Multiple studies have demonstrated an age-related attenuation in risk associations of lipoproteins and lipoprotein ratios with cardiovascular disease events. We recently reported a similar age-related attenuation in risk associations of lipoproteins and lipoprotein ratios with coronary artery calcium. We assessed risk associations of lipoproteins and lipoprotein ratios with carotid intima–media thickness (CIMT), which has not been reported previously. We performed multivariable linear regression using data from the Multi-Ethnic Study of Atherosclerosis (MESA). MESA participants were community-dwelling adults 45 to 84 years of age without clinically apparent cardiovascular disease at baseline, and 4,961 met inclusion criteria for these analyses. In fully adjusted models, differences in CIMT were similar across the MESA age spectrum, with differences in internal CIMT per SD increase in low-density lipoprotein of 0.037 mm (95% confidence interval 0.018 to 0.055) for those 45 to 54 years old and 0.087 mm (95% confidence interval 0.027 to 0.146) for those 75 to 84 years old (p for interaction = 0.2). Similarly, the difference in internal CIMT per SD increase in the total/high-density lipoprotein cholesterol ratio was 0.029 mm (95% confidence interval 0.009 to 0.049) for those 45 to 54 years old and 0.101 mm (95% confidence interval 0.033, 0.169) for those 75 to 84 years old (p for interaction = 0.03). In general, risk associations of lipoproteins and lipoprotein ratios were associated with similar differences in CIMT across all age categories. In conclusion, abnormal lipoproteins and lipoprotein ratios in middle-aged and older patients are powerful risk factors for early atherosclerosis as manifested by an increased CIMT.
Age and lipoproteins are strong risk factors for atherosclerosis. However, we recently reported an age-related attenuation in the risk association of lipoproteins and lipoprotein ratios with coronary artery calcium (CAC), a marker of subclinical atherosclerosis, in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA participants are an asymptomatic multiethnic cohort of contemporary community-dwelling subjects without clinical cardiovascular disease (CVD) at entry. Our finding raised the question as to whether a similar age-related attenuation might be seen in the risk association of lipoproteins with another marker of subclinical atherosclerosis, carotid intima–media thickness (CIMT). Previous studies have demonstrated that low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, triglycerides, and lipoprotein ratios are associated with CIMT progression. Although CAC and CIMT assess atherosclerosis in different vascular territories, the 2 measurements are associated strongly with risk for incident CVD. This study sought to investigates whether age modifies the association of specific lipid and lipoprotein parameters with internal and common CIMT in MESA.
Methods
MESA, which is sponsored by the National Heart, Lung, and Blood Institute, is a prospective evaluation of subclinical CVD in 6,814 men and women from 6 United States communities. Participants included men and women 45 to 84 years old and free of known CVD at baseline examination (2000 to 2002) and were selected from 4 race/ethnic groups (Caucasian, Chinese, Hispanic, or African-American). Further details regarding the design and objectives of the MESA study have been reported previously.
Participants missing data for covariates or lipid-lowering therapy were excluded (n = 1,853). The final sample for our analyses was 4,961 participants. Briefly, at the baseline examination age, race/ethnicity, and highest level of education were self-reported. Traditional risk factors were assessed including waist circumference, history of diabetes, hypertension, family history of coronary heart disease in a first-degree relative, current medication use, and tobacco usage. All biochemistry assays were performed on plasma drawn the morning of the baseline visit (2000 to 2002) and stored at −70°C. Measurements were performed at a central location (Laboratory for Clinical Biochemistry Research, University of Vermont, Burlington, Vermont) using standardized methods and reagents.
High-resolution B-mode ultrasonography was used to measure CIMT. CIMT was measured at each clinical site at baseline examination (2000 to 2002) by trained sonographers using standardized methods as described previously. Each center used a Logiq 700 ultrasound machine (General Electric Medical Systems, Waukesha, Wisconsin) to measure CIMT. CIMT recordings were analyzed and reported at a centralized reading center (Department of Radiology, Tufts–New England Medical Center, Boston, Massachusetts). Mean maximum CIMTs for the internal and common carotid arteries, defined as the average of the maximum CIMT for the near and far walls of the left and right carotid arteries, were reported separately. As reported previously, intraclass correlation coefficients for inter-reader reproducibility were 0.87 and 0.94 for the common and internal CIMTs, respectively, and exceeded 0.98 for intrareader reproducibility at the 2 sites.
