The Relationship Between Blood Pressure and C-Reactive Protein in the Multi-Ethnic Study of Atherosclerosis (MESA)

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1 Journal of the American College of Cardiology Vol. 46, No. 10, by the American College of Cardiology Foundation ISSN /05/$30.00 Published by Elsevier Inc. doi: /j.jacc The Relationship Between Blood Pressure and C-Reactive Protein in the Multi-Ethnic Study of Atherosclerosis (MESA) Susan G. Lakoski, MD, MS,* Mary Cushman, MD, MSC, Walter Palmas, MD, MS, Roger Blumenthal, MD, FACC, Ralph B. D Agostino, JR, PHD, David M. Herrington, MD, MHS, FACC* Winston-Salem, North Carolina; Burlington, Vermont; New York, New York; and Baltimore, Maryland OBJECTIVES BACKGROUND METHODS The goal of this study was to determine the relationship between resting blood pressure (BP) and C-reactive protein (CRP) in a multi-ethnic cohort of men and women from the Multi-Ethnic Study of Atherosclerosis (MESA). Several investigators have observed elevated levels of CRP in individuals with hypertension. Hypertension prevalence varies considerably across ethnic groups. Important questions remain regarding whether the relationship between hypertension and CRP is similar across ethnic and gender subgroups. The MESA participants had CRP levels determined at the baseline clinical examination (N 6,814). Hypertension, treated as a dichotomous variable (yes/no), was defined as a systolic or diastolic BP 140/90 mm Hg or a self-reported history of hypertension and use of antihypertensive medications. RESULTS The geometric mean CRP in hypertensive participants was mg/l compared with mg/l among normotensive participants (p ). The relative difference in CRP levels in hypertensives compared with normotensives was similar regardless of gender (13% in men and 13% in women). Ethnic comparisons showed that Chinese participants had the lowest CRP concentration but the largest difference in CRP by hypertension status (24%). Caucasians and African Americans had 10% to 15% higher CRP levels with hypertension, whereas Hispanics had no significant difference in CRP by hypertension status. CONCLUSIONS This study confirms the existence of an independent association between hypertension and inflammation in both men and women. Ethnic group differences were evident, with the strongest association observed in Chinese participants and no difference in CRP levels by hypertension status in Hispanics. (J Am Coll Cardiol 2005;46: ) 2005 by the American College of Cardiology Foundation From the Departments of *Internal Medicine/Cardiology and Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina; Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont; Department of Medicine, Columbia University, New York, New York; and the Ciccarone Preventive Cardiology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC through N01-HC and NHLBI research training grant 1 T32 HL Manuscript received May 6, 2005; revised manuscript received July 11, 2005, accepted July 18, Hypertension is an important modifiable risk factor contributing to an increased risk of myocardial infarction (MI) worldwide (1). Despite the longstanding recognition of an association between hypertension and MI, the precise mechanisms that account for this relationship remain unclear. Multiple substudies of large clinical trials have found that higher C-reactive protein (CRP) concentrations are associated with worse outcomes in patients with unstable coronary disease (2 4). Recently, several investigators have observed higher CRP concentrations in individuals with hypertension (5 7). This raises the possibility that higher CRP, or subclinical inflammation as indicated by CRP, may be one of the causal mechanisms contributing to an increased risk for MI in hypertensive patients. Although there have been several large studies looking at the association between hypertension and CRP, most participants have been Caucasian, potentially limiting the generalizability of results (5,6,8). Hypertension varies considerably across ethnic groups, with the highest rates among African-American women (9). In addition, CRP levels differ by ethnicity (10,11). It is not known whether the relationship between CRP and hypertension is present across multiple ethnic groups. A consistent pattern across ethnicity would provide additional evidence that the observed association reflects a fundamental feature of human biology and is not simply attributable to confounding by unmeasured factors that are common in Caucasian individuals. In the present study, our primary goal was to determine whether there was an association between hypertension and CRP among a multi-ethnic group of men and women ages 45 to 84 years old enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). A secondary goal was to ascertain whether gender and ethnicity modify the relationship between hypertension and CRP. METHODS The MESA study was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease in individuals without known cardio-

