Standardized ultrasound protocol, trained sonographers and digital system for carotid atherosclerosis screening.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (IMT), a valid measure of atherosclerotic disease, has been proposed to be included in the algorithms for cardiovascular risk stratification. However, assessment of carotid IMT is still not easily performed in an office setting. In the present study, we evaluated the reproducibility of a standardized protocol for carotid artery atherosclerosis screening. METHODS: Carotid arteries of 30 patients were scanned twice (interval 1-10 days) by six trained sonographers, using portable ultrasound systems. A screening protocol was adapted from methods used in clinical trials in which carotid IMT was the primary outcome measure. To test the reproducibility of the method, variability between the two scans was analyzed. RESULTS: A high level of agreement was found between the scans for measurement of mean common carotid IMT [mean difference S0.002, 95% confidence interval (CI) S0.011 to 0.006, PU0.435], maximum region common carotid IMT (mean difference S0.002, 95% CIS0.017 to 0.014, PU0.779) and mean maximum IMT including the common, bifurcation and internal carotid arteries (mean differences 0.021, 95% CI S0.006 to 0.047, PU0.166). No significant differences were found between scans with regard to the average number of carotid segments visualized, the number of atherosclerotic plaques or plaque burden. CONCLUSION: Reliable IMT measurements can be obtained using a standardized protocol performed by trained sonographers using a digital portable ultrasound system in an office setting.

G-6A polymorphism of angiotensinogen gene modulates the effect of blood pressure on carotid intima-media thickness. The Bogalusa Heart Study.

BACKGROUND: The adverse association between blood pressure and carotid artery intima-media thickness (IMT), a surrogate measure of subclinical atherosclerosis, is well-known. However, whether the G-6A polymorphism of the angiotensinogen (AGT) gene, a candidate gene of hypertension and vascular remodeling, modulates this relationship is unknown. METHODS: In 662 white and black subjects aged 25 to 43 years (73.4% white, 39.7% male), common carotid IMT was measured by B-mode ultrasonography. RESULTS: The variant A-6 allele frequency was higher in blacks than in whites (0.850 v 0.448, P < .0001). In a bivariate analysis, there were no differences in mean arterial blood pressure and common carotid IMT between carriers and noncarriers of the G allele in whites, blacks, or the total sample, after adjusting for gender, age, and race. In a multivariable regression analysis that included the status of the G allele (carriers versus noncarriers) along with gender, age, mean arterial blood pressure, body mass index, LDL cholesterol, triglycerides:HDL cholesterol ratio, homeostasis model assessment of insulin resistance, smoking, and race (in the total sample), mean arterial blood pressure was significantly and adversely associated with common carotid IMT in whites, blacks, and the total sample. This adverse positive relationship between mean arterial blood pressure and common carotid IMT was noted among noncarriers but not carriers of the G allele (comparison of slopes, P = .02) in the total sample. Although the interaction was not significant (P = .2 and P = .05 in whites and blacks, respectively), a trend similar to that in the total sample was found in both races. CONCLUSIONS: In a recessive manner, the genetic variant (G-6A) of the AGT gene modulates the association between blood pressure and carotid IMT in young adults.

Predictors of carotid intima-media thickness progression in young adults: the Bogalusa Heart Study.

BACKGROUND AND PURPOSE: We sought to evaluate the predictors of carotid intima-media thickness (CIMT) progression in young adults and to determine whether they differed between the sexes. Although risk factors for the progression of atherosclerosis in middle-aged and elderly adults are well known, they are less well understood in young adults. CIMT is a validated measure of subclinical atherosclerosis. METHODS: B-mode ultrasound images of the far walls of both carotid arteries were obtained in 336 young adults in the Bogalusa Heart Study, whose mean+/-SD age was 32.3+/-3.0 years. CIMT and risk factors were measured at baseline (1995-1996) and after 5.8+/-0.6 years. Multivariable regression was used to determine the predictors of CIMT progression. RESULTS: CIMT progression rates in women (0.015+/-0.024 mm/y) and men (0.020+/-0.027 mm/y) were not statistically different after controlling for body mass index (P=0.155). Smoking was a statistically significant predictor of common and composite CIMT progression in both sexes. In men, systolic blood pressure was an independent predictor of internal carotid and composite CIMT progression, fasting glucose predicted common CIMT progression, and family history predicted composite CIMT progression. CONCLUSIONS: In young adults, smoking was a consistent predictor of short-term CIMT progression in men and women. Traditional risk factors also predicted CIMT progression in men.

