Although abnormal lipoproteins and lipoprotein ratios are powerful risk factors for clinical cardiovascular events, these associations are stronger in younger than in older subjects. Whether age modifies the relation of lipoproteins and lipoprotein ratios to the relative risk of subclinical cardiovascular disease (CVD), as assessed by coronary artery calcium (CAC) scores, has not been examined in a contemporary, multiethnic cohort. We performed multivariate relative risk regression analyses to determine the relative risks for associations of lipoproteins and lipoprotein ratios with prevalent CAC in participants in Multi-Ethnic Study of Atherosclerosis (MESA). The participants were community-dwelling adults aged 45 to 84 years without clinically apparent CVD at baseline. We excluded those taking lipid-lowering therapy (15%) and stratified the results by decades of age. A total of 5,092 participants met the inclusion criteria. In the fully adjusted models, per SD of low-density lipoprotein, the age-stratified, adjusted relative risk for CAC was 1.17 (95% confidence interval [CI] 1.07 to 1.28) for those aged 45 to 84 years but was 1.05 (95% CI 1.01 to 1.10) for those aged 75 to 84 years ( p -interaction = 0.12). The relative risk per SD of total/high-density lipoprotein cholesterol ratio was 1.20 (95% CI 1.12 to 1.29) for those aged 45 to 54 years but only 1.04 (95% CI 1.00 to 1.09) for those aged 75 to 84 years ( p -interaction <0.001). The lipoproteins levels and lipoprotein ratios were associated with increased relative risks for CAC across all age categories. However, these associations were markedly attenuated by age. In conclusion, abnormal lipoprotein levels in middle age are a powerful risk factor for early atherosclerosis, as manifested by prevalent CAC.
The present study was undertaken to understand how age modifies the association of specific lipid parameters (ie, total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, non-HDL cholesterol, triglycerides [TG], total/HDL cholesterol ratio, LDL/HDL cholesterol ratio, and TG/HDL cholesterol ratio) with prevalent coronary artery calcium (CAC) in an asymptomatic, multiethnic cohort of contemporary, community-dwelling subjects without clinical cardiovascular disease (CVD).
Methods
The National Heart, Lung and Blood Institute (Bethesda, Maryland) sponsored the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective evaluation of subclinical CVD in 6,814 men and women from 6 United States communities. The participants included men and women aged 45 to 84 years and free of known CVD at the baseline examination (2000 to 2002). The participants were recruited through 6 field centers. The participants were classified as White, Chinese, Hispanic, or African-American. Additional details regarding the design and objectives of the MESA have been reported previously.
The participants who were missing data for the covariates and the use of lipid-lowering therapy were excluded (n = 1,722). The final sample size for our analyses was 5,092 participants. Age, race/ethnicity, and highest level of education were self-reported. Several CVD risk factors were measured or collected: waist circumference; medical history, including the presence of diabetes (defined using the 2003 American Diabetes Association criteria of a fasting glucose level of ≥126 mg/dl or taking medications for diabetes mellitus); hypertension (defined as systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg at the baseline visit or by a history of physician-diagnosed hypertension and taking medications for hypertension); a family history of coronary heart disease (first-degree relative); medication use; and an assessment of personal habits such as tobacco use. All biochemistry assays were performed on plasma drawn the morning of the baseline visit and stored at −70°C. Measurements were performed at a central location, the Laboratory for Clinical Biochemistry Research (University of Vermont, Burlington, Vermont), using standardized methods and reagents.
The baseline coronary artery calcium (CAC) was measured twice, averaged, and quantified using the Agatston scoring method. Depending on the field center, CAC was measured using either electron beam computed tomography or multidetector row helical computed tomography. The interobserver (κ = 0.93) and intraobserver (κ = 0.90) agreement were very high. Careful quality control and standardized protocols were used at each clinical site. Additional details regarding the protocol, acquisition, and interpretation of the CAC scans in the MESA have been reported previously.
Continuous variables were analyzed for significance using t tests or analysis of variance, and categorical variables using chi-square tests. Cross-sectional analyses were performed using multivariate relative risk regression analysis to evaluate the associations of specific lipids and lipoprotein ratios with CAC. Owens et al previously reported an age-independent association of the total/HDL cholesterol ratio with the risk of prevalent aortic valve calcium in MESA. We, therefore, also studied whether the total/HDL cholesterol and LDL/HDL cholesterol ratios might show a similar, age-independent association with prevalent CAC. In addition, we examined whether the TG/HDL cholesterol ratio was associated with risk of prevalent CAC. The TG/HDL cholesterol ratio is a validated marker of insulin resistance, with better sensitivity for insulin resistance than the National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome definition and a receiver operating characteristic score of 0.78 for insulin resistance in one study. Associations of each lipoprotein or ratio with CAC were determined in both unadjusted and adjusted models using multivariate relative risk regression. Tests for interactions of age (categorized as approximate decades of age: 45 to 54, 55 to 64, 65 to 74, and 75 to 84 years) with lipoprotein-associated CAC risks were specified a priori and deemed significant at p <0.05.