2 1870 Lakoski et al. JACC Vol. 46, No. 10, 2005 BP and CRP in MESA November 15, 2005: Abbreviations and Acronyms BP blood pressure CRP C-reactive protein HTN hypertension JNC 7 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure MESA Multi-Ethnic Study of Atherosclerosis MI myocardial infarction vascular disease (12). The cohort consisted of 6,814 men and women ages 45 to 84 years old recruited in six U.S. communities. There are 47% men with an ethnic representation of 38% white, 28% African-American, 22% Hispanic, and 12% Asian (of Chinese descent) individuals. History, measurements, and laboratory data for the present analysis were taken from the first examination of the MESA cohort beginning in July Information about age, gender, ethnicity, medical history, and alcohol consumption was obtained by questionnaires. A history of hypertension and the use of blood pressure (BP) medications for hypertension were obtained from medical history. Resting BP was taken three times in the seated position after a five-minute rest using a Dinamap model Pro 100 automated oscillometric sphygmomanometer (Critikon, Tampa, Florida) (13) with the average of the last two measurements recorded and verified. Diabetes was defined as normal, impaired fasting glucose, or diabetes based on 1997 American Diabetes Association guidelines (14). Smoking was defined as never, current, or former. Body mass index was derived from the equation weight (kg)/ height (m 2 ). Physical activity was defined as total of all light, moderate, and vigorous activities (min/week) multiplied by individual metabolic equivalent values. The CRP was measured using the BNII nephelometer (N High Sensitivity CRP; Dade Behring Inc., Deerfield, Illinois) at the Laboratory for Clinical Biochemistry Research (University of Vermont, Burlington, Vermont). Analytical intra-assay coefficient of variations ranged from 2.3% to 4.4%, and inter-assay coefficient of variation ranged from 2.1% to 5.7%. Statistical analysis. Hypertension, treated as a dichotomous variable (yes/no), was defined as a systolic or diastolic BP 140/90 mm Hg or a self-reported history of hypertension and current use of antihypertensive medications. In secondary analyses, systolic BP, diastolic BP, and pulse pressure were modeled as continuous variables. In addition, categories of BP defined by Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines ( 120/ 80 mm Hg, 120 to 139/80 to 89 mm Hg, 140/90 mm Hg) (15) were also used when analyzing the relationship between BP and CRP. The CRP as a continuous variable was log-transformed to more closely reflect a normal distribution for the statistical analysis. The geometric mean of CRP and its geometric mean standard error were used for tabular and graphical presentation. The standard error of CRP values was estimated for the backtransformed data using a delta method approximation. Differences in baseline characteristics by hypertension status were determined by chi-square and t tests. Linear regression modeling was used to determine the relationship between the outcome variable, CRP, and hypertension (HTN) in univariable and multivariable models and after stratifying by gender and ethnicity. The multivariable analysis included the following covariates: age, ethnicity, gender, clinic site, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, smoking, alcohol consumption, use of HMG-CoA reductase inhibitors, estrogen therapy, and aspirin. Similar linear models were used to determine the relationship between CRP and systolic BP, diastolic BP, or categories of BP by JNC 7 criteria after adjustment for the same covariates. For these models, participants on BP medications were excluded. The interaction terms, gender HTN and ethnicity HTN were tested separately in the full model. Logistic regression modeling was used to determine the relative odds of hypertension by category of CRP ( 1 mg/l, 1 to 3 mg/l, 3 mg/l) after stratifying by ethnicity in both an unadjusted and an adjusted analysis. The Zhang-Yu method was used to estimate the relative risk of hypertension from the calculated odds ratio given the outcome, hypertension, was common (16). Statistical analyses were performed using SAS 9.0 software (SAS Institute Inc., Cary, North Carolina). RESULTS The cohort consisted of 6,814 individuals with an average age of 63 years. Table 1 shows differences in baseline characteristics stratified by the presence of hypertension. Participants with hypertension were different from normotensive individuals in every category listed in Table 1 except for levels of high-density lipoprotein cholesterol. Adjustments in the statistical models were made to account for these differences. The geometric mean of CRP in hypertensive individuals was mg/l, compared with mg/l among normotensive individuals (p ). After adjustment for potential confounders, this difference remained statistically significant ( mg/l vs mg/l, p ). In 4,225 participants not taking BP medications, systolic BP and pulse pressure, but not diastolic pressure, were associated with CRP in univariable (p , , and 0.5, respectively) and multivariable models (p 0.003, 0.002, and 0.2, respectively). When treating CRP as a categorical variable, mean systolic BP was 2 mm Hg higher in those with CRP values 3 mg/l compared with 1 mg/l ( mm Hg vs mm Hg, p ) after multivariable adjustment. When resting BP was categorized by JNC 7 criteria, individuals with BPs of