Influence of nitric oxide synthase gene polymorphism (G894T) on carotid artery intima-media thickness in adults: the Bogalusa Heart Study.

Nitric oxide generated by the vascular endothelial nitric oxide synthase (eNOS) plays an important role in the regulation of vascular structure/function and blood pressure. However, information is scant regarding the influence of G894T polymorphism of the eNOS gene on arterial wall thickness in asymptomatic young adults. This aspect was examined for G894T polymorphism in 661 White and Black subjects, aged 25 to 43 years (73.2% White; 39.5% male). Arterial vascular changes were assessed by common carotid intima-media thickness (IMT) using B-mode ultrasonography. The variant T allele frequency of G894T was significantly higher in Whites compared with Blacks (0.339 vs. 0.102; P < .0001). In bivariate analysis, adjusted for gender, age, mean arterial blood pressure, and/or race, carotid IMT was marginally lower in carriers vs. non-carriers of T allele in Whites (P = .07), but significantly lower for the total number of subjects (P = .04). In multivariable regression analysis, adjusted for gender, age, mean arterial pressure, body mass index (BMI), low-density lipoprotein cholesterol, triglycerides/high-density lipoprotein cholesterol ratio, homeostasis model assessment of insulin resistance, smoking, and race (in the total sample), the variant allele was independently associated with lower carotid IMT in both the White subjects (P = .04), and total sample (P = .03). These results suggest that the allelic variation of G894T polymorphism of the eNOS gene beneficially influences vascular changes as measured by carotid IMT in asymptomatic young adults.

Blood leukocyte count is a risk factor for intima-media thickening and subclinical carotid atherosclerosis in middle-aged men.

Leukocytosis is known to predict future cardiovascular events even in subjects without coronary heart disease (CHD), but its association with early atherosclerotic changes has remained less certain. The aim of the present study was to investigate how the blood leukocyte count compares with several other risk factors for CHD in determining carotid artery intima-media thickness (IMT) and subclinical carotid atherosclerosis in a population sample. Both carotid arteries were investigated with high-resolution B-mode ultrasound in a community-based sample of 219 randomly selected men aged 50-59 years to calculate the mean maximum IMT (MMax IMT) of 12 standard sites. Risk factor assessment included several traditional biochemical risk factors, blood pressure, maximal oxygen consumption and work load on ergometry, life-style habits and hematologic parameters. As genetic determinants, apolipoprotein E and A-IV polymorphisms were studied. According to multivariate regression analysis, age (P<0.0001), blood leukocyte count (P<0.0001) and systolic blood pressure (P<0.042) were the only significant predictors of MMax IMT. MMax IMT increased linearly from the lowest tertile of blood leukocyte count (1.14+/-0.20mm) to the second (1.18+/-0.25 mm) and to the highest tertile (1.25+/-0.27 mm, P=0.019). This difference remained significant after adjustment with age, systolic blood pressure and smoking (P=0.032). Leukocytes seem to have an independent role in the early arterial damage and they may reflect subclinical disease. This implies that leukocyte count is undervalued in the diagnostics and prognostics of carotid atherosclerosis.

Cardiovascular risk profile of asymptomatic healthy young adults with increased femoral artery intima-media thickness: The Bogalusa Heart Study.