Continuous variables were analyzed using analysis of variance and categorical variables using chi-square tests. Cross-sectional analyses were performed using multivariable linear regression to evaluate the associations of specific lipids and lipoprotein ratios with internal and common CIMTs in separate models. Associations of each lipoprotein or ratio with internal or common CIMT were determined in unadjusted and adjusted models using multivariate linear regression. A priori covariates included in the model were age, race/ethnicity, gender, highest level of education completed, site of enrollment, diabetes as defined by the 2003 American Diabetes Association as a fasting glucose level ≥126 mg/dl or taking medication for diabetes, hypertension as defined by systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or by a history of hypertension diagnosed by a physician and taking antihypertensive medication, current smoking status, fasting glucose and insulin levels, adiposity as measured by waist circumference, education, family history of myocardial infarction in a first-degree relative, inflammation as determined by interleukin-6, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and serum creatinine. Tests for interactions of age (categorized as decades of age: 45 to 54, 55 to 64, 65 to 74, 75 to 84) with risk associations of lipoproteins with mean difference in CIMT were specified a priori and deemed significant at a p value <0.05.
A p value <0.05 was considered statistically significant for all major comparisons. All analyses were performed using STATA 10.2 for Windows (STATA Corp., College Station, Texas).
Results
Demographic and metabolic variables for each age category are presented in Table 1 . Mean age of the population was 61 years and 53% were women. There were no significant differences in race/ethnicity among age groups. The youngest group, 45 to 54 years old, had the largest number of participants with greater than a high school education. Prevalence of hypertension, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were each higher with older age category, whereas active smoking was lower with older age category. Family history of myocardial infarction in a first-degree relative was lowest in the youngest age group category. Mean glucose levels were higher with older age category, whereas median insulin levels were generally lower with older age category. Waist circumference was largest in the 55- to 64-year old and 65- to 74-year old categories. Creatinine was higher with older age category. Interleukin-6, an inflammatory marker, was higher with older age category. Total cholesterol, LDL cholesterol, and non-HDL cholesterol were highest in the 55- to 64-year old and 65- to 74-year old categories, whereas triglycerides were highest in the 55- to 64-year-old category. HDL cholesterol was also higher with older age category. Lipoprotein ratios were highest in the 45- to 54-year-old and 55- to 64-year-old categories. Mean maximum internal and common CIMTs were higher with increasing age category.
| Variable | All (n = 4,961) | 45–54 Years Old (n = 1,611) | 55–64 Years Old (n = 1,402) | 65–74 Years Old (n = 1,319) | 75–84 Years Old (n = 629) |
|---|---|---|---|---|---|
| Age (years) ⁎ | 61 ± 10 | 50 ± 3 | 58 ± 3 | 59 ± 3 | 78 ± 3 |
| Women | 53% | 54% | 54% | 53% | 51% |