3 JACC Vol. 46, No. 10, 2005 November 15, 2005: Lakoski et al. BP and CRP in MESA 1871 Table 1. Baseline Characteristics of MESA Cohort With and Without Hypertension Hypertension (n 3,093) No Hypertension (n 3,721) p Value Gender Male (%) Female (%) Race Caucasian (%) Asian (of Chinese descent) (%) African American (%) Hispanic (%) Age (yrs, mean SD) Body mass index (mean SD) Alcohol use (%) Never Former Current Cigarette smoking (%) Never Former Current Diabetes, ADA fasting criteria (%) No Impaired Yes Medications HMG-CoA reductase inhibitors (%) Estrogens (%) Aspirin (%) LDL cholesterol (mg/dl), mean SD HDL cholesterol (mg/dl), mean SD ADA American Diabetes Association; HDL high-density lipoprotein; LDL low-density lipoprotein; MESA Multi-Ethnic Study of Atherosclerosis; SD standard deviation. 120/80 mm Hg or between 120 to 139/80 to 89 mm Hg had significantly lower values than those with a BP of 140/90 mm Hg (Fig. 1). When testing for an association between CRP and systolic or diastolic BP, pulse pressure, or JNC 7 BP category, including participants on BP medications produced similar results. Women had higher CRP levels than men in both hypertensive categories (Fig. 2). The relative difference in CRP levels in hypertensive participants compared with normotensive participants was similar regardless of gender (13% in men and 13% in women). Gender did not modify the relationship between hypertension status and CRP levels (p 0.81). Chinese participants had the lowest CRP concentration, but the largest difference in CRP by hypertension status ( mg/l vs mg/l, p 0.002) in fully Figure 1. Adjusted levels of C-reactive protein (CRP) by blood pressure category. Adjusted for age, gender, site, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, smoking, alcohol consumption, physical activity, HMG-CoA reductase inhibitors, estrogen therapy, and aspirin. Figure 2. Adjusted differences in C-reactive protein (CRP) levels by hypertension category in women and men. Adjusted for age, site, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, smoking, alcohol consumption, physical activity, HMG- CoA reductase inhibitors, estrogen therapy, and aspirin. Open bars normal; solid bars hypertension.

4 1872 Lakoski et al. JACC Vol. 46, No. 10, 2005 BP and CRP in MESA November 15, 2005: Table 2. Unadjusted and Adjusted Mean C-Reactive Protein Levels by Ethnic Group in Participants With and Without Hypertension Ethnic Group n Normal Unadjusted Hypertension p Value Normal Adjusted* Hypertension Caucasian 2, (.09) 2.18 (.14) 2.13 (.16) 2.44 (.18) Chinese (.08) 1.20 (.14) 1.54 (.21) 1.91 (.25) African American 1, (.17) 2.76 (.17) 2.45 (.23) 2.78 (.21) 0.01 Hispanic 1, (.15) 2.57 (.19) (.22) 2.78 (.23) 0.88 p Value *Adjusted for age, gender, site, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, smoking, alcohol consumption, HMG-CoA reductase inhibitors, estrogen therapy, and aspirin. adjusted models (Table 2). Other ethnic groups had differences in CRP between 10% and 15% by hypertension status, except Hispanics, who had the highest CRP concentrations but no significant difference in CRP by hypertension. Similar results were found when determining the risk of hypertension by CRP category among different ethnic groups. Table 3 shows the relative odds of hypertension by category of CRP with the largest risk of hypertension among Chinese with CRP 3 mg/l. Estimating the relative risk from the calculated odds ratios did not change the interpretation of these results. These apparent ethnic differences in the relationship between CRP and hypertension status were of borderline statistical significance when tested for a formal interaction (p 0.09). Figure 3 depicts the adjusted mean CRP values by BP category ( 120/ 80 mm Hg, 120 to 139/80 to 89 mm Hg, 140/90 mm Hg), showing no statistical differences in any one ethnic group. When individuals on BP medications were not excluded, a statistical difference in CRP by BP category was evident in Chinese participants (p 0.02). DISCUSSION In the present study, hypertension was associated with higher CRP levels in both men and women. Systolic BP and pulse pressure, but not diastolic BP, were associated with CRP. The strength of the association varied across ethnic groups, with the strongest association observed in Chinese participants and no difference in CRP levels by hypertension status in Hispanic participants. Previous studies have reported an association between BP and CRP. Blake et al. (5) showed an independent association between CRP and BP in the Women s Health Study cohort. Increasing categories of BP were significant predictors of CRP after adjustment for potential confounders. Subsequent studies have confirmed an association between CRP and hypertension (6 8) except in a Spanish (17) and a Colombian population (18). In a study by Bautista et al., (18) CRP did not increase risk of prevalent hypertension among Colombians when comparing those in the highest quartile of CRP ( 5.2 mg/l) with those in the lowest