The association between systemic inflammation and the estimated 10-year risk for coronary artery disease (CAD) according to the Framingham risk score is largely unknown. In this study, 6,371 participants in the Third National Health and Nutrition Examination Survey (NHANES III) aged 40 to 79 years, who had no histories of heart attack, stroke, peripheral artery disease, or diabetes mellitus, were categorized into groups at low (<10%), intermediate (10% to 20%), and high (>20%) risk according to 10-year risk for CAD, calculated using the Framingham risk score modified by the National Cholesterol Education Program Adult Treatment Panel III. After adjustments for age, gender, race, body mass index, and co-morbidities, participants at high risk were more likely to have elevated circulating C-reactive protein levels (≥2.2 mg/L: adjusted odds ratio [OR] 1.61, 95% confidence interval [CI] 1.30 to 2.01, p <0.0001; >10.0 mg/L: OR 1.41, 95% CI 1.03 to 1.93, p = 0.034). The high-risk group had circulating fibrinogen, homocysteine, leukocyte, and platelet levels that were 20.98 mg/dl (95% CI 12.53 to 29.43, p <0.0001), 1.54 μmol/L (95% CI 0.76 to 2.32, p = 0.002), 0.90 μmol/L (95% CI 0.36 to 1.43, p = 0.001), 910/μl (95% CI 670 to 1,160, p <0.0001), and 10,220/μl (95% CI 2,830 to 17,610, p <0.0001) higher, respectively, than in those in the low-risk group. There was also a dose-dependent increase in circulating levels of inflammatory markers across the categories of CAD risk. In conclusion, these findings indicate that low-grade systemic inflammation and hyperhomocysteinemia were present in participants with high 10-year risk for CAD.
Recently, much evidence has indicated that elevated levels of inflammation markers, particularly C-reactive protein (CRP), are associated with a higher risk for coronary artery disease, suggesting that inflammation plays a key role in the development of CAD. However, the association between the estimated 10-year risk for CAD and systemic inflammation is largely unknown. Therefore, we sought to determine whether the distribution of 10-year risk for CAD is dose-dependently associated with novel inflammatory markers in healthy adults in the United States.
Methods
The methods of the Third National Health and Nutrition Examination Survey (NHANES III) have been described in detail previously. Briefly, NHANES III was a cross-sectional, multistage probability sample recruited from 1988 to 1994 that was representative of the total noninstitutionalized civilian population of the United States. NHANES III data collection included a home interview and a detailed clinical examination at a mobile examination center. We restricted our study to the 6,371 participants of NHANES III, aged 40 to 79 years, who had no histories of heart attack, stroke, peripheral artery disease, or diabetes. The study participants were categorized into groups at low (<10%), intermediate (10% to 20%), and high (>20%) risk according to 10-year risk for CAD, calculated using the Framingham risk score modified by the National Cholesterol Education Program Adult Treatment Panel (ATP) III.
Laboratory procedures used in NHANES III are described elsewhere. CRP levels were measured by latex-enhanced nephelometry. Because 4,033 participants (63.3%) had CRP values less than the lowest detectable level (2.2 mg/L), CRP was treated as a categorical rather than a continuous variable for analytic purposes. CRP levels ≥2.2 mg/L were considered elevated, and levels >10 mg/L were categorized as highly elevated. Fibrinogen levels were measured using enzyme assay methods. Serum homocysteine levels were measured by high-performance liquid chromatography. Homocysteine levels were also measured from 1991 to 1994 (during phase 2 of NHANES III) and were available for 3,860 participants in this analysis. We included leukocyte and platelet counts as well as total serum cholesterol and high-density lipoprotein cholesterol levels in the analysis. Fibrinogen, homocysteine, leukocyte, and platelet levels were defined as elevated if they were included in ≥85th percentile (377 mg/dl, 13.3 μmol/L, 9.05 × 10 3 /μL, and 340.5 × 10 3 /μL, respectively).