For the 1,016 participants (15%) taking lipid-lowering therapy and those with LDL cholesterol that was unable to be calculated because the TGs were >400, sensitivity analyses were performed using imputed lipid values. We used imputation to estimate the untreated levels of total, LDL, and HDL cholesterol and TG for these participants. Details regarding imputation methods have been published previously.
p values <0.05 were considered statistically significant for all major comparisons. All analyses were performed using Stata, version 10.0 for Windows (StataCorp, College Station, Texas).
Results
The demographic and metabolic variables for each age category are summarized in Table 1 . No significant differences were found in gender or race/ethnicity among the age categories. As expected, the prevalences of hypertension and diabetes mellitus increased with age. The prevalence of smoking and the proportion of participants with more than a high school education decreased with age. A family history of myocardial infarction was lowest in the 45 to 54-age group category. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use increased with age. The waist circumference generally increased with age but then decreased in the oldest age category (75 to 84 years). Glucose, interleukin-6, and creatinine increased with age. LDL cholesterol, non-HDL cholesterol, TG, total/HDL cholesterol ratio, LDL/HDL cholesterol ratio, and TG/HDL cholesterol ratio were greatest in the 55 to 64-age group category. Regardless of age group, LDL cholesterol, non-HDL cholesterol, and TG were greater, HDL cholesterol lower, and the total/HDL cholesterol, LDL/HDL cholesterol, and TG/HDL cholesterol ratios were greater in those with CAC than in those without CAC ( Table 2 ). The prevalence of CAC increased significantly with age (p <0.001). The median CAC score for the entire cohort was 0 Agaston units. For those aged 45 to 54, 55 to 64, 65 to 74, and 75 to 84 years, the median CAC scores were 0, 0, 19, and 98 Agaston units, respectively. The prevalences of CAC were 23% in those aged 45 to 54 years, 42% for those aged 55 to 64 years, 62% for those aged 65 to 74 years, and 80% for those aged 75 to 84 years ( Table 1 ).
| Variable | All (n = 5,092) | Age Category (years) | |||
|---|---|---|---|---|---|
| 45–54 (n = 1,650) | 55–64 (n = 1,436) | 65–74 (n = 1,356) | 75–84 (n = 650) | ||
| Age ⁎ (years) | 61 ± 10 | 50 ± 3.4 | 60 ± 3.2 | 69 ± 3.3 | 78 ± 3.2 |
| Women | 53% | 54% | 54% | 52% | 52% |
| Race/ethnicity | |||||
| White | 38% | 36% | 37% | 40% | 41% |
| Chinese | 12% | 12% | 12% | 12% | 12% |
| African-American | 27% | 27% | 27% | 28% | 25% |
| Hispanic | 23% | 25% | 24% | 20% | 21% |
| More than high school education ⁎ | 65% | 75% | 64% | 59% | 54% |
| Hypertension ⁎ | 44% | 25% | 42% | 57% | 67% |
| Diabetes mellitus ⁎ | 10% | 7% | 11% | 12% | 14% |
| Current smoker ⁎ | 14% | 19% | 15% | 10% | 4% |
| Family history of myocardial infarction ⁎ | 41% | 37% | 43% | 43% | 42% |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use ⁎ | 15% | 9% | 14% | 19% | 21% |
| Waist circumference ⁎ (cm 2 ) | 98 ± 14 | 96 ± 15 | 98 ± 14 | 99 ± 14 | 98 ± 13 |
| Glucose ⁎ (mg/dl) | 96 ± 29 | 92 ± 28 | 97 ± 32 | 98 ± 25 | 99 ± 31 |
| Insulin ⁎ (mu/U) | 5.3 (3.4–8.2) | 5.3 (3.5–8.4) | 5.4 (3.6–8.8) | 5.1 (3.3–8.1) | 5.1 (3.2–7.3) |
| Creatinine ⁎ (mg/dl) | 0.9 ± 0.2 | 0.9 ± 0.2 | 0.9 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.3 |
| Interleukin-6 ⁎ (pg/ml) | 1.2 (0.8–1.9) | 1.0 (0.6–1.7) | 1.1 (0.7–1.8) | 1.3 (0.9–2.1) | 1.4 (1.0–2.1) |
| Total cholesterol ⁎ (mg/dl) | 196 ± 35 | 193 ± 34 | 199 ± 36 | 198 ± 34 | 193 ± 34 |
| Low-density lipoprotein cholesterol † (mg/dl) | 120 ± 32 | 119 ± 31 | 122 ± 33 | 120 ± 30 | 117 ± 31 |
| High-density lipoprotein cholesterol ⁎ (mg/dl) | 51 ± 15 | 50 ± 14 | 51 ± 15 | 52 ± 16 | 53 ± 15 |
| Non-high-density lipoprotein cholesterol ⁎ (mg/dl) | 145 ± 35 | 143 ± 35 | 148 ± 36 | 145 ± 34 | 141 ± 34 |
| Triglycerides ⁎ (mg/dl) | 109 (76–157) | 105 (74–156) | 114 (81–164) | 109 (78–156) | 106 (75–147) |
| Total cholesterol/high-density lipoprotein cholesterol ratio ⁎ | 4.1 ± 1.2 | 4.1 ± 1.3 | 4.2 ± 1.2 | 4.0 ± 1.2 | 3.9 ± 1.1 |
| Low-density lipoprotein/high-density lipoprotein cholesterol ratio ⁎ | 2.5 ± 1.0 | 2.6 ± 1.0 | 2.6 ± 1.0 | 2.5 ± 0.9 | 2.4 ± 0.9 |
| Triglycerides/high-density lipoprotein cholesterol ratio ⁎ | 2.8 ± 2.0 | 2.8 ± 2.1 | 2.9 ± 2.0 | 2.7 ± 1.9 | 2.6 ± 1.7 |
| Median (50%) coronary artery calcium score ⁎ | 0 (0–63) | 0 (0–0) | 0 (0–33) | 19 (0–166) | 98 (8–366) |
† p <0.05 by chi-square for categorical variables and analysis of variance for continuous variables across group comparisons.
