Gender-specific association between pulse pressure and C-reactive protein in a Chinese population

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1 (2005) 19, & 2005 Nature Publishing Group All rights reserved /05 $ ORIGINAL ARTICLE Gender-specific association between pulse pressure and C-reactive protein in a Chinese population XLi 1, H Zhang 1, J Huang 1, S Xie 2, J Zhu 2, S Jiang 1,YLi 3 and J-G Wang 3 1 Section of Hypertension and Cardiovascular Epidemiology, Department of Cardiology, Jiangsu Provincial Hospital, Nanjing Medical University, Nanjing, China; 2 Taicang 2nd Hospital, Taicang, Jiangsu Province, China; 3 Center for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Second Medical University, Shanghai, China There is growing evidence that low-grade chronic inflammation, as reflected by the raised serum concentration of C-reactive protein, might be a risk factor for hypertension, in particular in women. We therefore investigated gender-specific associations of systolic and diastolic blood pressure and pulse pressure with serum C-reactive protein concentration in a Chinese population sample. In 463 participants, we measured serum C-reactive protein concentration using a highsensitivity immunonephelometric latex-enhanced assay. We performed single and multiple linear regression analyses. The 224 male and 239 female subjects were of similar age (51.0 years) and had similar levels of systolic blood pressure (124.7 mmhg) and pulse pressure (47.1 mmhg), but men, compared with women, had higher diastolic blood pressure (79.6 vs 75.8 mmhg; Po0.0001) and body mass index (24.3 vs 23.4 kg/m 2 ; P ¼ 0.003). Both before and after adjustment for age, age 2, body mass index, current smoking, alcohol intake, and use of antihypertensive drugs, pulse pressure was significantly associated with serum C-reactive protein concentration in women (Pp0.002) but not in men (P40.10; P ¼ 0.02 for interaction between gender and serum C-reactive protein). In women, with one-fold increase in serum C-reactive protein concentration, pulse pressure was 1.94 mmhg higher. The categorical analyses confirmed our findings. With similar adjustments applied, women in the fourth quartile, compared with those in the lowest quartile, had a 7.6 mmhg higher pulse pressure (95% confidence interval mmhg; P ¼ ). Furthermore, when women were analysed according to menopausal status, the association between pulse pressure and C-reactive protein was only significant in postmenopausal (Pp0.04), but not in premenopausal, subjects (PX0.21). In conclusion, taken together with the previous gender-specific observations on carotid lesions and hypertension, our finding suggests that chronic low-grade inflammation might play a role in the widening of pulse pressure in Chinese women. This cross-sectional observation warrants further investigation in prospective studies. (2005) 19, doi: /sj.jhh Published online 27 January 2005 Keywords: blood pressure; pulse pressure; C-reactive protein; Chinese; gender; menopause Introduction Hypertension is one of the most powerful risk factors for stroke and coronary heart disease. 1 In older persons, pulse pressure is a better cardiovascular risk predictor than systolic or diastolic blood pressure. 2 7 Systolic pressure increases with age until the eighth or ninth decade of life, whereas Correspondence: Dr J-G Wang, Center for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Institute of Hypertension, Ruijin 2nd Road 197, Shanghai , China. jiguangwang@netscape.net or Dr X Li, Department of Cardiology, Jiangsu Provincial Hospital, Guangzhou Road 300, Nanjing , China. Received 14 August 2004; revised 19 November 2004; accepted 21 November 2004; published online 27 January 2005 diastolic pressure rises only until middle age and then either levels off or slightly decreases, explaining why pulse pressure and the prevalence of isolated systolic hypertension increase with aging. 8,9 In the elderly, the widening of pulse pressure is mainly due to increased arterial stiffness. 10 However, the predisposing or precipitating factors of this process remain under investigation. There is growing evidence that low-grade chronic inflammation, as reflected by increased serum C-reactive protein concentration, is a predictor of atherosclerotic disorders, 11 and might also be a risk factor for human hypertension. 12 Indeed, several recent studies have demonstrated significant and independent positive associations of blood pressure and pulse pressure with serum C-reactive protein

