Carotid intima-media thickness (CIMT) progression is predictive of future cardiovascular events in middle-age and older adults. However, information is scant on segment-specific CIMT progression by race (black vs white) and gender and its predictors during short-term follow-up in asymptomatic young adults. B-mode ultrasound images of the far walls of both carotid arteries were obtained in 842 subjects aged 24 to 43 years and enrolled in the Bogalusa Heart Study (70% whites and 42% men). The CIMT and cardiometabolic risk variables were measured at baseline and after an average of 2.4 years. The mean CIMT progression rates/year adjusted for age, race, and gender were greatest at the bulb, followed by the internal and common carotid segments (p <0.0001). In a multivariate logistic model, age, mean arterial pressure, and high-density lipoprotein cholesterol were significantly associated with common CIMT progression. Smoking, age, insulin resistance index, and mean arterial pressure were significantly associated with bulb CIMT progression; and the waist/height ratio, smoking, age, and mean arterial pressure were significantly associated with internal CIMT progression, independent of the baseline CIMT and traditional cardiometabolic risk variables, including adiponectin, C-reactive protein, and intercellular adhesion molecules. In addition, the status of progression was associated with a greater prevalence of metabolic syndrome (common and internal CIMT, p <0.05; bulb CIMT, p <0.0001) and diabetes (bulb CIMT only, p <0.001). In conclusion, in younger adults, the magnitude of progression of CIMT within a short period varied in a segment-specific manner, regardless of race or gender, and was predictable using modifiable traditional risk factors. This could have implications for preventive and interventional cardiology.
Most studies of longitudinal carotid intima-media thickness (CIMT) changes have been performed on middle-age and older age adults. These observations have involved certain carotid artery segments individually or combined. However, information is scant regarding the segments of CIMT progression and their relations to risk factor variables in apparently healthy younger adults. The relations have varied among specific segments within the carotid artery, and these need to be examined. The present analysis studied specific segments and risk factors in a biracial (black vs white) population.
Methods
The prospective study cohort was derived from the 2 cross-sectional surveys conducted in Bogalusa, Louisiana, a biracial community. In the 2001 to 2002 survey, 1,143 participants (mean ± SD age 36.4 ± 4.4 years; 70% white; 43% men) underwent B-mode ultrasonography of the carotid artery. In the 2003 to 2005 survey, the CIMT was measured in 958 participants (39.0 ± 4.3 years old). The mean follow-up interval was 2.4 ± 0.3 years. The present report included a cohort of 842 subjects who had undergone ultrasound scanning for both surveys. This subgroup was not significantly different statistically from the total study population in regard to age, race, gender, overall adiposity (body mass index), and other risk factors.
All participants provided informed consent, and institutional review board of the Tulane University Health Sciences Center approved the study.
Standardized protocols were used by trained examiners for all surveys. The participants were instructed to fast for 12 hours before venipuncture, and compliance was ascertained by an interview on the day of the examination. Anthropometric and blood pressure measurements were made in replicate, and the mean values were used. The body mass index (weight in kilograms divided by the square of the height in meters) was used as a measure of overall adiposity. The waist circumference was used as an indicator of abdominal visceral fat. The right upper arm length and circumference were used to select the cuff size for the blood pressure measurements using mercury sphygmomanometers. Two randomly assigned nurses measured the blood pressure (3 replicates each) with the subjects in a relaxed, sitting position. The systolic and diastolic blood pressure was recorded at the first and fifth Korotkoff sound, respectively. The mean arterial pressure, calculated as the diastolic blood pressure plus 1/3 of the pulse pressure, was used in the analysis. Information on personal health history (e.g., hypertension, dyslipidemia, or diabetes and medical treatment for these conditions) was obtained by questionnaires. Information on smoking status (yes vs no) was obtained as a part of the health habit questionnaires. Participants were considered smokers if they reported current use of cigarettes or having stopped smoking within the previous year; the remainder were considered as nonsmokers.