BACKGROUND: Femoral artery intima-media thickness (IMT), like carotid IMT, is a surrogate indicator of atherosclerotic coronary and peripheral vascular diseases in middle-aged and older adults. This study examined the cardiovascular disease risk profile of asymptomatic young adults with increased femoral artery IMT. METHODS: Femoral artery IMT was measured by B-mode ultrasonography in 1080 black and white subjects (aged 24-43 years; 71% white, 43% male) enrolled in the Bogalusa Heart Study. Individuals in the top (n=54) versus bottom fifth (n=54) percentiles distribution of femoral IMT were compared for traditional cardiovascular risk factors profile. Univariate analysis compared the two groups, t-tests and chi tests were performed. RESULTS: The top and bottom fifth percentiles of IMT differed with respect to age (P<0.001), systolic blood pressure (P<0.05), diastolic blood pressure (P<0.05), total cholesterol (P<0.01), low-density lipoprotein (LDL) cholesterol (P<0.001), non-high-density lipoprotein (HDL) cholesterol (P<0.01) and smoking status (P<0.01). In terms of prevalence of clinically defined traditional risk factors, individuals at the top versus bottom fifth percentile of IMT distribution had significantly higher prevalence of high LDL cholesterol (>OR=130 mg/dL), non-HDL cholesterol (>OR=160 mg/dL), and cigarette smoking. The odds ratio for individuals with three or more risk factors versus no risk factors having IMT in the top fifth percentile was 4.7 (P=0.01). CONCLUSION: The observed adverse effect of cardiovascular risk factors on IMT of femoral artery, a surrogate measure of coronary and peripheral atherosclerosis, in asymptomatic young individuals underscores the need for risk factors profiling in early life. These observations have important implications in preventive medicine.

Impact of multiple cardiovascular risk factors on femoral artery intima-media thickness in asymptomatic young adults (the Bogalusa Heart Study).

Femoral artery intima-media thickness (IMT), like carotid IMT, is a surrogate indicator of atherosclerotic coronary and peripheral vascular diseases in middle-aged and older adults. Although risk factors for coronary artery disease are also associated with increased IMT, especially as measured in carotid arteries, there is a paucity of information with respect to the femoral artery in this regard in the asymptomatic, younger adult population. This study examined the impact of multiple risk factors on the common femoral artery IMT as measured by B-mode ultrasonography in 1,080 black and white subjects aged 24 to 43 years (71% white and 43% men) enrolled in the Bogalusa Heart Study. Femoral IMT showed gender difference (men more than women, p = 0.001), but no racial difference. In a multivariate model, systolic blood pressure, age, male gender, cigarette smoking, and total cholesterol/high-density lipoprotein cholesterol ratios related independently, in that order, to IMT. Mean IMT increased with an increasing number of risk factors defined as values above the age-, race-, and gender-specific 75th percentile of systolic blood pressure, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, and insulin along with smoking status (p for trend = 0.003), with respective mean IMT values of 0.66, 0.69, 0.73, and 0.79 mm for 0, 1 to 2, 3, and 4 to 5 risk factors. The odds ratio for patients with >/=3 risk factors versus no risk factors having IMT in the top fifth percentile was 4.7 (p = 0.01). The observed adverse trend of increasing femoral IMT with an increasing number of risk factors in free-living, asymptomatic young subjects underscores the need for multiple risk factors profiling in early life. Further, ultrasonography of the femoral artery in conjunction with multiple risk factor profiling can be helpful in risk stratification.

Q192R polymorphism of the paraoxanase 1 gene and its association with serum lipoprotein variables and carotid artery intima-media thickness in young adults from a biracial community. The Bogalusa Heart Study.

Paraoxanase (PON 1), a high-density lipoprotein-associated enzyme, exerts an antiatherogenic effect by protecting low-density lipoproteins (LDL) against oxidation. A common polymorphism at codon 192(Q/R) of the PON 1 gene has been shown to be associated with an adverse lipoprotein profile and increased coronary artery disease (CAD) risk. However, these observations are based mostly on case-control studies involving relatively older adults. This study examined the frequency and phenotypic (lipoprotein variables) effect of the Q192R variant in a community-based sample of 1786 black and white young adults (mean age: 32.5 years; 69% white, 44% males). In addition, the genotypic effect of this polymorphism on ultrasonographically measured carotid artery intima-media thickness (IMT), a surrogate measure of CAD risk, was examined in a subsample of 436 young adults (mean age: 32.6 years; 70% white, 42% male). The frequency of the variant allele (R192) was higher in blacks than in whites (0.668 versus 0.297, P <0.001). After adjusting for age, sex, body mass index, and smoking status, the R versus Q allele was associated with increased HDL cholesterol in whites (P=0.041), whereas the opposite was true in blacks (P=0.008). Neither the Q nor the R allele was associated with LDL cholesterol and triglycerides in both races. The genotypic effect on the carotid IMT adjusted for the covariates including lipoprotein variables was not apparent in whites or blacks. However, among whites, the carotid IMT was lower in carriers (QR + R) versus non-carriers (QQ) of the variant allele among females (P=0.008) and non-smokers (P=0.026). In addition, the variant allele negated the adverse positive relationship between the carotid IMT and triglycerides among whites (P=0.212 for carriers versus P <0.001 for non-carriers). These results indicate a differential effect of the Q192R variant on HDL cholesterol in whites versus blacks and a beneficial interaction effect of the variant allele with individual's sex, smoking status or triglyceride levels on the carotid IMT among whites.

