ORIGINAL INVESTIGATION. High Attributable Risk of Elevated C-Reactive Protein Level to Conventional Coronary Heart Disease Risk Factors

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1 ORIGINAL INVESTIGATION High Attributable Risk of Elevated C-Reactive Protein Level to Conventional Coronary Heart Disease Risk Factors The Third National Health and Nutrition Examination Survey Michael Miller, MD; Min Zhan, PhD; Stephen Havas, MD, MPH, MS Background: C-reactive protein (CRP), a marker of systemic inflammation, is predictive of coronary heart disease (CHD) events. However, the extent to which high CRP levels ( 3 mg/l) may be attributable to high cholesterol levels and other CHD risk factors has not been well defined. Methods: The prevalence of high CRP levels in the third National Health and Nutrition Examination Survey (n=15 341) was studied using CHD risk-factor cut points designated as abnormal (total cholesterol values, 240 mg/dl [ 6.22 mmol/l]; fasting blood glucose levels, 126 mg/dl [ 6.99 mmol/l]; blood pressure, 140/90 mm Hg; body mass index [BMI], 30 kg/m 2 ; highdensity lipoprotein cholesterol values, 40 mg/dl [ 1.04 mmol/l] for men and 50 mg/dl [ 1.30 mmol/l] for women; triglyceride levels, 200 mg/dl [ 2.26 mmol/l]; current smoking status) or borderline (total cholesterol values, mg/dl [ mmol/l]; fasting blood glucose levels, mg/dl [ mmol/l]; blood pressure, /80-89 mm Hg; BMI, kg/m 2, and triglyceride values mg/dl [ mmol/l], former smoking status), or normal. Results: Weighted multiple logistic regression analysis demonstrated that high CRP level was significantly more common with obesity (odds ratio [OR], 3.78; 95% confidence interval [CI], ]), overweight (OR, 1.88; 95% CI, ), and diabetes (OR, 1.91; 95% CI, ) and that high CRP level was rare in the absence of any borderline or abnormal CHD risk factor in men (4.4%) and women (10.3%). Overall, the risk of elevated CRP level attributable to the presence of any abnormal or borderline CHD risk factor was 78% in men and 67% women. Conclusions: These data suggest that elevated CRP levels in the general population are in large measure attributable to traditional CHD risk factors. Moreover, CRP level elevation is rare in the absence of borderline or abnormal risk factors. As such, CRP measurements may have limited clinical utility as a screening tool beyond other known CHD risk factors. Arch Intern Med. 2005;165: Author Affiliations: Departments of Medicine (Drs Miller and Havas) and Epidemiology and Preventive Medicine (Drs Miller, Zhan, and Havas), University of Maryland School of Medicine, Baltimore. INFLAMMATION HAS BEEN IMPLIcated in the origination and progression of cardiovascular disease, 1 and among the most actively studied biomarkers is C- reactive protein (CRP), an acute-phase reactant released predominantly by hepatocytes. 2 While low-grade inflammation is predictive of coronary heart disease (CHD), 3 even in the absence of elevated For editorial comment see page 2058 low-density lipoprotein cholesterol levels, 4 the extent to which high CRP level is attributable to well-established CHD risk factors has not been well studied. This is an important issue to investigate in view of the numerous proponents for or against CRP level as a CHD screening tool 5-8 and a recent Centers for Disease Control and CME course available at Prevention and the American Heart Association scientific statement 9 reserving CRP measurements for those patients at intermediate CHD risk (defined as a 10-year CHD risk range of 10%-20%). If elevated CRP level is intimately linked to conventional CHD risk factors, then routine screening of this biomarker would seemingly be less valuable to clinicians. Therefore, the present study was undertaken to evaluate the extent to which high CRP levels ( 3 mg/l) may simply reflect expres- 2063

