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Introduction: Leucocyte telomere length (LTL) is an important determinant of telomere function and cellular replicative capacity. The aim of the present study was to examine prospectively the associations between telomere shortening (TS) and both the progression of atherosclerosis and the incidence of cardiovascular events (CVEs).Materials and Methods: Leucocyte telomere length was measured by quantitative polymerase chain reaction to determine the ratio of telomere length to single-copy gene (T/S) in 768 subjects (462 female and 306 male) enrolled in a large general population survey [the Progressione della Lesione Intimale Carotidea (PLIC study)]. Common carotid artery intima-media thickness was determined at baseline and after 6 years of follow-up, and the associations between TS and the progression of atherosclerosis and incidence of CVEs were evaluated.Results: Mean LTL was 1.25 ± 0.92 T/S (median 1.14) at baseline and 0.70 ± 0.37 T/S (median 0.70) after 6 years of follow-up. Median 6-year LTL change was -0.46 T/S [interquartile range (IQR) -0.57 to 1.06], equating to -0.078 T/S [IQR(-0.092 to 0.176)] per year. Of note, telomere lengthening occurred in 30.4% of subjects. After adjustment for classical cardiovascular disease (CVD) risk factors (age, gender, smoking, physical activity, alcohol consumption, systolic blood pressure, glucose levels, lipid profile and therapies), TS was associated with incident subclinical carotid vascular damage [hazard ratio (HR) 5.19, 95% confidence interval (CI) 1.20-22.4, P = 0.028]. Finally, subjects in whom LTL shortened over time showed an increased risk of incident CVE, compared to those in whom LTL lengthened (HR 1.69, CI 1.02-2.78, P = 0.041).Conclusion: These data indicate that TS is associated with increased risk of subclinical carotid vascular damage and increased incidence of CVEs beyond CVD risk factors in the general population, whereas LTL lengthening is protective. [ABSTRACT FROM AUTHOR]

Objectives Patients with chronic kidney disease ( CKD) often present with reduced plasma HDL cholesterol ( HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease. Design A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min−1] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study ( n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects. Results Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level ( P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917-0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group. Conclusions CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression. [ABSTRACT FROM AUTHOR]

Objective. Resistin is an adipokine that has been suggested to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type II diabetes in humans. A common single nucleotide polymorphism (SNP) (-420C/G) in the promoter of resistin is associated with increased resistin plasma levels and susceptibility to type II diabetes. The aim of this study was to investigate the association of the -420C/G polymorphism with metabolic syndrome, obesity, myocardial infarction and kidney disease. Design and results. First we studied 1542 subjects from the PLIC study (a population based cohort). GG carriers showed an higher prevalence of obesity and metabolic syndrome as well as increased plasma triglycerides levels, BMI, systolic and diastolic blood pressure and cardiovascular risk according to Framingham algorithm (P < 0.05 for all). Next we investigated the presence of the -420C/G resistin polymorphism in a case-control study that included 300 subject with myocardial infarction and 300 age and sex matched controls and then we studied the role of the -420C/G SNP in 88 patients with mild to moderate renal dysfunction. No statistically significant differences in allele frequencies between the PLIC study, the myocardial infarction (MI) cases and the subjects with renal dysfunction were observed. Pro-inflammatory gene expression profiling of peripheral blood mononuclear cells failed to detect any difference between wild type subjects and carriers of the rare allele. Conclusion. Our data suggest that the presence of the -420C/G SNP of the resistin gene is associated with increased obesity and metabolic syndrome, although it is not different in subjects at high cardiovascular risk such as patients with myocardial infarction or patients with renal dysfunction compared with controls. [ABSTRACT FROM AUTHOR]