quartile of CRP ( 1.3 mg/l) (p 0.2). Ethnic differences in the relationship between CRP and hypertension were evident in the current study. Of particular interest was the large relative difference in CRP by hypertension status in the Chinese participants, which was not apparent in the Hispanic population. There are three possible explanations for these ethnic differences. First, Hispanics may be exposed to some environmental, nutritional, or intrinsic factor that competes with hypertension as a cause for elevated CRP, therefore masking an association between CRP and hypertension in the Hispanic population. Alternatively, a relationship between inflammation and hypertension may not be present in Hispanics, as seen in two previous studies (17,18), suggesting that an inflammatory mechanism related to hypertension varies by ethnicity. Lastly, the relationship seen between CRP and hypertension in the Caucasian, Chinese, or African-American populations may be spurious because of residual confounding of unmeasured variables related to ethnic-related differences in Table 3. Relative Odds of Hypertension by Category of C-Reactive Protein Ethnic Group CRP >3 vs. 1 3 mg/l Unadjusted p Value CRP >3 vs. <1 mg/l Unadjusted p Value Caucasian 1.52 ( ) 1.97 ( ) Chinese 2.05 ( ) 2.12 ( ) African-American 1.15 ( ) ( ) Hispanic 1.20 ( ) ( ) Adjusted* p Value Adjusted p Value Caucasian 1.10 ( ) ( ) 0.05 Chinese 1.70 ( ) ( ) 0.02 African-American 1.02 ( ) ( ) 0.01 Hispanic 1.09 ( ) ( ) 0.27 *Adjusted for age, gender, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, physical activity smoking, alcohol consumption, use of HMG-CoA reductase inhibitors, estrogen therapy, and aspirin. CRP C-reactive protein.

5 JACC Vol. 46, No. 10, 2005 November 15, 2005: Lakoski et al. BP and CRP in MESA 1873 diet, air pollution, family crowding, and so on. Future MESA studies may be able to clarify these questions. There are a number of plausible mechanisms that could explain an association between CRP and hypertension. Wang et al. (19) showed that CRP independently up-regulates angiotensin II type 1 receptors in smooth muscle cells. CRP, acting through the angiotensin II type 1 receptors, could theoretically result in subsequent elevation in BP. Conversely, in vitro studies indicate that hypertension can stimulate the release of inflammatory cytokines secondary to biomechanical activation (20), up-regulation of monocyte chemoattractant protein-1 (20), and generation of reactive oxygen species (21). Thus, the causal direction in the relationship between inflammation and hypertension is unclear and could even be bidirectional. Whether these mechanisms differ by ethnicity is unknown. There are several limitations to the current study. This is a cross-sectional study, thus the temporal relationship between elevations in CRP and development of hypertension cannot be inferred. Secondly, unmeasured variables related to either BP and/or CRP may confound an association between inflammation and hypertension. Finally, isolated resting BPs may be an incomplete reflection of an individual s daily BP exposure. In summary, we report a significant association between CRP levels and hypertension. This was evident when systolic BP or pulse pressure, but not diastolic BP, was the independent variable of interest. The higher CRP levels by hypertension status were present in both men and women. Some ethnic group differences were observed, with a greater association among Chinese participants and no difference in CRP values by hypertension status in Hispanic participants. Although studies have shown that CRP levels vary by ethnicity and hypertension prevalence differs by ethnic group, no previous studies have examined whether the relationship between inflammation and hypertension was preserved across multiple ethnic groups. Thus, the current study presents new data concerning the association between inflammation and hypertension in a multi-ethnic cohort, and provides a stimulus to understand whether a causal relationship between CRP and hypertension is truly present and preserved across ethnic groups. Understanding the cause for the association between CRP and hypertension, as well as the explanation for ethnic variation in this relationship, may provide new insight into the pathogenesis of hypertension and the role of inflammation in vascular disease. Figure 3. Adjusted C-reactive protein (CRP) levels by blood pressure category stratified by ethnicity. Adjusted for age, gender, body mass index, low-density lipoprotein and high-density lipoprotein cholesterol, diabetes, smoking, physical activity, alcohol consumption, HMG-CoA reductase inhibitors, estrogen therapy, and aspirin. Diamonds Caucasian; squares Chinese; triangles Hispanic; circles African American. Reprint requests and correspondence: Dr. Susan G. Lakoski, Division of Internal Medicine/Cardiology, Medical Center Boulevard, Winston-Salem, North Carolina slakoski@ wfubmc.edu. REFERENCES 1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364: Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis In Myocardial Infarction. 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