The cholesterol and triglyceride levels were measured using enzymatic procedures on the Hitachi 902 Automatic Analyzer (Roche Diagnostics, Indianapolis, Indiana). Serum lipoprotein cholesterol levels were analyzed using a combination of heparin–calcium precipitation and agar–agarose gel electrophoresis procedures. The laboratory was monitored for precision and accuracy of lipid measurements by the surveillance program of the Centers for Disease Control and Prevention (Atlanta, Georgia). The plasma glucose was measured enzymatically as a part of a multichemistry (SMA20) profile with an Olympus Au-5000 Analyzer (Olympus, Lake Success, New York). The plasma immunoreactive insulin levels were measured using a commercial radioimmunoassay kit (Phadebas, Pharmacia Diagnostics, Piscataway, New Jersey). Plasma high-sensitivity C-reactive protein was measured using latex particle-enhanced immunoturbidimetric assay on a Hitachi 902 Automatic Analyzer. The soluble form of plasma intercellular adhesion molecule-1 levels were measured using a sandwich enzyme immunoassay (R&D Systems, Minneapolis, Minneapolis). The serum adiponectin levels were measured by radioimmunoassay (Linco Research, St. Charles, Missouri). Insulin resistance was calculated according to the homeostasis model assessment–insulin resistance (HOMA-IR) formula: [insulin (μU/mL) × glucose (mmol/L)/22.5]. The intraclass correlation coefficients between the blind duplicate (10% random sample) values ranged from 0.86 to 0.98 for high-density lipoprotein (HDL) cholesterol, 0.86 to 0.98 for low-density lipoprotein (LDL) cholesterol, 0.88 to 0.99 for triglycerides, 0.86 to 0.98 for glucose, 0.94 to 0.98 for insulin, 0.99 for C-reactive protein (CRP), 0.93 for adiponectin, and 0.97 for intercellular adhesion molecule-1.
Using the American Diabetes Association criteria, the adult subjects were classified as diabetic if the fasting glucose level was ≥126 mg/dl (7 mmol/L) or taking medication for diabetes. The metabolic syndrome risk factors in adults were identified if the subjects were centrally obese (waist circumference >102 cm for men and >88 cm for women), dyslipidemic (LDL cholesterol ≥160 mg/dl [4.14 mmol/L], triglycerides ≥150 mg/dl [1.69 mmol/L], HDL cholesterol <40 mg/dl [1.03 mmol/L] for men or 50 mg/dl [1.29 mmol/L] for women, or taking medication for dyslipidemia); hyperglycemic (fasting glucose ≥100 mg/dl (5.6 mmol/L) or treated for diabetes); or hypertensive (≥130 mm Hg/≥85 mm Hg or taking antihypertensive medication). The metabolic syndrome was defined as the coexistence of ≥3 risk factors as defined by the National Cholesterol Education Program Adult Treatment Panel III.
Carotid ultrasound images were obtained using a Toshiba ultrasound instrument (Power Vision Toshiba SSH-380 ultrasound system, Toshiba America Medical System, Tustin, California), with a 7.5-MHz linear array transducer. The images were recorded at the common carotid, carotid bulb (bifurcation), and internal carotid arteries bilaterally according to the previously developed protocol for the Atherosclerosis Risk In Communities (ARIC) study. The images were recorded on S-VHS tapes and read by a certified single reader from the division of vascular ultrasound research at Wake Forest University School of Medicine, Winston-Salem, North Carolina, using a semiautomatic ultrasound image-processing program developed by the California Institute of Technology and Jet Propulsion Laboratory (Pasadena, California). The mean of the maximum CIMT readings of the 3 right and 3 left far walls for the common, bulb, and internal segments was used to determine the composite intima-media thickness values. If bilateral images could not be obtained, one side was used in the calculation. The reproducibility (mean difference ± SD) of the common, bulb, and internal CIMT scans in 73 subjects who had undergone repeat measurements after 10 to 12 days was 16.2 ± 80.4, 18.3 ± 172.5, and 32.8 ± 129.8 μm for the mean maximum thickness, corresponding to a 99% confidence interval of −8.7 to 41.1, −35.5 to 72.1, and −8.3 to 73.9 μm, respectively. As previously reported, progression of common, bulb, and internal CIMT after an average of 2.4 years of follow-up was defined as a difference between the follow-up and baseline values >41.1, >72.1, and >73.9 μm, respectively. The rates of progression were annualized on the basis of the interval between the measurements.