Race was divided into 3 categories: white, black, and other. Smoking status was divided into 3 strata: current, former, and never. We divided body mass index (BMI) into quintiles: ≤23.5, 23.6 to 26.0, 26.1 to 28.5, 28.6 to 31.8, and ≥31.9 kg/m 2 . The presence of co-morbidities was determined by participants’ responses to the question “Has the doctor ever told you that you had diabetes (congestive heart failure, chronic bronchitis, etc.)?” Participants were deemed to have rheumatoid arthritis or a related inflammatory disorder if they had significantly elevated titers of rheumatoid factor (≥1:40) on a serum dilution latex fixation test.
The baseline characteristics of the study participants with moderate or high 10-year risk were compared with those of the low 10-year risk group using chi-square tests for binary variables and Student’s t tests for continuous variables. To assess whether there was a gradient in various baseline demographic and clinical factors across 10-year risk for CAD, we used a Mantel-Haenszel test for trend. We used multiple logistic modeling to determine whether 10-year risk for CAD was associated with elevations in circulating inflammatory markers and performed a weighted multiple linear regression analysis, with 1 degree of freedom, as a test for trend. In all of these models, we adjusted for age, gender, BMI, race, and co-morbidities (rheumatoid arthritis, gout, chronic obstructive pulmonary disease, thyroid disease, and cancer) for their potential effects on systematic inflammation. All tests were 2 tailed. Statistical analyses were carried out using Stata version 8.0 (StataCorp LP, College Station, Texas) using methods that accounted for the complex sample design of NHANES III. Continuous variables are expressed as mean ± SD unless otherwise indicated.
Results
The baseline characteristics and laboratory profiles, according to the estimated 10-year risk for CAD, are listed in Table 1 . Patients at intermediate and high risk for CAD tended to be older, male, and of white racial identification. The incidence of current smoking was not different among the 3 groups. Laboratory profiles showed that subjects in the low-risk group had lower creatinine, glucose, total cholesterol, and low-density lipoprotein cholesterol levels than those in the moderate- or high-risk group, as predicted. The levels of high-density lipoprotein cholesterol were significantly lower in the high-risk group compared to those in the low- and moderate-risk groups. Laboratory profiles of the inflammatory markers, classified according to estimated 10-year risk for CAD per ATP III, are listed in Table 2 . Elevated and highly elevated CRP levels were more commonly observed in participants in the high-risk group than in those in the low-risk group. In the intermediate- and high-risk groups, the levels of fibrinogen, homocysteine, and leukocytes were also increased. And the proportion of subjects with increased levels of inflammatory markers was also higher in the intermediate- and high-risk groups. There was no significant difference in the platelet count among the groups.
