tel: (+39) 081-7462303
Fax: (+39) 081-5466152
E-mail: margenti@unina.it

The prevalence of the metabolic syndrome (MS) is growing in the general population, particularly in women, and has received increased attention in the past few years. Increasing evidence indicates that the large population of individuals with MS includes a heterogeneous group of disorders with different cardiovascular risk [1].

          Recently, small dense LDL particles (sd-LDL) have attracted considerable attention among the biochemical markers associated with this metabolic abnormality [2,3]. A predominance of sd-LDL particles is associated with a two-to-three-fold increase in risk of coronary heart disease [4] and is also characterized by several abnormalities of the plasma lipid profile, notably elevated triglycerides and low HDL-C concentration [5]; furthermore, sd-LDL have greater susceptibility to oxidative modification than native particles and higher affinity for the arterial wall [6-8].

          Worldwide, changes in dietary pattern (increasing caloric intake especially from animal fat) together with sedentary life-style have produced high prevalence of overweight, obesity, glucose intolerance, and diabetes particularly in women [9,10], even in the Mediterranean area [10,11]. The present analysis has been performed in a population-based sample (N = 210) of middle-aged women with MS from southern Italy, participating to Progetto Atena (N = 5,062 women) to evaluate in women with MS both the prevalence and the risk factor associations of sd-LDL.

          LDL particle separation was performed by an electrophoretic method, Lipoprint System: 7 LDL subfractions were obtained, mean LDL particle size and LDL score (% of sd-LDL) were calculated. Out of the 210 participants, 86 (40.9%) meet the metabolic syndrome criteria. Women with the MS diagnosis have LDL scores (% of sd-LDL particles) significantly higher compared to participants without the metabolic syndrome (median 0 versus 3.6, p < 0.001 by Mann Whitney). Women with the MS diagnosis are slightly older and have higher levels of serum cholesterol, LDL-cholesterol, Apo B, insulin, and high-sensitive CRP. Moreover, the group with the MS shows higher values of insulin, body mass index (BMI), homeostatic assessment model index (HOMA), and lower mean LDL particle diameter, compared with the group without MS.

          Univariate logistic analysis shows a positive and significant relationship of the MS diagnosis, some MS components (HDL and triglycerides), apo B, and insulin levels with the LDL score. In multivariate logistic analysis between LDL score, MS diagnosis, MS components, and other covariates, after controlling for age, insulin, and apo B, metabolic syndrome diagnosis is independently related to high LDL score (upper quintile) (OR 4.00; 95% CI 1.76-9.09; p < 0.001 for MS diagnosis).

          We performed a separate analysis where the individual components of MS were analyzed in their relationship with the top quintile of LDL score. It was demonstrated a significantly independent relationship between two MS components, triglycerides and HDL-C, (OR 4.41; 95% CI 1.22-15.87; p < 0.023 for Ln triglycerides); (OR 0.94; 0.89-0.98; p < 0.009 for HDL-C) and higher LDL score. The independent association of apo B was also confirmed in this model. The sensitivity and specificity of LDL score in relation to the MS diagnosis were 33% and 90%, respectively, while the positive predictive value in our women was 70.7% and the negative predictive value was 66.2%.

          The prevalence of the metabolic syndrome in our population-based sample of southern Italian women is about 41%. This high rate, found for women living in a Mediterranean area, is similar to that found in other North-European [12] and American populations of the same age range [13] and was also recently found in other Italian or Greek population samples [14,15]. It could be due to changes in dietary pattern (increasing caloric intake and intake of animal fat and high glycemic index foods), together with sedentary life-style causing a sharp increase in the prevalence of overweight, obesity, and glucose intolerance, especially in women. Besides the clustering of the usual risk factors in participants with the metabolic syndrome, we detected a significantly higher prevalence of high LDL score for small dense LDL (sd-LDL) in this group of women compared to those without disease. The prevalence of high LDL score in our sample is about 5%, lower than findings of Rizzo et al. [16], but consistent with the prevalence reported by other studies carried out in postmenopausal women of other non-Mediterranean countries [12]. Using similar criteria for defining small dense LDL, the prevalence of small LDL was 35-45% in adult men, 5-10% in men less than 20 years and in premenopausal women, and 15-25% in menopausal women [17]. We detected a strong association between LDL score and MS diagnosis, independent of other covariates (age, insulin level, and apo B). The MS components significantly related to higher LDL score were high triglycerides and low HDL-C. The inverse relationship of LDL score with HDL-C can be explained with the triglyceride enrichment of LDL and HDL particles, observed in many patients with MS, and related to increased activity of cholesteryl ester transfer protein (CETP). This enrichment makes HDL-C and LDL more prone to the lipolytic activity of hepatic lipase witch reduces cholesteryl ester content of both particles [18].

          LDL score, which is the proportion of small LDL particles (subfractions 3-7) to the whole LDL area (subfractions 1-7), has been shown to be significantly related to coronary heart disease (CHD) in multivariate analysis [19-21]. LDL size is considered an important predictor of cardiovascular events and progression of coronary artery disease and the predominance of sd-LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III [22].

          In our population LDL score has a relatively low sensitivity (33%) but a high specificity (90%) in relation to the metabolic syndrome diagnosis. Since a highly specific test is rarely positive in the absence of the disease, the detection of small LDL particle could be helpful for screening among women, whose blood sample is stored in biological bank; it may be also confirmatory, in addition to the usual risk factors, to the diagnosis of metabolic syndrome in the general population.

          In conclusion, since the therapeutic modulation of small LDL particles is possible and helpful in reducing coronary risk [23], the LDL size measurement could be useful in identifying a subsample of high risk patients, with prominent lipoprotein abnormality, among those with the metabolic syndrome diagnosis [22], deserving lipid lowering intervention. Future prospective epidemiological studies are envisaged to explore the specific contribution of this marker to cardiovascular risk.

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