Objective. Resistin is an adipokine that has been suggested to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type II diabetes in humans. A common single nucleotide polymorphism (SNP) (−420C/G) in the promoter of resistin is associated with increased resistin plasma levels and susceptibility to type II diabetes. The aim of this study was to investigate the association of the -420C/G polymorphism with metabolic syndrome, obesity, myocardial infarction and kidney disease. Design and results. First we studied 1542 subjects from the PLIC study (a population based cohort). GG carriers showed an higher prevalence of obesity and metabolic syndrome as well as increased plasma triglycerides levels, BMI, systolic and diastolic blood pressure and cardiovascular risk according to Framingham algorithm ( P < 0.05 for all). Next we investigated the presence of the −420C/G resistin polymorphism in a case-control study that included 300 subject with myocardial infarction and 300 age and sex matched controls and then we studied the role of the −420C/G SNP in 88 patients with mild to moderate renal dysfunction. No statistically significant differences in allele frequencies between the PLIC study, the myocardial infarction (MI) cases and the subjects with renal dysfunction were observed. Pro-inflammatory gene expression profiling of peripheral blood mononuclear cells failed to detect any difference between wild type subjects and carriers of the rare allele. Conclusion. Our data suggest that the presence of the −420C/G SNP of the resistin gene is associated with increased obesity and metabolic syndrome, although it is not different in subjects at high cardiovascular risk such as patients with myocardial infarction or patients with renal dysfunction compared with controls. [ABSTRACT FROM AUTHOR]

Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, Maggi FM, Catapano AL (University of Milan; and Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo; Italy). Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med 2005; 258: 21–27. Toll-like receptor 4 (TLR-4) is believed to contribute to the initiation and progression of atherosclerosis. The association of the D299G polymorphism of the TLR-4 gene with the progression of coronary and carotid atherosclerosis, risk of cardiovascular events and myocardial infarction is controversial. We have investigated whether the presence of the D299G polymorphism and the co-segregated T399I polymorphism affects the intima-media thickness (IMT) in the general population. The PLIC study population ( n = 1256) was genotyped for the D299G and the T399I polymorphisms. The presence of both the D299G and T399I alleles was observed in the 13.0% of the population, carriers of the T399I alone were 1.8% and of the D299G alone were 0.9%. No difference in IMT was detected within the carriers of the D299G and T399I alleles and the wild-type subjects in the PLIC population. Furthermore, we investigated whether monocyte from D299G to T399I subjects present a defective response to CD40, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, cyclo-oxygenase (COX)-2 and PTX3 expression induced by lipopolysaccharide (LPS). When the monocyte-derived macrophages of these subjects were challenged with LPS (1 μg mL−1), no impact of the polymorphisms on the induction of CD40, MCP-1 and PTX3 was observed. Only IL-6 and COX-2 induction by LPS resulted reduced in the D299G/T399I carriers. The presence of the D299G and T399I polymorphisms of the TLR-4 gene does not play a major role on the progression of carotid atherosclerosis. Macrophages from the subjects carrying the polymorphisms show an impaired response to LPS limited only to a IL-6 and COX-2. [ABSTRACT FROM AUTHOR]

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I 2 =63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I 2 =59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I 2 =57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

BACKGROUND#ENTITYSTARTX02014;: Adaptive T-cell response is promoted during atherogenesis and results in the differentiation of naïve CD4(+)T cells to effector and/or memory cells of specialized T-cell subsets. Aim of this work was to investigate the relationship between circulating CD4(+)T-cell subsets and atherosclerosis. METHODS AND RESULTS#ENTITYSTARTX02014;: We analyzed 57 subsets of circulating CD4(+)T cells by 10-parameter/8-color polychromatic flow cytometry (markers: CD3/CD4/CD45RO/CD45RA/CCR7/CCR5/CXCR3/HLA-DR) in peripheral blood from 313 subjects derived from 2 independent cohorts. In the first cohort of subjects from a free-living population (n=183), effector memory T cells (T(EM): CD3(+)CD4(+)CD45RA(-)CD45RO(+)CCR7(-) cells) were strongly related with intima-media thickness of the common carotid artery, even after adjustment for age (r=0.27; P<0.001). Of note, a significant correlation between T(EM) and low-density lipoproteins was observed. In the second cohort (n=130), T(EM) levels were significantly increased in patients with chronic stable angina or acute myocardial infarction compared with controls. HLA-DR(+)T(EM) were the T(EM) subpopulation with the strongest association with the atherosclerotic process (r=0.37; P<0.01). Finally, in animal models of atherosclerosis, T(EM) (identified as CD4(+)CD44(+)CD62L(-)) were significantly increased in low-density lipoprotein receptor and apolipoprotein E deficient mice compared with controls and were correlated with the extent of atherosclerotic lesions in the aortic root (r=0.56; P<0.01). CONCLUSIONS#ENTITYSTARTX02014;: Circulating T(EM) cells are associated with increased atherosclerosis and coronary artery disease in humans and in animal models and could represent a key CD4(+)T-cell subset related to the atherosclerotic process. (J Am Heart Assoc. 2012;1:27-41.).