| Variable | Estimated 10-Year Risk | ||
|---|---|---|---|
| Low (n = 2,527) | Intermediate (n = 3,336) | High (n = 508) | |
| Age (years) | 52.5 ± 10.2 | 57.8 ± 11.3 ⁎ | 68.4 ± 8.3 ⁎ |
| Men | 40.4% | 53.8% ⁎ | 43.1% ⁎ |
| White | 69.8% | 72.3% ⁎ | 72.0% ⁎ |
| Current smokers | 22.9% | 27.3% | 27.2% |
| Body mass index (kg/m 2 ) | 27.2 ± 5.5 | 27.8 ± 5.5 ⁎ | 28.6 ± 5.4 ⁎ |
| Systolic blood pressure (mm Hg) | 118.0 ± 15.6 | 136.9 ± 15.2 ⁎ | 150.9 ± 17.9 ⁎ |
| Diastolic blood pressure (mm Hg) | 73.8 ± 9.2 | 79.4 ± 9.8 ⁎ | 78.8 ± 11.4 ⁎ |
| Creatinine (μmol/L) | 94.3 ± 22.3 | 96.3 ± 28.3 ⁎ | 107.1 ± 31.8 ⁎ |
| Glucose (mmol/L) | 5.4 ± 1.1 | 5.6 ± 1.3 ⁎ | 5.9 ± 1.5 ⁎ |
| Total cholesterol (mmol/L [mg/dl]) | 5.45 ± 1.08 (201.8 ± 41.8) | 5.67 ± 1.12 ⁎ (219.3 ± 43.3 ⁎ ) | 6.12 ± 1.15 (236.7 ± 44.5) |
| Triglyceride (mmol/L [mg/dl]) | 1.60 ± 1.11 (141.7 ± 98.3) | 1.80 ± 1.30 (159.4 ± 115.1) | 2.11 ± 1.42 (186.9 ± 125.8) |
| LDL cholesterol (mmol/L [mg/dl]) | 3.42 ± 0.99 (132.3 ± 38.3) | 3.54 ± 0.99 ⁎ (136.9 ± 38.3 ⁎ ) | 3.99 ± 1.01 ⁎ (154.3 ± 39.1 ⁎ ) |
| HDL cholesterol (mmol/L [mg/dl]) | 1.36 ± 0.41 (52.6 ± 15.9) | 1.33 ± 0.43 (51.4 ± 16.6) | 1.26 ± 0.46 ⁎ (48.7 ± 17.8 ⁎ ) |
| Variable | Estimated 10-Year Risk | ||
|---|---|---|---|
| Low (n = 2,527) | Intermediate (n = 3,336) | High (n = 508) | |
| CRP ≥0.22 mg/dl | 33.5% | 37.0% | 51.0% ⁎ |
| CRP >1.00 mg/dl | 8.9% | 9.8% ⁎ | 15.0% ⁎ |
| Fibrinogen (mg/dl) | 299.6 ± 81.8 | 306.9 ± 82.1 ⁎ | 340.9 ± 90.1 ⁎ |
| Elevated fibrinogen level † | 13.0% | 14.1% ⁎ | 24.3% ⁎ |
| Homocysteine (μmol/L) | 9.6 ± 4.5 | 10.3 ± 5.5 ⁎ | 12.2 ± 5.3 ⁎ |
| Elevated homocysteine level † | 15.1% | 19.2% ⁎ | 37.2% ⁎ |
| Leukocytes (×10 3 /μl) | 6.8 ± 2.2 | 7.2 ± 2.2 ⁎ | 7.6 ± 3.7 ⁎ |
| Elevated leukocyte level | 12.5% | 15.7% ⁎ | 20.3% ⁎ |
| Platelets (×10 3 /μl) | 273.3 ± 69.8 | 274.2 ± 74.5 | 271.1 ± 72.3 |
| Elevated platelet level | 14.3% | 15.7% ⁎ | 14.7% |
⁎ p <0.05 vs first-quartile group.
† Elevated fibrinogen and homocysteine levels were defined as ≥85th percentile of either variable.
Table 3 lists the adjusted odds ratios and 95% confidence intervals of elevated levels of circulating inflammatory markers. After adjustments for age, gender, race, BMI, and co-morbidities, participants at high CAD risk were more likely to have elevated circulating CRP levels. The elevated levels of fibrinogen and homocysteine were also higher in participants in the high-risk group.
| Variable | Estimated 10-Year Risk | |||
|---|---|---|---|---|
| Intermediate | p Value | High | p Value | |
| C-reactive protein ≥0.22 mg/dl | 1.12 (1.00–1.26) | 0.052 | 1.61 (1.30–2.01) | <0.0001 |
| C-reactive protein >1.00 mg/dl | 1.07 (0.89–1.30) | 0.464 | 1.41 (1.03–1.93) | 0.034 |
| Elevated fibrinogen level ⁎ | 0.97 (0.83–1.14) | 0.705 | 1.36 (1.05–1.78) | 0.022 |
| Elevated homocysteine level ⁎ | 1.11 (0.89–1.38) | 0.351 | 2.11 (1.48–3.01) | <0.0001 |
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