Carotid Atherosclerosis In Subjects Research Articles

A comparison of the NCEP-ATPIII, IDF and AHA/NHLBI metabolic syndrome definitions with relation to early carotid atherosclerosis in subjects with hypercholesterolemia or at risk of CVD: Evidence for sex-specific differences

The metabolic syndrome is associated with increased risk of cardiovascular disease. However, the association between metabolic syndrome and atherosclerosis in hypercholesterolemic patients remains unknown. We examined the association between carotid atherosclerosis and metabolic syndrome definitions using the NCEP-ATPIII, International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) definitions in 1782 subjects at risk of cardiovascular disease including 926 with hypercholesterolemia (LDL cholesterol ≥160 mg/dL; mean = 203 mg/dL). Irrespective of definition, carotid intima-media thickness was significantly higher in both men and women diagnosed with the MetS compared to those without MetS. This relationship persists in males with hypercholesterolemia, independently of LDL cholesterol level. Regression analyses, both unadjusted and adjusted for traditional risk factors, indicate that in males the AHA/NHLBI definition, and in females the IDF definition are the strongest predictors of carotid atherosclerosis. These results highlight important gender differences that exist in the current clinical definitions of the metabolic syndrome, with regards to predicting early atherosclerotic lesions. In addition, this study shows that in males with hypercholesterolemia, MetS is independently associated with increased atherosclerosis, supporting screening for MetS among people at risk of CVD.

Components of the Metabolic Syndrome and Carotid Atherosclerosis

Elevated blood pressure is among the factors that contribute to the metabolic syndrome (MetS). It is not known whether subjects with MetS and elevated blood pressure are at the same cardiovascular risk as subjects with MetS but without elevated blood pressure. To clarify this point, we have evaluated the prevalence of carotid atherosclerosis in subjects with MetS with or without elevated blood pressure. A large population was examined (842 women and 1011 men). Blood pressure, lipids, glucose, and waist were measured by routine methods. Carotid atherosclerosis was evaluated by echo Doppler examination. The prevalence of MetS was 24.4% in women and 28.7% in men. The prevalence of carotid atherosclerosis was 35.1% in women and 37.3% in men (p=NS), and increased with increasing number of MetS components. Age, smoking, and systolic blood pressure (SBP) were associated with the presence of carotid atherosclerosis (logistic model), whereas age, high-density lipoprotein cholesterol, and SBP were associated with the extent of atherosclerosis (linear model). When comparing subjects with an equal number of MetS components, the prevalence of carotid atherosclerosis was significantly higher in subjects with elevated blood pressure than in those without. No difference in carotid atherosclerosis prevalence was found in subjects bearing or not bearing components of the syndrome other than elevated blood pressure. The present findings demonstrate that subjects with MetS and elevated blood pressure have increased carotid atherosclerosis compared with subjects with MetS but without elevated blood pressure. The diagnosis of MetS per se might not adequately identify subjects at elevated cardiovascular risk.

Associations Between Liver Histology and Early Carotid Atherosclerosis in Subjects With Nonalcoholic Fatty Liver Disease *