2 294 Pulse pressure and C-reactive protein concentration A prospective study in women found that the incidence of hypertension was associated with increased serum C-reactive protein. 18 Furthermore, in the Framingham heart study, carotid intima-media thickness, which is closely related to systolic blood pressure and pulse pressure, 19 is associated with serum C-reactive protein concentration only in women, but not in men. 20 We therefore investigated gender-specific associations of systolic and diastolic blood pressure, and pulse pressure with the serum concentration of highsensitivity C-reactive protein in a Chinese population sample. Laboratory methods Venous blood was sampled after overnight fast. All biochemical measurements were performed in the central laboratory of the Jiangsu Provincial Hospital, Nanjing Medical University Hospital (Nanjing, China). C-reactive protein was measured using a high-sensitivity immunonephelometric latexenhanced assay on a BN II analyser (BNA, Dade Bering). Serum creatinine and uric acid were measured using Jaffé s method and the uricase method, 21 respectively (Chemistry Analyser AU2700, Olympus Medical Engineering Company, Tokyo, Japan). Methods Study population We performed the present study in Taicang, a city 50 km west of Shanghai, China. The Taicang study was conducted according to the principles outlined in the Helsinki declaration for investigation of human subjects. The Institutional Review Board of the Jiangsu Provincial Hospital, Nanjing Medical University approved the study protocol. All subjects gave written informed consent. We recruited nuclear families via specialized hypertension clinics using hypertensive family members as index persons. Nuclear families had to consist of either one parent and at least two offspring, or two parents and one or more siblings. The minimum age for participation was 18 years. In 2003, 493 subjects were enrolled. The participation rate among the subjects contacted was 93.5%. In all, 29 subjects had incomplete anthropometrical (n ¼ 10), blood pressure (n ¼ 1), or biochemical (n ¼ 18) measurements. In addition, we excluded one subject with laboratory signs of rheumatic activity. Thus, the number of subjects included in the present analysis totalled to 463. Field work All subjects were first invited for technical examinations in the outpatient clinic and then visited in their homes 1 2 weeks later. On each of these two occasions, blood pressure was measured five times consecutively after 5 min rest in the sitting position by sphygmomanometry. For the present analysis, we averaged these 10 blood pressure readings. Hypertension was diagnosed if the average of the 10 blood pressure readings was at least 140 mmhg systolic or 90 mmhg diastolic, or if the subjects were on antihypertensive medication. We used a questionnaire to collect information on medical history (including stroke, coronary heart disease consisting of myocardial infarction and angina pectoris, and other diseases), smoking habits, alcohol intake, and use of medications. Statistical methods We used SAS version 8.1 (SAS Institute, Cary, NC, USA) for database management and statistical analysis. Measurements with a skewed distribution were normalized by logarithmic transformation. Means and proportions were compared with the standard normal z-test and Fisher s exact test, respectively. Correlation coefficients were calculated using Pearson s method. We searched for possible correlates using stepwise multiple regression with the P-value for covariables to enter and stay in the model set at We used analysis of covariance and multiple linear regression to test associations of interest, while controlling for covariables. We adjusted blood pressure components for age and age 2 because the association between blood pressure and age was curvilinear. We performed statistical tests for interaction between gender (0, women; 1, men) or menopausal status (0, premenopausal; 1, postmenopausal) and serum C-reactive protein concentration by including these variables and their crossproduct term in the same model. Results Characteristics of the participants The 224 male and 239 female participants were of similar age (51.0 years; Table 1), and had similar systolic blood pressure (124.7 mmhg) and pulse pressure (47.1 mmhg), but men, compared with women, had significantly higher diastolic blood pressure (79.6 vs 75.8 mmhg; Po0.0001) and body mass index (24.3 vs 23.4 kg/m 2, P ¼ 0.003). The study sample included 191 (41.3%) hypertensive patients of whom 172 took antihypertensive drugs (calcium-channel blockers, n ¼ 103; diuretics, n ¼ 83; angiotensin-converting enzyme inhibitors, n ¼ 56; b-blockers, n ¼ 55; angiotensin II type 1 receptor blockers, n ¼ 2; and various combination tablets with very low doses of hydrochlorothiazide, reserpine, and dihydralazine, n ¼ 21). In all, 15 (3.2%) subjects had symptoms or signs suggestive of coronary heart disease (n ¼ 14) or a history of