| Variable | Age 45–54 yrs (n = 1,650) | Age 54–64 yrs (n = 1,436) | Age 65–74 yrs (n = 1,356) | Age 75–84 yrs (n = 650) | ||||
|---|---|---|---|---|---|---|---|---|
| No CAC (n = 1,273; 77%) | CAC (n = 377; 23%) | No CAC (n = 830; 58%) | CAC (n = 606; 42%) | No CAC (n = 518; 38%) | CAC (n = 838; 62%) | No CAC (n = 131; 20%) | CAC (n = 519; 80%) | |
| Total cholesterol | 191 ± 34 | 199 ± 34 | 199 ± 35 | 199 ± 37 | 197 ± 33 | 198 ± 34 | 188 ± 34 | 195 ± 35 |
| p Value † | <0.001 | 0.08 | 0.69 | 0.06 | ||||
| Low-density lipoprotein cholesterol | 117 ± 31 | 125 ± 32 | 120 ± 32 | 124 ± 34 | 118 ± 30 | 122 ± 30 | 112 ± 29 | 119 ± 31 |
| p Value † | <0.001 | 0.015 | 0.007 | 0.017 | ||||
| High-density lipoprotein cholesterol | 51 ± 14 | 46 ± 13 | 53 ± 16 | 49 ± 14 | 56 ± 16 | 50 ± 15 | 54 ± 15 | 52 ± 15 |
| p Value † | <0.001 | <0.001 | <0.001 | 0.18 | ||||
| Non-high-density lipoprotein cholesterol | 140 ± 35 | 153 ± 35 | 146 ± 35 | 151 ± 37 | 141 ± 34 | 148 ± 34 | 134 ± 32 | 142 ± 34 |
| p Value † | <0.001 | 0.006 | <0.001 | 0.01 | ||||
| Triglycerides | 100 (71–147) | 124 (85–179) | 111 (78–162) | 119 (84–165) | 104 (73–148) | 114 (82–159) | 102 (72–142) | 107 (76–150) |
| p Value † ‡ | <0.001 | 0.07 | 0.001 | 0.24 | ||||
| Total/high-density lipoprotein cholesterol ratio | 4.0 ± 1.2 | 4.7 ± 1.4 | 4.0 ± 1.2 | 4.4 ± 1.7 | 3.8 ± 1.1 | 4.2 ± 1.2 | 3.7 ± 1.0 | 4.0 ± 1.1 |
| p Value † | <0.001 | <0.001 | <0.001 | 0.005 | ||||
| Low-density lipoprotein/high-density lipoprotein cholesterol ratio | 2.5 ± 0.9 | 3.0 ± 1.1 | 2.4 ± 0.9 | 2.8 ± 1.0 | 2.3 ± 0.9 | 2.6 ± 0.9 | 2.2 ± 0.8 | 2.5 ± 0.9 |
| p Value † | <0.001 | <0.001 | <0.001 | 0.003 | ||||
| Triglycerides/high-density lipoprotein cholesterol ratio | 2.6 ± 1.9 | 3.5 ± 2.5 | 2.7 ± 2.0 | 3.1 ± 2.1 | 2.4 ± 1.8 | 2.9 ± 2.0 | 2.4 ± 1.6 | 2.6 ± 1.7 |
| p Value † | <0.001 | <0.001 | <0.001 | 0.15 | ||||
⁎ p <0.001 for no CAC versus CAC and age category using chi-square analyses
† comparing no CAC versus CAC for each lipid variable in preceding row within each age category using analysis of variance.
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