I read with interest the article by Villanova et al.1 regarding the significant associations between liver histology and endothelial dysfunction, as measured by flow-mediated vasodilation (FMV), in patients with nonalcoholic fatty liver disease (NAFLD). They reported that NAFLD patients had a significant decrease in percent FMV when compared to age- and sex-matched controls, and that the severity of NAFLD strongly correlated with a low FMV, independently of age, sex, body mass index, and homeostasis model assessment (HOMA)-IR insulin resistance score. Additionally, the 10-year estimated probability of cardiovascular events was moderately higher in those with NAFLD.1 These findings confirm and extend the observations of some recent cross-sectional studies documenting that patients with NAFLD, as diagnosed by ultrasonography, had a markedly greater carotid artery intima-media thickness (IMT) and increased prevalence of carotid plaques compared with controls.2-4 More recently, we enrolled 50 consecutive NAFLD patients and 40 healthy controls with normal liver ultrasonography and normal liver enzymes who were matched for sex (M/F 30/20 vs. 26/14), age (46 ± 4 vs. 46 ± 3 years) and BMI (26.6 ± 1.6 vs. 26.2 ± 1.8 kg/m2). The diagnosis of NAFLD was based on liver biopsy and the exclusion of known etiological factors of chronic liver disease. According to classification of Brunt et al.,5 liver histopathology results were steatosis alone in 7 patients, NASH with fibrosis score of 0 in 14 patients, NASH/fibrosis score 1 in 16 patients, NASH/fibrosis score 2 in 8 patients, and NASH/fibrosis score 3 in 5 patients. None had cirrhosis (a fibrosis score of 4). Compared with controls, NAFLD patients had a significantly higher prevalence of the metabolic syndrome (MetS)6 (54% vs. 2.5%) and higher values of liver enzymes (AST 48 ± 21 vs. 22 ± 3 U/L; ALT 102 ± 50 vs. 24 ± 4 U/L) and HOMA-IR score (4.14 ± 2 vs. 1.73 ± 1). Smoking history and low-density lipoprotein (LDL) cholesterol concentration did not differ between the groups. Importantly, NAFLD patients had a markedly greater carotid IMT (1.10 ± 0.2 vs. 0.84 ± 0.13 mm; P < .001), with no differences between sexes. The significant differences in carotid IMT that were observed between the groups were little affected by adjustment for age, sex, HOMA-IR score, and presence of MetS (P = .005 by analysis of covariance). Among NAFLD patients there was a strong association between the degree of hepatic fibrosis and carotid IMT (P < .001). By logistic regression analysis, hepatic fibrosis score independently predicted (P < .001) carotid IMT after adjustment for age, sex, HOMA-IR score, and MetS. Overall, therefore, the evidence from this and other studies1-4 supports the possibility that NAFLD is atherogenic beyond its close relationship to the MetS phenotype, possibly through increased oxidative stress, subclinical inflammation, postprandial lipemia, and decreased adiponectin concentrations.7-10 These findings might have important clinical and public health implications. Since NAFLD patients are at increased cardiovascular risk, the casual detection of NAFLD on an ultrasound examination should alert to the possible coexistence of multiple underlying cardiovascular risk factors warranting evaluation and treatment as much as the risk for advancing liver disease. Prospective studies are clearly needed to validate these findings and better estimate the individual cardiovascular risks associated with the presence of MetS and NAFLD. Giovanni Targher M.D.*, * Division of Internal Medicine, “Sacro Cuore–don G. Calabria” Hospital of Negrar, Verona, Italy.

Associations Between Liver Histology and Early Carotid Atherosclerosis in Subjects With Nonalcoholic Fatty Liver Disease *

The above letter is very timely. It presents data demonstrating that subjects with nonalcoholic fatty liver disease have increased atheroma mass, as demonstrated by an increased carotid intima-medial thickness (IMT) when compared to controls. Carotid IMT is another marker of atheroma progression. While abnormalities of flow-mediated vasodilation identify early mechanical abnormalities in the arterial wall, IMT tends to demonstrate later atherosclerotic structural abnormalities. Interestingly, an IMT < 0.87 mm carries a low odds ratio of coronary heart disease, and an IMT ≥ 1.10 carries a high odds ratio of coronary heart disease: IMTs found by these authors in their controls and subjects with NAFLD.1 Although no specific structural characterization of the increased IMT (fatty infiltration, fibrofatty disease, or fibrocalcific) is made by the authors, it would seem that these patients most likely will have fatty and fibrofatty infiltrates. The fatty atheroma components are amenable to therapy. Therefore, patients with nonalcoholic fatty liver disease having either altered flow-mediated vasodilation or increased carotid IMT could be candidates for aggressive treatment of the liver disease, cholesterol lowering, and treatment of any related metabolic syndromes. This would help to modify and potentially decrease atheroma mass and progression. These findings emphasize the importance of evaluating cardiovascular risk and cardiovascular disease in patients diagnosed with nonalcoholic fatty liver disease. David McPherson*, * Northwestern University, Chicago, IL.

Carotid Atherosclerosis in Subjects with Diabetes

Carotid Atherosclerosis in Subjects with Diabetes

Relation of low bone mineral density and carotid atherosclerosis in postmenopausal women

Due to the lack of convincing data about the association between atherosclerosis and osteoporosis, we evaluated the association between carotid atherosclerosis and bone mineral density in a sample of apparently healthy postmenopausal women who underwent health-screening in our hospital. We also evaluated a bone turnover marker, osteocalcin; we divided the population into 2 groups according to osteocalcin levels. We found a high prevalence of carotid atherosclerosis in subjects with high osteocalcin levels and low bone mineral density.