3 Pulse pressure and C-reactive protein Table 1 Characteristics of the participants 295 Variables a Men (n ¼ 224) Women (n ¼ 239) P Age (years) Body mass index (kg/m 2 ) Systolic pressure (mmhg) b Diastolic pressure (mmhg) b o Pulse pressure (mmhg) Taking antihypertensive drugs (%) 84 (37.5) 88 (36.8) 0.88 Diabetic patients (%) c 32 (14.3) 20 (8.4) 0.04 Stroke (%) 4 (1.8) 5 (2.1) 0.81 Coronary heart disease (%) d 10 (4.5) 5 (2.1) 0.15 Use of aspirin (%) 2 (0.9) 5 (2.1) 0.29 Current smoking (%) 82 (36.6) 2 (0.8) o Alcohol intake (%) 93 (41.5) 6 (2.5) o Serum total cholesterol (mmol/l) Serum creatinine (mmol/l) o Serum uric acid (mmol/l) o Serum C-reactive protein (mg/dl) e 1.37 ( ) 1.32 ( ) 0.60 a Values are arithmetic means7s.d., geometric means (95% confidence interval), or number of subjects (%). b Mean of 10 blood pressure readings (five at outpatient clinic and five at subjects homes). c Use of antidiabetic agents or a fasting plasma glucose X7.1 mmol/l. 31 d Patients with a history of myocardial infarction or symptoms or signs suggestive of coronary heart disease. e Unadjusted geometric means (95% confidence interval). myocardial infarction (n ¼ 1), and nine (1.9%) had a history of stroke. Seven (1.5%) subjects took aspirin for cardiovascular prevention, and only one (0.2%) subject took statin. A total of 124 (51.9%) women reported natural (n ¼ 122) and surgical (n ¼ 2) menopause. None of the female subjects took oral contraceptives or hormone replacement therapy. In stepwise multiple regression, we considered gender, age, body mass index, waist-to-hip ratio, current smoking, alcohol intake, white blood cell count, serum concentrations of uric acid and total cholesterol, diabetes mellitus, and use of angiotensin-converting enzyme inhibitors, b-blockers, calcium-channel blockers, or diuretics as potential correlates of serum C-reactive protein concentration. Of these variables, gender (r ¼ 0.16, P ¼ 0.001), age (r ¼ 0.12, P ¼ 0.02), waist-to-hip ratio (r ¼ 0.13, P ¼ 0.008), white blood cell count (r ¼ 0.21, Po0.0001), serum uric acid (r ¼ 0.19, P ¼ ), and use of b-blockers (r ¼ 0.12, P ¼ 0.01) entered the model. After adjustment for the other significant correlates, serum C-reactive protein concentration was higher in men than in women (geometric mean 1.73 vs 1.30 mg/dl), and in users of b-blockers than in nonusers (1.72 vs 1.30 mg/dl). In women, after adjustment for age, serum C-reactive protein concentration was higher in postmenopausal than premenopausal subjects (1.60 vs 1.06 mg/dl, P ¼ 0.02). Association between blood pressure components and serum C-reactive protein In single regression, pulse pressure in women and systolic blood pressure in both sexes were significantly (Pp0.01) associated with serum C-reactive protein concentration (Table 2). The associations were significantly more pronounced in women than in men for systolic blood pressure (P ¼ 0.05) as well as pulse pressure (P ¼ 0.004; Figure 1). After adjustment for age, age 2, body mass index, and use of antihypertensive drugs in both sexes and also for current smoking and alcohol intake in men, these associations were weakened (Table 2). Nonetheless, the association between pulse pressure and serum C-reactive protein concentration in women remained statistically significant (P ¼ 0.002). The interaction between gender and serum C-reactive protein concentration in relation to pulse pressure also reached statistical significance (P ¼ 0.02). In women, with one-fold increase in serum C-reactive protein concentration, pulse pressure was 1.94 mmhg higher. In further analyses, we stratified men and women separately by quartiles of serum C-reactive protein concentration. With similar adjustments applied, women in the fourth quartile, compared with those in the lowest quartile, had significantly higher levels of systolic blood pressure ( þ 5.67 mmhg, 95% confidence interval mmhg; P ¼ 0.03) and pulse pressure ( þ 7.62 mmhg, 95% confidence interval mmhg; P ¼ ). We did not find any significant between-quartile differences in men (P40.12; Table 3 and Figure 2). Furthermore, these categorical analyses demonstrated a significant interaction between gender and serum C-reactive protein concentration in relation to pulse pressure (P ¼ 0.005; Figure 2), but not systolic pressure (P ¼ 0.06). We did not observe any significant interaction between menopausal status and C-reactive protein in relation to pulse pressure in either continuous or categorical analyses (PX0.21). Nonetheless, we

