Tumor necrosis factor-alpha is a marker of familial combined hyperlipidemia, independently of metabolic syndrome.

It is unclear whether an association between familial combined hyperlipidemia (FCHL) and inflammatory markers exists, independently of age, sex, body weight, insulin resistance, and metabolic syndrome. Serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein 1, interleukin 6, tumor necrosis factor-alpha (TNF-alpha), and high-sensitive C-reactive protein were determined in 135 probands with FCHL and in 146 normolipidemic, normotensive, normoglycemic healthy subjects. Insulin resistance was evaluated using homeostasis model assessment (HOMA). All inflammatory parameters, except interleukin 6, were significantly higher in FCHL according to medians or mean comparisons. After adjustment for age, sex, body mass index, and HOMA, only TNF-alpha remained an independent predictor of FCHL status by binary logistic regression (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.07-1.31; P = .001). In particular, elevated levels of TNF-alpha (above the 90th and 95th percentiles of the value observed in the control group, 9.6 and 9.8 pg/mL, respectively) were independent predictors of FCHL status: for TNF-alpha above the 90th percentile, OR was 7.91 (95% CI, 3.27-19.13; P < .001), and for TNF-alpha above 95th percentile, OR was 13.08 (95% CI, 4.60-37.15; P < .0001). The independent role of TNF-alpha as predictor of FCHL status was confirmed after adjustment for components of the metabolic syndrome (P = .007 and P = .003, for TNF-alpha values above 90th and 95th percentiles, respectively). In conclusion, among the inflammatory markers most commonly measured, only TNF-alpha was associated with FCHL independently of age, sex, body mass index, and HOMA. The association of TNF-alpha with FCHL was also independent of the metabolic syndrome.

Small dense LDL particles and metabolic syndrome in a sample of middle-aged women. Findings from Progetto Atena.

Metabolic Syndrome (MS) is highly prevalent in the general population. Recently, small dense LDL (sd-LDL) particles have been considered a risk marker in MS diagnosis. We analyzed cross-sectionally the association between sd-LDL and MS in a population-based sample of 210 middle-aged southern Italian women; among them 86 participants had MS (prevalence 40.9%). LDL particle separation was performed by Lipoprint System: seven LDL subfractions were obtained and LDL score (% of sd-LDL particles) calculated. Women with the MS diagnosis had significantly higher LDL score as compared to participants without MS diagnosis (median 0 vs. 3.6, p<0.001 by Mann Whitney). The univariate analysis showed a positive and significant association between MS diagnosis (OR 4.80; 95% CI 2.29-10.18; p<0.001 for MS diagnosis) and some MS components Triglycerides (TG), HDL Cholesterol (HDL-C), (OR 14.82; 95% CI 5.24-41.88; p<0.001 for Ln TG); (OR 0.92; 95% CI 0.89-0.95; p<0.001 for HDL-C) and LDL score. Apo B and insulin levels were also positively related to the presence of sd-LDL (OR 31.56; 95% CI 5.58-178.29; p<0.001 for apo B); (OR 1.07; 95% CI 1.00-1.15; p<0.05 for insulin). After controlling for age, insulin and apo B, MS diagnosis (OR 4.0; 95% CI 1.76-9.09; p<0.001 for MS diagnosis) and MS components (TG, HDL-C) (OR 4.41; 95% CI 1.22-15.87; p=0.023 for Ln TG); (OR 0.94; 95% CI 0.89-0.98; p=0.009 for HDL-C) remained significantly associated with high LDL score (upper quintile). Our results suggest that sd-LDL particles could be a valuable marker for diagnosis and severity of the MS. Future prospective epidemiological studies are envisaged to explore the specific contribution of this marker on cardiovascular risk. LDL size measurement could be an useful tool for identifying a subsample patients with prominent lipoprotein abnormality, within the large population with the MS diagnosis, and who are candidates for intensive lipid-lowering interventions.

Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia.

Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.

Small dense low-density lipoprotein in familial combined hyperlipidemia: Independent of metabolic syndrome and related to history of cardiovascular events.

INTRODUCTION: It is unclear whether small dense low-density lipoprotein (sdLDL) are associated with familial combined hyperlipidemia (FCHL), independently of the metabolic syndrome (MS). It is also unclear whether sdLDL are related to history of cardiovascular (CVD) events in FCHL patients, independently of MS. PATIENTS AND METHODS: Serum levels of sdLDL, expressed as percentage of total LDL cholesterol (LDL score), were determined in 137 probands with FCHL and in 133 normolipidemic, normotensive, normoglycemic healthy subjects. RESULTS: In binary logistic regression age- and gender-adjusted LDL score values above the 90th and 95th percentiles of the values in the control group (10.23 and 13.11%, respectively) were found to be significant predictors of FCHL status, independently of MS diagnosis (p=0.007 and p<0.0001, respectively). Values of the LDL score above the 90th and the 95th percentile of the control group resulted to be significantly related to FCHL status, even after adjustment for the components of MS (p=0.006 and p=0.001, respectively). Among FCHL patients, values of the LDL score above 95th percentile of the values in the control group were found to be significantly related to personal and/or family history of CVD events, independently of age, gender, total cholesterol, apolipoprotein (apo) B, and MS status (p=0.016). The same significant relationship was found adjusting for all components of MS (p=0.034). CONCLUSIONS: High concentrations of sdLDL are highly specific markers of FCHL, independently of concomitant MS. In FCHL patients high levels of sdLDL are related to history of CVD events, independently of MS, total cholesterol and apo B.