Wall shear stress is associated with intima-media thickness and carotid atherosclerosis in subjects at low coronary heart disease risk.

Systemic and local coronary heart disease (CHD) risk factors participate in atherogenesis. The role of wall shear stress, a major local risk factor, remains to be elucidated. Two hundred thirty-four subjects were carefully characterized for the presence of hypertension, hyperlipidemia, diabetes mellitus, obesity, and cigarette smoking and were divided into low- and high-risk groups. They underwent echo-Doppler examination of the carotid arteries. Atherosclerotic plaques and stenoses were detected, intima-media thickness (IMT) was measured, and wall shear stress was calculated. One hundred eight subjects were classified as low-risk individuals. The prevalence of carotid atherosclerosis in this group was 18.5%. Wall shear stress was 24.23+/-7.21 dyne/cm(2) in individuals without atherosclerosis and 16.89+/-5.48 in those with atherosclerosis (P<0.000). In multiple regression analyses, wall shear stress, body mass index, and HDL cholesterol were inversely associated and total cholesterol was directly associated with the presence of atherosclerosis; only wall shear stress was associated with IMT. In the high-risk group the prevalence of atherosclerosis was 45.2%. Wall shear stress was 20.44+/-6.82 dyne/cm(2) in subjects without atherosclerosis and 17.84+/-6.88 dyne/cm(2) in those with atherosclerosis (P=0.037). Age was the only variable associated with both carotid atherosclerosis and IMT. In subjects traditionally considered at low CHD risk, intima-media thickening and carotid atherosclerosis are significantly associated with low wall shear stress. In contrast, in subjects at high CHD risk, the contribution of wall shear stress seems to be masked, and age becomes the only factor significantly associated with both carotid atherosclerosis and IMT.

Association of high sensitivity C-reactive protein with coronary heart disease prediction, but not with carotid atherosclerosis, in patients with hypertension.

Inflammation is believed to predict coronary heart disease (CHD) in healthy subjects and in patients with atherosclerosis. We investigated the association of high sensitivity C-reactive protein (HS-CRP) and other inflammatory markers on cardiovascular outcome, and carotid atherosclerosis in hypertensive patients. We conducted a cross-sectional study of 122 hypertensive patients and compared them with 64 normotensive volunteers. We measured circulating levels of HS-CRP, white blood cells (WBC), albumin, fibrinogen, erythrocyte sedimentation rate, and interleukin-6, and examined the associations with traditional risk factors of CHD, carotid atherosclerosis, and a 10-year risk of CHD, based on the risk prediction algorithm of the Framingham model. The mean of blood pressure (BP) of the hypertensive patients was 163/102 mmHg (normotensives; 118/79 mmHg). The 10-year risk of CHD was higher in the hypertensive patients (9.3 +/- 7.3%) compared with the normotensive volunteers (4.3 +/- 4.2%). Albumin and HS-CRP were significantly higher in the hypertensive patients. Multivariate analysis showed that among markers, only HS-CRP was associated with 10-year risk of CHD (beta=0.13, p=0.03). The BP, body mass index, high-density lipoprotein, WBC count, fibrinogen, and cardiac hypertrophy increased across quartiles of HS-CRP. There was no association between HS-CRP and carotid atherosclerosis in subjects with hypertension and normotension. A higher HS-CRP level was associated with a higher risk score of CHD, but not with carotid atherosclerosis, in patients with hypertension.

Characterization of polymorphic structure of SREBP-2 gene: role in atherosclerosis

Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors that control the metabolism of cholesterol and fatty acids in mammalian cells. We postulated that polymorphisms (SNPs) in SREBP-2 gene might influence lipid parameters and the risk of coronary atherosclerosis. PCR-SSCP analysis and direct sequencing of DNA from 64 asymptomatic hypercholesterolemic men revealed seven genetic SREBP-2 SNPs. The genotype distribution of four of these SNPs (1668G>T, 1784G>C, 3474T>C and 3705C>T), and their influence on plasma lipid values and clinical parameters was studied in 655 asymptomatic men previously selected for the presence of at least one cardiovascular risk factor (hypertension, hypercholesterolemia, tobacco consumption). No significant relation was found with lipid parameters but there was a significant association between the 1784G>C polymorphism and intima-media thickness (IMT) measured in 497 subjects. Thus, a common variation in the SREBP-2 gene is related with early-stage carotid atherosclerosis in subjects with a risk of cardiovascular events without detectable change in plasma lipid levels.