4 Pulse pressure and C-reactive protein 296 Table 2 Associations of systolic and diastolic blood pressure and pulse pressure with one-fold increase in serum C-reactive protein concentration by gender Unadjusted analyses Adjusted analyses a r Regression coefficient7s.e. P Partial r Regression coefficient7s.e. P Men (n ¼ 224) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Pulse pressure (mmhg) Women (n ¼ 239) Systolic blood pressure (mmhg) o Diastolic blood pressure (mmhg) Pulse pressure (mmhg) o a The analyses were adjusted for age, age 2, body mass index, and use of antihypertensive drugs in both sexes and also for current smoking and alcohol intake in men. values were 0.84 (0.66) and 1.95 ( 2.65 to 6.55) mmhg, respectively. We performed sensitivity analyses in 200 male and 208 female participants who did not take b-blockers. With similar adjustments applied, these analyses confirmed our gender-specific observations in all subjects. Cardiovascular risk of increased serum C-reactive protein concentration Figure 1 Unadjusted association between pulse pressure and serum C-reactive protein concentration in men (closed symbols with solid regression line; r ¼ 0.11; P ¼ 0.10) and women (open symbols with dashed regression line; r ¼ 0.34; Po0.0001) separately. P ¼ for interaction between gender and serum C-reactive protein concentration. analysed postmenopausal and premenopausal women separately, because of the menopause-based significant difference in serum C-reactive protein concentration. With similar adjustments applied, the association between pulse pressure and C-reactive protein was only significant in postmenopausal women (Pp0.04) but not in premenopausal subjects (PX0.21). In 124 postmenopausal women, pulse pressure was 2.13 (s.e., 1.00) mmhg higher with one-fold increment in serum C-reactive protein concentration, and 9.89 (95% confidence interval ) mmhg higher in women in quartile 4 as compared with those in quartile 1. In 115 premenopausal women, the corresponding In 61 (13.2%) subjects, serum C-reactive protein concentration was higher than 3.0 mg/dl. These subjects had a higher prevalence of hypertension than those with a serum C-reactive protein concentration below 3.0 mg/dl (54.1 vs 39.3%, P ¼ 0.03). However, after adjustment for gender, age, body mass index, current smoking, and alcohol intake, the prevalence of hypertension was not significantly (PX0.43) associated with serum C-reactive protein concentration in all subjects, nor in men or women separately. The prevalence of cardiovascular complications (n ¼ 24) was similar in subjects with a serum C-reactive protein beyond or below 3.0 mg/dl (PX0.50). Discussion Our new finding was that pulse pressure was associated with serum C-reactive protein concentration in Chinese women, but not in men. The significant association in women was independent of age, body mass index, and use of antihypertensive drugs, and seemed slightly more prominent in postmenopausal subjects, who also had higher serum C-reactive protein concentration than premenopausal women. Several previous studies demonstrated a significant association between pulse pressure and C-reactive protein, but none of these studies reported results in men and women separately

5 Pulse pressure and C-reactive protein Table 3 Systolic and diastolic blood pressure and pulse pressure by gender and quartiles of the serum C-reactive protein concentration 297 Quartiles of serum C-reactive protein a P for trend Men (n ¼ 224) Quartile 1 (n ¼ 56) Quartile 2 (n ¼ 56) Quartile 3 (n ¼ 56) Quartile 4 (n ¼ 56) Serum C-reactive protein (mg/dl) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Pulse pressure (mmhg) Women (n ¼ 239) Quartile 1 (n ¼ 60) Quartile 2 (n ¼ 60) Quartile 3 (n ¼ 60) Quartile 4 (n ¼ 59) Serum C-reactive protein (mg/dl) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Pulse pressure (mmhg) a Values are means7s.e., adjusted for age, age 2, body mass index, and use of antihypertensive drugs in both sexes and also for current smoking and alcohol intake in men. Figure 2 Mean pulse pressure according to quartiles of the serum C-reactive protein concentration in men (closed symbols with solid line) and women (open symbols with dashed line) separately. Values were adjusted for age, age 2, body mass index, and use of antihypertensive drugs in both sexes and also for current smoking and alcohol intake in men. Vertical lines denote s.e. s. P-values for trend and for interaction (P-int) between gender and C-reactive protein are given. For the number of subjects in each quartile, see Table 3. In two studies conducted in healthy American 14 or European 22 men and women, pulse pressure was associated with C-reactive protein, independent of systolic and diastolic pressure 14 or mean blood pressure. 22 However, in stroke survivors 13 or nevertreated hypertensive patients, 15 the positive association between pulse pressure and C-reactive protein was mainly driven by systolic blood pressure. These studies did not specifically explore the association between pulse pressure and C-reactive protein. 16,23 However, several of these studies showed that systolic but not diastolic blood pressure was associated with serum C-reactive protein level, 23 suggesting an association with pulse pressure. Thus, current literature evidence supports an association between pulse pressure and C-reactive protein. Our finding was in line with the prospective analysis of the Framingham heart study on the association between carotid atherosclerosis and serum C-reactive protein concentration. 