2 Table 1. Baseline Characteristics of the NHANES III 10 Cohort* Characteristic sion of the pathobiologic changes induced by conventional CHD risk factors. METHODS Men (n = 7215) Women (n = 8126) Age, y Blood pressure, mm Hg Systolic Diastolic BMI Diabetes mellitus, % Ethnicity, % Black White Other Lipids/lipoproteins, mg/dl HDL cholesterol Triglycerides Total cholesterol Physical activity, % Vigorous Moderate Light Sedentary Smoking status, % Active Former Never Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); HDL, high-density lipoprotein; NHANES III, third National Health and Nutrition Examination Survey. SI conversion factors: To convert HDL cholesterol and cholesterol to millimoles per liter, multiply by ; to convert triglycerides to millimoles per liter, multiply by *Data are presented as mean values or percentages. The third National Health and Nutrition Examination Survey (NHANES III) 10 was conducted between and used a stratified, multistage, probability sampling design to produce estimates generalizable to the US population. A total of adults 18 years or older were screened for the study. A total of subjects were included in the study, excluding subjects with any of the following data points missing from the record: CRP values (n=3081), glucose levels (n=1394), highdensity lipoprotein cholesterol levels (n=84), triglyceride levels (n=80), body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) (n=32), blood pressure values (n=29), race designation (n=8), and smoking status (n=1). The dependent variable, serum CRP concentrations, was measured at the University of Washington Department of Laboratory Medicine using a Behring (Dade Behring, Deerfield, Ill) latex-enhanced nephelometer analyzer system; the assay was not of high sensitivity. We defined elevated levels of CRP as greater than 3 mg/l based on the recent Centers for Disease Control and Prevention and the American Heart Association scientific statement. 9 Established cut points were used for the categorical variables in defining normal, borderline, or abnormal CHD risk factors. They included cigarette smoking (never, former, or current); blood pressure (normal, 120/80 mm Hg; prehypertension, /80-89 mm Hg; and hypertension, 140/90 mm Hg or receiving blood pressure medications) 11 ; fasting glucose levels (normal, 100 mg/dl [ 5.55 mmol/l]; pre diabetes mellitus, mg/dl [ mmol/l]; and diabetes mellitus, 126 mg/dl [ 6.99 mmol/l] or receiving insulin or oral hypoglycemic agents) 12 ; total cholesterol levels (normal, 200 mg/dl [ 5.18 mmol/l]; borderline high, mg/dl [ mmol/l]; and high, 240 mg/dl [ 6.22 mmol/l] or receiving lipid-lowering medications) 13 ; triglyceride levels (normal, 150 mg/dl [ 1.70 mmol/l]; borderline high, mg/dl [ mmol/l]; and high, 200 mg/dl [ 2.26 mmol/l] or receiving lipid-lowering medications) 13 ; highdensity lipoprotein cholesterol values (normal, 40 mg/dl [ 1.04 mmol/l] in men and 50 mg/dl [ 1.30 mmol/l] in women; low, 40 mg/dl [ 1.04 mmol/l] in men and 50 mg/dl [ 1.30 mmol/l] in women) 13 ; and BMI (normal, 25; overweight, 25-29; and obese, 30). 14 We selected total cholesterol rather than low-density lipoprotein cholesterol because of the high number of missing values for the latter (n=7829). Finally, we also classified physical activity into 4 categories: vigorous activity, moderate activity, light activity, and sedentary as previously defined. 15 We also determined the use of estrogen replacement therapy in women who had surgical or natural menopause. The association between CHD risk factors and the prevalence of elevated CRP levels was assessed using 2 tests. Additional analyses were conducted using SAS statistical software, version 9 (SAS Institute Inc, Cary, NC). Because NHANES III oversampled minority populations, weighted analyses were performed to ensure that results were generalizable to US population demographics (SAS/STAT, version 9.1). The odds ratio of elevated CRP levels was determined in the presence (or absence) of each of the above CHD risk factors, and their 95% confidence intervals (CIs) were calculated by a multiple logistic regression model that used survey weights. The attributable risk of elevated CRP level due to one or more CHD risk factors was computed using the following formula: (P D/E P D/E fl) NE/ND, where P D/E is the weighted percentage of high CRP levels with abnormal or borderline CHD risk factors, P D/E fl is the weighted percentage of high CRP levels without CHD risk factors, NE is the number of estimated individuals with abnormal or borderline CHD risk factors in the population, and ND is the estimated total number of cases in the population. RESULTS A total of adult men and women were included in the analysis. Table 1 provides