Increased carotid artery intima-media thickness is associated with a novel mutation of low-density lipoprotein receptor independently of major cardiovascular risk factors.

The current study sought to investigate the role of low-density lipoprotein receptor (LDLr) mutations in assessing the risk profile of familial hypercholesterolemia (FH) patients, independently of major cardiovascular risk factors. FH due to LDLr mutations is associated with premature atherosclerosis. The variable clinical severity of the disease in heterozygotes has been related to cholesterol levels and the coexistence of other cardiovascular risk factors, but the independent role of different LDLr mutations is still unclear. cDNA of LDL gene was sequenced in 102 patients with clinical features of heterozygous FH. Carotid artery intima-media thickness (IMT) was measured by B-mode ultrasound imaging in all patients. Sixteen different mutations (5 never described) were found in 82 patients (49 families; mean age, 39 years; 53% women). One of the newly described mutations, the 2312-3 C-->A, was found in 24 patients (13 families). The mean of maximum thicknesses was significantly higher in the 2312-3 C-->A group than in patients with other LDLr mutations (P=.004 after adjustment for major cardiovascular risk factors). Similar results (P=.001) were obtained in the adjusted comparisons of probands only, and of the patients with similar baseline cholesterol (P=.002). This study indicates that the identification of an LDLr mutation can help to assess the risk profile of FH patients independently of the major cardiovascular risk factors.

Framingham risk score is related to carotid artery intima-media thickness in both white and black young adults: the Bogalusa Heart Study.

The Framingham risk score (FRS), developed in a white cohort aged 30-74 years, is increasingly used in the early risk identification for coronary artery disease (CAD). This study examines the relationship between FRS and carotid artery intima-media thickness (IMT), a surrogate marker of coronary atherosclerosis, in black and white individuals aged 20-37 years. Five hundred seventeen young adults (aged 20-37 years; 71% white, 39% male) enrolled in the Bogalusa Heart Study had carotid artery ultrasonography. Age, gender, systolic blood pressure, total cholesterol to HDL cholesterol ratio, cigarette smoking habit, type 2 diabetes, and left ventricular hypertrophy (LVH) were used to calculate FRS. Results indicated a significant, positive linear relationship between tertiles of FRS and IMT of the common, bulb, and internal carotid segments in blacks and whites alike. In a multivariate analysis including FRS, race, BMI, parental history of CAD, stroke, type 2 diabetes, or hypertension, logtriglycerides, loginsulin, alcohol consumption (ml/week), and regular physical activity, the FRS was independently associated with all three carotid segments. Further, the FRS as a main predictor variable explained relatively more of the variance in the IMT of the carotid bulb (9%) than in the common (5%) or internal (3%) carotid segments. These results support the use of FRS in both white and black young adults and underscore the importance of prevention and control of multiple risk factors in youth.

Association of obesity and central fat distribution with carotid artery wall thickening in middle-aged women.

BACKGROUND AND PURPOSE: The association between obesity and atherosclerotic disease is controversial. In the present analysis, we evaluated whether common carotid intima-media thickness (IMT) and area, 2 markers of preclinical atherosclerosis, were increased in obese subjects. METHODS: More than 5000 middle-aged women (n=5062; age, 30 to 69 years) living in the area of Naples, Southern Italy, were recruited for a prospective, currently ongoing study on the etiology of cardiovascular disease and cancer in the female population (the Progetto ATENA study). A subsample of 310 participants underwent high-resolution B-mode ultrasound examination, and the IMTs, intima-media areas, and lumen diameters of common carotid arteries were measured with a semiautomated computerized program. Subjects were divided into 3 groups on the basis of the recently published obesity guidelines for body mass index (BMI), a marker of general obesity, and tertiles of waist-to-hip ratio (WHR), a marker of regional obesity. RESULTS: Women with a BMI >/=30 kg/m(2) showed higher systolic and diastolic blood pressures, triglycerides, and fasting glucose and insulin, as well as lower high-density lipoprotein concentrations, than subjects with lower BMI. A gradual increase in common carotid IMT and intima-media area was observed when lean women (0.94+/-0.01 mm and 19.8+/-0.5 mm(2), respectively) were compared with overweight (0.98+/-0.01 mm and 21.0+/-0.4 mm(2)) and obese (1.02+/-0.02 mm and 22.6+/-0.8 mm(2), P<0.005 for linear trend) individuals. Similarly, women in the highest tertile of WHR (>0.85) had adverse risk factor profiles and thicker carotid intima-media complex than those in the first 2 tertiles (P<0.01 and P<0.05 for IMT and intima-media area, respectively). In multivariate analyses, BMI and WHR were significant predictors of carotid wall thickness, independently of other traditional and nontraditional cardiovascular risk factors (age, blood pressure, lipid abnormalities, fasting insulin). CONCLUSIONS: The present results indicate a graded and independent association between general and abdominal obesity-reflected by high BMI and WHR-and carotid artery wall thickening in a population of middle-aged women.

Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study).

Although risk factors for coronary artery disease are also associated with increased carotid artery intima-media thickness (IMT) as measured by B-mode ultrasonography in middle-aged and older persons, information on the impact of multiple risk factors on the IMT of different segments of the carotid artery in young adults is limited. This relation was examined in a sample of 518 black and white subjects (mean age 32 years; 71% white, 39% male) enrolled in the Bogalusa Heart Study. IMT was thicker and more skewed in the bulb compared with other carotid segments. Race differences (blacks more than whites) were noted for the common carotid (p <0.001) and carotid bulb (bifurcation) IMT (women only, p <0.001). Men had a greater IMT in the common carotid (p <0.05), internal carotid (p <0.05), and carotid bulb (whites only, p <0.001). In a multivariate analysis, systolic blood pressure, race, age, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol weree entered into a model in that order and accounted for the 16.7% variance in the common carotid IMT; age, systolic blood pressure, HDL cholesterol, LDL cholesterol, race, and insulin levels explained the 19.4% variance in the carotid bulb IMT. Gender and body mass index (BMI) accounted for the 4.7% variance in the internal carotid IMT. Increases in IMT with increasing number of risk factors (cigarette smoking, higher total cholesterol to HDL cholesterol ratio, higher systolic blood pressure, greater waist circumference, and higher insulin level) were noted for the common carotid and carotid bulb segments (p for trend <0.001 for both). The observed deleterious trend of increasing IMT at different carotid segments with increasing number of risk factors in free-living, asymptomatic young subjects underscores the importance of profiling multiple risk factors early in life. Ultrasonography of carotid arteries, especially at the bifurcation, may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.

Association of impaired glucose homeostasis with preclinical carotid atherosclerosis in women: Impact of the new American Diabetes Association criteria.

The aim of this study was to determine whether impaired glucose regulation, defined according to the new American Diabetes Association (ADA) criteria, is associated with early signs of carotid atherosclerosis. We examined 310 clinically healthy women from southern Italy, aged 30 to 69 years, recruited for a prospective study, currently ongoing, on the etiology of cardiovascular disease and cancer in the female population (Progetto Atena). All subjects underwent cardiovascular risk factor assessment and high resolution B-mode ultrasound to measure intima-media thickness (IMT) of common carotid arteries and carotid bifurcations. At the time of our survey, fasting glucose levels > or = 7.0 mmol/L had already been found in 7 women, 17 participants were diagnosed on that occasion as having new diabetes, 38 had impaired fasting glucose (IFG), and the remaining 248 presented normal fasting glucose values (NFG). Diabetic women showed a worse cardiovascular risk profile, with higher values of triglycerides, body mass index, and diastolic blood pressure than either normoglycemic or IFG subjects. The frequency of atherosclerotic plaques (IMT > 1.2 mm) increased as glucose homeostasis worsened. In multivariate logistic regression analyses, only diabetes mellitus was associated with a significantly increased risk of carotid atherosclerosis (odds ratio [OR], 11.5; 95% confidence interval [CI], 1.4 to 92.7). Our findings suggest a definite association between diabetes mellitus, as defined by the new ADA diagnostic criteria and early carotid structural changes. Furthermore, the condition of IFG does not seem to identify subjects at significantly increased atherosclerotic risk.