Relation of C-reactive protein and fibrinogen to coronary artery calcium in subjects with systemic hypertension.

C protein (CRP) and fibrinogen, which are markers of inflammation, are associated with increased risk of cardiovascular events,1,2 but their relation to coronary atherosclerotic burden in asymptomatic subjects remains poorly defined. Both CRP and fibrinogen have been described as “conditional” risk factors, implying that the risk conferred may depend on the background risk.3 We hypothesized that in hypertensive subjects without a history of cardiovascular events, CRP and fibrinogen may be associated with coronary artery calcium (CAC), a surrogate of coronary atherosclerotic burden. • • • Subjects included 354 non-Hispanic white hypertensive subjects from Rochester, Minnesota, who participated in the Genetic Network of Arteriopathy (GENOA) study, a community-based study of hypertensive siblings to identify genes influencing blood pressure.4 By November 2001, 512 participants had completed measurement of CAC by electron beam computed tomography (EBCT). We excluded 106 normotensive subjects, 29 subjects with a history of myocardial infarction or stroke, and 23 subjects with missing data. Diabetes was considered present if a subject was being treated with insulin or oral agents, or had a fasting glucose level 126 mg/dl. “Ever” smoking was defined as having smoked 100 cigarettes in the past. Hypertension diagnosis was based on blood pressure at the study visit ( 140/90 mm Hg), a report of prior diagnosis of hypertension, or current treatment with antihypertensive medications. Information about the use of statins, oral estrogen, and aspirin was provided by participants. The 10-year risk of a cardiovascular event was estimated based on the Framingham risk score.5 Blood was drawn after an overnight fast. Serum cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured by standard enzymatic methods. Plasma glucose was measured by the glucose oxidase method. Fibrinogen was measured by the von Clauss (clotting time-based) method6 and CRP by a highly sensitive immunoturbidimetric assay.7 Presence and quantity of CAC were measured with an Imatron C-150 EBCT scanner (Imatron Inc., South San Francisco, California) as previously described.8 CAC score was determined using Agatston et al’s method.9 Ageand gender-specific CAC score percentiles were also estimated as previously described.10 Analyses were performed separately in men and women. Because the distribution of CAC scores was positively skewed and not all subjects had detectable CAC, the scores were log-transformed after adding 1. CRP values were log-transformed to reduce skewness. Log (CAC 1) was determined in quintiles of CRP and fibrinogen, and Spearman’s correlations for log (CAC 1) with log CRP and fibrinogen were computed. Univariate predictors of CAC were identified by simple linear regression. Multiple linear regression was used to investigate the association of log CRP and fibrinogen with quantity of CAC and with CAC score percentile after adjusting for conventional risk factors, body mass index, and use of statins, estrogen, and aspirin. Because of the sibling relations in the sample (187 in all), population-averaged generalized estimating equations11 were used to assess the possible impact of familial correlations on the relation between independent and dependent variables. Because inferences were the same, only the regression analyses are presented. Subject characteristics are listed in Table 1. Mean CRP levels were significantly higher in women, but mean fibrinogen levels did not differ between genders. Most of the subjects had detectable CAC; the quantity of CAC was significantly higher in men. Approximately 1/3 of subjects reported statin use. Half of the women were on estrogen but were less likely than men to be receiving aspirin. CRP and fibrinogen were significantly correlated both in women (r 0.32, p 0.0001) and in men (r 0.49, p 0.0001). CRP levels increased with age and body mass index and were higher in women (vs men, even after exclusion of women on estrogen), in women on estrogen (vs those not on estrogen), and in current smokers; fibrinogen levels also increased with age and body mass index and were higher in women and current smokers, and lower in women on estrogen (data not shown). Factors associated with CAC included age, highFrom the Divisions of Cardiovascular Diseases, Biostatistics, and Hypertension; and Departments of Laboratory Medicine and Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, Minnesota; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan; and Human Genetics Center, University of Texas Health Science Center, Houston, Texas. This study was supported by a Grant-in-Aid to Dr. Kullo from the American Heart Association (Northland Affiliate), and by grants U10-HL54464, HL-46292, HL54457, and the General Clinical Research Center Grant M01 RR00585 from the National Institutes of Health, Bethesda, Maryland. Dr. Kullo’s address is: Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905. E-mail: kullo.iftikhar@mayo.edu. Manuscript received January 22, 2003; revised manuscript received and accepted March 20, 2003.