baseline and demographic information of the NHANES III cohort. The frequency and prevalence of high CRP levels for each of the CHD risk factors are listed in Table 2. Blacks had higher CRP levels than whites. Overall, there were marked increases in the prevalence of elevated CRP levels especially associated with higher blood pressure, glucose levels, and BMI. Compared with never smokers, high CRP level was more common in both former and active cigarette smokers. A graded increase in the prevalence of high CRP levels was also apparent as blood pressure, glucose, cholesterol, triglyceride, and BMI cut points increased from normal to borderline and abnormal levels, with larger increases occurring between borderline and abnormal ranges. Similar changes were also observed in univariate analysis comparing sedentary and physically active subjects. 2064

3 Table 2. Prevalence of High C-Reactive Protein Levels Based on Univariate Analysis of Ethnicity and Coronary Heart Disease Risk factors Characteristic Frequency Prevalence, % P Value Ethnicity Black White Other Cigarette smoking Never Former Active Blood pressure, mm Hg Normal ( 120/80) Prehypertensive ( /80-89) Hypertensive ( 140/90) Glucose, mg/dl Normal ( 100) Prediabetes ( ) Diabetes ( 125) Cholesterol, mg/dl Normal ( 200) Borderline ( ) High ( 240) Triglycerides, mg/dl Normal ( 150) Borderline ( ) High ( 200) HDL-C, mg/dl Normal ( 40, men; 50, women) Low ( 40, men; 50, women) BMI Normal ( 25) Overweight (25-29) Obese ( 30) Physical activity Vigorous Moderate Light Sedentary Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); HDL-C, high-density lipoprotein cholesterol. SI conversion factors: To convert glucose to millimoles per liter, multiply by ; to convert HDL cholesterol and cholesterol to millimoles per liter, multiply by ; and to convert triglycerides to millimoles per liter, multiply by The overall prevalence of elevated CRP level was 25.7%. Compared with subjects who never smoked cigarettes and were normotensive, normolipidemic, euglycemic, and not overweight (n=813), the presence of at least 1 borderline or abnormal CHD risk factor (n=14 528) was associated with an approximate 3-fold higher prevalence of CRP level higher than 3 mg/l (8.7% vs 26.7%) (P) (Figure). Only 4.4% of men and 10.3% of women with a favorable risk-factor profile had elevated CRP levels. In the presence of any borderline CHD risk factor, high CRP level increased 1.5- to 2-fold and approximately 3- to 5-fold with at least 1 abnormal CHD risk factor. The prevalence of elevated CRP level was also higher among postmenopausal women receiving estrogen replacement therapy (51%; n=473) than among estrogen nonusers or former users (37%; n=3105) (P). These data are consistent with previous studies that have shown higher CRP levels in women than in men 16 and higher levels in women undergoing estrogen replacement therapy than in women not undergoing such therapy. 17,18 However, because of the small number of women receiving estrogen replacement therapy, this variable was not included in our multiple logistic regression model. The inclusion of moderate and/or vigorous physical activity sharply reduced the number of men and women without any CHD risk factors from 813 to 71 of subjects. Because only a very small fraction of these normal subjects had elevated CRP levels (n=7, or 0.05% of the total cohort), physical activity was not included in multiple logistic regression analysis. Weighted multiple logistic regression analysis adjusted for age and race identified the factors that were most highly associated with elevated CRP level: excess weight, hypertension, female sex, diabetes, cigarette smoking, and low high-density lipoprotein cholesterol values (Table 3). Table 4 demonstrates that the attributable risk of high CRP level in men and women was primarily accounted for by the presence of at least 1 abnormal CHD risk factor. In NHANES III, the attributable risk of high CRP level for the presence at least 1 abnormal or borderline CHD risk factor was approximately 78% for men and 67% for women. 2065