Statistical analyses were performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina). In the analyses, the race-gender groups were combined to increase the statistical power and simplify the presentation. Continuous variables were tested for normality using a Kolmogorov-Smirnov test. The values of the common CIMT, bulb CIMT, internal CIMT, triglycerides, glucose, insulin, and HOMA-IR variables used in the analyses were log transformed to improve normality. General linear models were used to examine race and gender differences in the segment-specific CIMT. All p values were 2-tailed and adjusted for covariates as appropriate.
In agreement with previous reports, we found an inverse correlation between the baseline CIMT and the CIMT rates of change per year (r = −0.35, r = −0.31, and r = −0.45 for the common, bulb, and internal CIMT, respectively; p <0.0001). As a result, all analyses were adjusted for the corresponding CIMT values observed at the 2001 to 2002 survey (baseline). General linear models were used to examine the CIMT progression differences in the risk factor variables by specific segments, adjusted for age, race, gender, and baseline CIMT.
Models assessing the independent relations between the baseline cardiometabolic risk factor variables and the follow-up site-specific CIMT progression status were constructed using a stepwise multiple logistic regression analysis, adjusted for the corresponding CIMT variable measured at baseline. The independent variables included in the initial model were age, race, gender, smoking status (yes vs no), waist/height ratio, mean arterial pressure, HDL cholesterol, LDL cholesterol, triglycerides, HOMA-IR, adiponectin, CRP, and the soluble form of the intercellular adhesion molecule-1 at baseline. The odds ratio and 95% confidence interval of developing CIMT progression by specific segments were then computed. Collinearity was checked in the fixed model. To assess the overall fit of the logistic regression model, Hosmer-Lemeshow goodness-of-fit test was performed. Because the alternate analysis using the Cox proportional hazard model gave essentially identical results, only the results of the logistic regression analysis estimating the relative risk of CIMT progression status are presented.
Finally, the prevalence of baseline metabolic syndrome and diabetes observed at baseline by CIMT progression status in adulthood was examined according to the segment-specific CIMT. Significant differences in the prevalence of these variables stratified by common, bulb, and internal CIMT were tested using the Pearson chi-square test.
Results
Specific segments of CIMT at baseline by race and gender are listed in Table 1 . Blacks versus whites had greater common CIMT, and men versus women had greater common CIMT, bulb CIMT, and internal CIMT.
| Carotid Intima-Media Thickness (μm) | White Men (n = 268) | Black Men (n = 85) | White Women (n = 325) | Black Women (n = 164) | p Value ⁎ | |
|---|---|---|---|---|---|---|
| Gender | Race | |||||
| Common | 786.0 ± 136.1 | 841.0 ± 156.1 | 705.1 ± 102.3 | 771.2 ± 132.3 | <0.01 | <0.01 |
| Bulb | 1,014.6 ± 310.6 | 1,050.5 ± 351.9 | 907.8 ± 214.0 | 944.9 ± 297.0 | <0.05 | 0.231 |
| Internal | 754.4 ± 291.4 | 826.5 ± 475.3 | 671.1 ± 183.1 | 703.0 ± 170.3 | <0.05 | 0.077 |
Figure 1 illustrates the mean levels of segment-specific CIMT progression rates annually, adjusted for age, race, gender, and corresponding baseline CIMT in young adults. With respect to segment-specific CIMT differences, the rates of change in bifurcation CIMT showed significantly greater progression compared to the other segments (p <0.0001), with internal versus common CIMT displaying greater values (p <0.0001). No significant race and/or gender differences in the progression rates were observed for CIMT in each specific site (data not shown).