The Arg allele in position 192 of PON1 is associated with carotid atherosclerosis in subjects with elevated HDLs

Human serum paraoxonase (PON1) is an HDL-associated enzyme involved in the protection of lipoproteins from oxidation. A polymorphism at position 192 (Gln/Arg) influences its activity in a substrate-dependent manner. The aim of the present study was to evaluate, in vivo, the contribution of the PON1-192 polymorphism to the protective effect of HDLs. Three hundred and forty seven subjects in the upper and lower decile of sex-specific HDL cholesterol distribution were selected from participants in a cardiovascular disease prevention study. PON1 genotypes were determined by PCR amplification and restriction analysis. Blood pressure, height, weight, smoking and alcohol habits, as well as the presence of familial or personal history of CHD were recorded. Plasma lipids and blood glucose were measured by routine enzymatic methods. As a measure of antiatherogenic HDL effect, carotid atherosclerosis was assessed by ultrasonography. Allele and genotype frequencies did not differ significantly between low- and high-HDL groups. Similarly, no significant difference was observed among genotypes in all variables studied. Subjects with Gln/Arg or Arg/Arg had more carotid abnormalities than Gln/Gln with an adjusted odds ratio (OR) of 3.27 (95% CI, 1.61–6.64, P=0.001) for abnormal carotid score. Stepwise logistic regression analysis showed that in the whole population age and presence of low-HDL were the only independent predictors for abnormal carotid score. In low-HDL, age was the only independent predictor entered into the model (OR 1.09/year, P<0.0001); in high-HDL, age entered first (OR, 1.07/year, P=0.001), followed by the presence of Gln/Arg or Arg/Arg (OR, 2.94, 95% CI, 1.47–5.91, P=0.002). In conclusion, in subjects with low levels of HDL cholesterol, carotid atherosclerosis is not related to PON1-192 polymorphism. On the other hand, in subjects with elevated concentration of HDL cholesterol, the presence of carotid atherosclerosis is significantly associated with the arginine variant in position 192 of the PON1 gene.

Mechanical Forces and Carotid Atherosclerosis in Patients with Risk Factors for Atherosclerosis

P115 Mechanical stresses to the arterial wall were evaluated in the carotid artery in 117 patients with risk factors for atherosclerosis including hypertension, dyslipidemia, and diabetes mellitus. Circumferential wall tension and shear stress were evaluated using Laplace’s law and Poiseuillean‘s parabolic model of flow velocity distribution. Arterial strain was also evaluated as the circumferential wall stretch. Wall tension was significantly related to BMI (r=0.40, p&lt;0.0001), systolic pressure (r=0.79, p&lt;0.0001), triglyeride (r=0.19, p&lt;0.05) as well as HDL cholesterol (r=-0.22, p&lt;0.05), while shear stress showed significant relationships with age (r=-0.34, p&lt;0.001), pulse pressure (r=-0.27, p&lt;0.01) and HDL-cholesterol (r=0.19, p&lt;0.05). On the other hand, arterial strain did not correlate with any risk factor. Carotid intima-media thickness (IMT) showed a significant positive correlation with peak wall tension (r=0.44, p&lt;0.0001) and mean wall tension (r=0.31, p&lt;0.001), and a significant negative correlation with peak systolic shear stress (r=0.34, p&lt;0.001) and mean shear stress (r=-0.42, p&lt;0.0001), while there was no significant relationship between arterial strain and IMT. Stepwise regression analysis revealed that low shear stress and high wall tension were independently associated with IMT in the total subjects with risk factors. Furthermore, it revealed that wall tension was independently associated with IMT in hypertensive patients, while shear stress was an independent determinant of IMT in normotensive subjects. These findings indicate that both wall tension and shear stress are associated with carotid atherosclerosis in subjects with risk factors for atherosclerosis. However, the degree of contribution of mechanical forces to atherosclerosis differs among risk factors.

Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus ( PON1) are the leucine (L allele)→methionine (M allele) and the glutamine (Q allele)→arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age ( β=0.34, P<0.0001), total plasma cholesterol ( β=0.17, P=0.0109) and the LL/QQ genotype of the PON1 gene ( β=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.