4 Prevalence, % Normal Borderline High Table 4. Attributable Risk of High C-Reactive Protein Level in Men and Women With at Least 1 Borderline or Abnormal CHD Risk Factor* Attributable Risk Due to Men Women 1 Abnormal CHD risk factor Borderline CHD risk factor Abnormal or borderline CHD risk factor Abbreviation: CHD, coronary heart disease. *Data are presented as percentages. 0 Risk Factor None 1 Borderline 1 Abnormal Men Women Percentage (No.) of Subjects 4.4 (236) 9.2 (1282) 23.3 (5697) COMMENT 10.3 (577) 14.2 (1157) 37.4 (6392) Figure. Prevalence of high C-reactive protein levels in men and women based on coronary heart disease risk factors (cigarette smoking, borderline or elevated blood pressure, impaired fasting glucose level or diabetes mellitus, borderline-high or high cholesterol levels, borderline-high or high triglyceride levels, elevated body mass index, and low high-density lipoprotein levels, as specified in the Methods section). Asterisk indicates P within sex. Prevalence of high C-reactive protein level was significantly higher in women than in men (30.95% vs 19.7%; P). Table 3. Weighted Multiple Logistic Regression Analysis of High C-Reactive Protein Level and Coronary Heart Disease Risk Factors Risk Factor OR (95% CI) BMI Obese vs normal 3.78 ( ) Overweight vs normal 1.88 ( ) Blood pressure Hypertension vs normal 1.49 ( ) Prehypertensive vs normal 1.23 ( ) Cholesterol High vs normal 0.99 ( ) Borderline high vs normal 0.93 ( ) Sex Female vs male 2.11 ( ) Glucose Diabetes vs normal 1.91 ( ) Prediabetes vs normal 1.06 ( ) HDL-C Low vs normal 1.45 ( ) Smoking Current vs never 1.62 ( ) Former vs never 1.14 ( ) Triglycerides High vs normal 1.10 ( ) Borderline-high vs normal 1.02 ( ) Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; OR, odds ratio. Until recently, many believed that only 50% of CHD was accounted for by traditional risk factors such as cigarette smoking, diabetes mellitus, hypertension, and high blood cholesterol level. 19 This in turn led to intensive investigations to uncover other potentially important biomarkers influencing atherothrombosis and CHD risk. Among the numerous markers surveyed, CRP level has been the most thoroughly examined with more than 1900 entries in PubMed during the past 9 years. However, recent studies have affirmed that traditional risk factors account for the overwhelming majority of CHD cases in the United States The present study reinforces the central role that traditional CHD risk factors play in atherothrombosis by demonstrating that a pivotal biomarker of systemic inflammation, elevated CRP level, is generally accompanied by borderline or abnormal CHD risk factors and rarely occurs in their absence. Thus, while these data in no way negate the important influence that inflammation plays in promoting or accelerating CHD, 23 they underscore the likely role that well-established risk factors contribute to the inflammatory process. Several lines of evidence support a strong interrelationship between inflammatory biomarkers and CHD risk factors. For example, hepatic production of CRP is up-regulated by visceral adipocyte-mediated secretion of inflammatory cytokines. 24 In addition to interleukin 6 and nuclear factor, other proinflammatory mediators released from adipocytes, notably angiotensin II, contribute to dyslipidemia, insulin resistance, and systemic hypertension. 25,26 The present study reaffirms that elevated CRP level is strongly correlated with measures of adiposity 27 as defined by BMI measurements for overweight and obesity. These close-knit relationships make it difficult to disentangle the distinctive impact of CRP level beyond wellestablished risk factors. Moreover, the treatments commonly used to reduce conventional CHD risk factors also lower CRP levels Therefore, given the tight interrelationship between systemic inflammation and CHD risk factors, and in view of the extremely low prevalence of high CRP level in the absence of the 8 risk factors in NHANES III (ie, 0.05%), it is difficult, if not impossible, to prove the CRP hypothesis (ie, reduction of CRP level independently diminishes CHD event rates). This would necessitate the development of targeted agents that would lower CRP levels and reduce CHD without affecting values for lipids, blood pressure, glucose, and visceral adiposity. Unless these concerns can be assuaged, we do not recommend screening for elevated CRP levels. In fact, CRP screening may be counterproductive because finding normal levels ( 1 mg/l) could dissuade patients and physicians from using intensive lifestyle therapy that might prove 2066