| Caucasian | 38% | 36% | 37% | 40% | 42% |
| Chinese | 12% | 12% | 12% | 12% | 12% |
| African-American | 27% | 27% | 27% | 28% | 25% |
| Hispanic | 23% | 25% | 24% | 20% | 21% |
| Greater than high school education ⁎ | 65% | 75% | 64% | 59% | 54% |
| Hypertension ⁎ | 40% | 23% | 39% | 53% | 63% |
| Diabetes mellitus ⁎ | 10% | 6% | 11% | 12% | 13% |
| Current smoker ⁎ | 13% | 19% | 15% | 10% | 4% |
| Family history of myocardial infarction ⁎ | 41% | 37% | 43% | 44% | 43% |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use ⁎ | 15% | 9% | 14% | 19% | 21% |
| Waist circumference (cm 2 ) ⁎ | 97.4 ± 14.3 | 96.0 ± 15.1 | 98.0 ± 14.4 | 98.4 ± 13.9 | 97.2 ± 12.6 |
| Glucose (mg/dl) ⁎ | 95.6 ± 29.0 | 91.8 ± 28.4 | 97.2 ± 31.6 | 97.4 ± 25.4 | 98.2 ± 31.1 |
| Insulin (mu/U) ⁎ | 5.2 (3.4–8.2) | 5.3 (3.5–8.3) | 5.3 (3.5–8.6) | 5.0 (3.3–8.0) | 5.1 (3.2–7.3) |
| Creatinine (mg/dl) ⁎ | 0.94 ± 0.23 | 0.91 ± 0.19 | 0.93 ± 0.20 | 0.96 ± 0.25 | 1.0 ± 0.33 |
| Interleukin-6 (pg/ml) ⁎ | 1.2 (0.76–2.9) | 1.0 (0.64–1.7) | 1.11 (0.72–1.8) | 1.3 (0.87–2.1) | 1.4 (0.72–2.1) |
| Total cholesterol (mg/dl) ⁎ | 196 ± 35 | 193 ± 34 | 199 ± 36 | 198 ± 34 | 193 ± 35 |
| Low-density lipoprotein cholesterol (mg/dl) † | 120 ± 32 | 118 ± 31 | 122 ± 33 | 120 ± 30 | 117 ± 31 |
| High-density lipoprotein cholesterol (mg/dl) ⁎ | 51 ± 15 | 50 ± 14 | 51 ± 15 | 52 ± 16 | 53 ± 15 |
| Nonhigh-density lipoprotein cholesterol (mg/dl) ⁎ | 145 ± 35 | 143 ± 35 | 148 ± 36 | 145 ± 34 | 141 ± 34 |
| Triglycerides (mg/dl) ⁎ | 109 (77–156) | 106 (73–156) | 113 (80–163) | 109 (77–156) | 105 (75–146) |
| Total cholesterol/high-density lipoprotein cholesterol ratio ⁎ | 4.1 ± 1.2 | 4.1 ± 1.3 | 4.1 ± 1.2 | 4.0 ± 1.2 | 3.9 ± 1.1 |
| Low-density lipoprotein/high-density lipoprotein cholesterol ratio ⁎ | 2.5 ± 0.97 | 2.6 ± 1.0 | 2.6 ± 0.99 | 2.5 ± 0.94 | 2.4 ± 0.87 |
| Triglyceride/high-density lipoprotein cholesterol ratio † | 2.8 ± 2.0 | 2.8 ± 2.1 | 2.9 ± 2.0 | 2.7 ± 1.9 | 2.5 ± 1.7 |
| Mean maximum internal carotid intima–media thickness (mm) | 1.027 ± 0.569 | 0.830 ± 0.346 | 0.978 ± 0.497 | 1.168 ± 0.659 | 1.34 ± 0.736 |
| Mean maximum common carotid intima–media thickness (mm) | 0.858 ± 0.189 | 0.764 ± 0.150 | 0.840 ± 0.158 | 0.931 ± 0.189 | 0.987 ± 0.206 |
† p <0.05 by chi-square test for categorical variables and analysis of variance for continuous variables across group comparisons.
In analyses adjusted for all covariates studied there were significant positive interactions of age (p <0.05) with difference in mean maximum internal CIMT per SD increase in total/HDL cholesterol and LDL/HDL cholesterol ratios. In analyses adjusted for all covariates studied there were significant positive interactions of age (p <0.05) with difference in mean maximum common CIMT per SD increase in total cholesterol, LDL cholesterol, non-HDL cholesterol, and total/HDL cholesterol and LDL/HDL cholesterol ratios. Results are presented in Figures 1 through 4 . Findings similar to those of the fully adjusted models were seen in models adjusted for demographic variables only (age, gender, race/ethnicity, and education) except that the p value for the interaction of age with the association of total cholesterol with mean difference in common CIMT was not significant in demographic-adjusted models (data not shown).
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