The baseline characteristics of the study cohort by segment-specific progression status (yes vs no) adjusted for age, race, gender, and corresponding baseline CIMT are listed in Table 2 . Progression was significantly and adversely associated with age, waist circumference, waist/height ratio, mean arterial pressure, systolic blood pressure, diastolic blood pressure, low HDL cholesterol (common CIMT group only), LDL cholesterol (except for the common CIMT group), triglycerides (except for the common CIMT group), glucose (except for the internal CIMT group), insulin (except for the internal CIMT group), HOMA-IR, positive smoking (except for the common CIMT group), adiponectin (bifurcation CIMT group only), and CRP (bifurcation CIMT group only).
| Variable | Common Carotid Progression | Carotid Bulb Progression | Internal Carotid Progression | |||
|---|---|---|---|---|---|---|
| No (n = 678) | Yes (n = 125) | No (n = 627) | Yes (n = 145) | No (n = 577) | Yes (n = 132) | |
| Age (years) ⁎ | 36.4 ± 4.4 | 37.3 ± 3.5 † | 36.3 ± 4.4 | 37.6 ± 4.1 ‡ | 36.3 ± 4.5 | 37.8 ± 3.7 ‡ |
| White (%) § | 70.7 | 65.6 | 71.6 | 67.6 | 71.6 | 68.9 |
| Men (%) § | 42.5 | 41.6 | 42.3 | 42.1 | 43.3 | 42.4 |
| Waist (cm) ¶ | 93 ± 17 | 98 ± 18 ∥ | 92 ± 16 | 98 ± 20 ‡ | 92 ± 17 | 95 ± 18 † |
| Waist/height ratio ¶ | 0.55 ± 0.10 | 0.58 ± 0.10 † | 0.55 ± 0.09 | 0.58 ± 0.11 ‡ | 0.54 ± 0.10 | 0.56 ± 0.09 † |
| Systolic blood pressure (mm Hg) ¶ | 116 ± 14 | 121 ± 16 ‡ | 116 ± 14 | 122 ± 15 ‡ | 116 ± 13 | 120 ± 15 ‡ |
| Diastolic blood pressure (mm Hg) ¶ | 79 ± 10 | 82 ± 11 † | 78 ± 10 | 83 ± 11 ‡ | 79 ± 10 | 81 ± 11 † |
| Mean arterial pressure (mm Hg) ¶ | 91 ± 11 | 95 ± 13 ∥ | 91 ± 11 | 96 ± 12 ‡ | 91 ± 11 | 94 ± 12 † |
| High-density lipoprotein cholesterol (mg/dl) ¶ | 48 ± 14 | 46 ± 11 # | 47 ± 14 | 48 ± 13 | 47 ± 13 | 48 ± 16 |
| Low-density lipoprotein cholesterol (mg/dl) ¶ | 124 ± 35 | 130 ± 37 | 124 ± 35 | 128 ± 36 # | 123 ± 35 | 127 ± 32 # |
| Triglycerides (mg/dl) ¶ | 131 ± 99 | 134 ± 105 | 128 ± 97 | 147 ± 117 ∥ | 129 ± 98 | 144 ± 118 # |
| Glucose (mg/dl) ¶ | 87 ± 27 | 90 ± 25 # | 85 ± 22 | 96 ± 41 ‡ | 85 ± 21 | 87 ± 24 |
| Insulin (μU/ml) ¶ | 13.0 ± 13.3 | 13.5 ± 8.9 # | 12.4 ± 12.9 | 14.7 ± 12.3 † | 12.4 ± 13.4 | 13.1 ± 9.7 |
| Homeostasis model assessment of insulin resistance ¶ | 3.0 ± 3.8 | 3.2 ± 2.9 † | 2.8 ± 3.3 | 3.9 ± 4.9 ∥ | 2.8 ± 3.4 | 3.0 ± 2.9 # |
| Adiponectin (μg/ml) ¶ | 8.7 ± 4.3 | 8.1 ± 4.4 | 8.8 ± 4.5 | 7.8 ± 3.7 † | 8.7 ± 4.4 | 8.5 ± 4.5 |
| C-reactive protein (mg/L) ¶ | 2.9 ± 3.3 | 3.6 ± 3.8 | 2.8 ± 3.2 | 3.7 ± 3.7 † | 2.8 ± 3.3 | 3.0 ± 3.3 |
| Soluble form of intercellular adhesion molecule-1 (ng/ml) ¶ | 276 ± 112 | 279 ± 109 | 276 ± 113 | 284 ± 108 | 278 ± 114 | 273 ± 112 |
| Smoking (%) ¶ | 33.9 | 32.0 | 32.9 | 38.9 # | 31.5 | 44.7 † |
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