5 useful. For example, a low CRP level ( 1 mg/dl) in an overweight, dyslipidemic, prehypertensive, or prediabetic subject might provide false reassurance that no further therapy is required. However, failure to institute lifestyle strategies aimed at normalizing body weight, lipid levels, blood pressure, and glucose values leads to greater disease progression and increased CHD event rates, 32 regardless of CRP levels. In an era where obesity-related illnesses have grown to epidemic proportions, 33 more intensive efforts should be directed toward eradicating the primary culprit of elevated CRP levels, visceral adiposity. There are several limitations associated with the present study. First, to circumvent oversampling of selected groups in NHANES III (eg, blacks), weighted analyses were performed. Second, the highly sensitive CRP assay currently in widespread use, enabling detection of lower CRP levels (eg, 2.1 mg/l), was not used in NHANES III. While this shortcoming did not affect the primary question raised in the present study related to high CRP level, it restricted further analyses using moderate to high CRP cut points (ie, 1-3 mg/l). 34 Third, 15% of the cohort had missing data for CRP levels, resulting mostly from refusal to have blood drawn or insufficient blood sampling. However, there were no material differences in demographic characteristics between the subjects with and without blood for analysis. Finally, the objective cut points used to define normal, borderline, and abnormal lipid levels, blood pressure, glucose values, and measures of adiposity were considerably easier to quantify in NHANES III compared with more subjective risk factors, such as mental stress. Even though a strong association between CRP level and overall CHD risk exists, 1 cross-sectional study did not demonstrate that CRP level correlated with individual CHD risk factors. 35 However, the size of that cohort was considerably smaller than NHANES III (n=1666 vs ), and measures of adiposity, the most powerful variable influencing CRP level, were not undertaken. Because the presence of multiple risk factors (as opposed to a single factor) increases the likelihood of CHD, 36 focusing on individual parameters may underestimate overall CHD risk, especially in the United States, where the prevalence of multiple risk factors (eg, metabolic syndrome) is high. 37 In the present study, elevated CRP level was very prevalent in the presence of at least 1 borderline or abnormal risk factor. Based on the recent results of the INTERHEART study 38 of about people, where 90% of CHD could be accounted for by 9 measures of risk (abdominal obesity, alcohol intake, cigarette smoking, hypertension, diabetes, abnormal lipids [apolipoprotein B/apolipoprotein A-I ratio], low consumption of fruits and vegetables, physical inactivity, and psychosocial factors), it is tempting to speculate that a similarly high attributable risk relating CRP level and CHD risk factors might have been ascertained had NHANES III enrolled twice the number of subjects and been able to measure parameters such as physical activity with greater precision. In summary, these data suggest that elevated CRP level is primarily attributable to traditional CHD risk factors. As such, measurement of CRP levels may have limited clinical utility as a screening tool for CHD risk assessment unless randomized clinical trials can demonstrate that lowering CRP levels offsets CHD events beyond wellestablished lifestyle and pharmacologic modalities. In the meantime, more intensified efforts should be aimed at promotion of smoking cessation, increasing physical activity, and lowering of elevated blood pressure, lipid levels, and visceral adiposity because all have proven impact on CHD reduction. Accepted for Publication: March 17, Correspondence: Michael Miller, MD, Division of Cardiology, Room S3B06, 22 S Greene St, Baltimore, MD (mmiller@heart.umaryland.edu). Financial Disclosure: None. Funding/Support: This work was supported in part by National Institutes of Health grant HL and a Veterans Affairs Merit Award to Dr Miller. 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