19 In the offspring cohort of the Framingham heart study, C- reactive protein at baseline significantly predicted carotid stenosis and intima-media thickening at 4 years of follow-up in 1665 women, but not in 1508 men. 19 Carotid stenosis and intima-media thickening are closely correlated with the widening of pulse pressure, 19 which is in fact the consequence of an increased stiffness of the large arteries. 10 In addition, in a large Korean study, the association between the risk of hypertension and a higher serum C-reactive protein concentration was significantly greater in 3534 women than in 4813 men. 16 Considering the similar results of previous population studies on carotid atherosclerosis 19 and hypertension, 16 our gender-specific observation was probably not a chance finding due to the relatively small sample size. Why pulse pressure was associated with C-reactive protein in women but not in men remains to be elucidated. It is known that exogenous female hormones used as oral contraceptives or replacement therapy may increase serum C-reactive protein concentration, 24,25 and activate the renin angiotensin aldosterone system. 26 The activation of the renin angiotensin aldosterone system may lead to an increase in blood pressure. However, none of the female participants in our study used hormonal medication. It is also known that endogenous female hormones exert protective effects on the cardiovascular system. 27 Our insignificant findings in premenopausal women might be due to their low levels of serum C-reactive protein. In contrast, without cardiovascular protection by endogenous female hormones in women after menopause, the increased serum C-reactive protein

6 298 concentration might lead to an increased pulse pressure. Our study was cross-sectional, and hence was unable to establish a causal relationship between pulse pressure and C-reactive protein. Our hypothesis is that chronic low-grade inflammation as a risk factor for atherosclerosis 19 and endothelial dysfunction 12 in women might lead to increased pulse pressure. Inflammation is increasingly recognized as a cardiovascular risk factor. The circulatory markers of inflammation predict cardiovascular disease, such as stroke and coronary heart disease, 28,29 and are associated with several traditional cardiovascular risk factors including hypertension. 30 The recently published population-based prospective study in women showed that C-reactive protein predicted the incidence of hypertension, 18 and provided direct support for a cause effect relationship between blood pressure and C-reactive protein. However, since hypertension is a reversible cardiovascular risk factor, it is also possible that high blood pressure induces inflammation, and increases serum C-reactive protein concentration. 13 Finally, the possibility that high pulse pressure and a raised serum C-reactive protein concentration are just bystanders in high-risk patients cannot be entirely excluded. In conclusion, taken together with the previous gender-specific observations on carotid lesions 19 and hypertension, 16 our finding suggests that chronic low-grade inflammation, as reflected by an increased serum C-reactive protein concentration, might play a role in the widening of pulse pressure in Chinese women. This cross-sectional observation warrants further investigation in prospective studies. Acknowledgements The study was supported by a grant (2002) from Natural Science Foundation of Jiangsu Province (Nanjing, China). We acknowledge the expert assistance of Drs Lirong Liang and Zhenzhen Wang from Nanjing Medical University (Nanjing, China) and Dr Lifang Liu from the Department of Geriatrics, General Hospital of the Air Force (Beijing, China). References Pulse pressure and C-reactive protein 1 Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: Franklin SS et al. Hemodynamic patterns of agerelated changes in blood pressure. The Framingham Heart Study. Circulation 1997; 96: Blacher J et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med 2000; 160: Sesso HD et al. Systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure as predictors of cardiovascular disease risk in men. Hypertension 2000; 36: Benetos A et al. 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7 22 Amar J et al. Relationship between C reactive protein and pulse pressure is not mediated by atherosclerosis or aortic stiffness. J Hypertens 2004; 22: Yamada S et al. Distribution of serum C-reactive protein and its association with atherosclerotic risk factors in a Japanese population: Jichi Medical School Cohort Study. Am J Epidemiol 2001; 153: Dreon DM, Slavin JL, Phinney SD. Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003; 73: Kluft C, Leuven JA, Helmerhorst FM, Krans HM. Proinflammatory effects of oestrogens during use of oral contraceptives and hormone replacement treatment. Vascul Pharmacol 2002; 39: Oelkers W et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995; 80: Pulse pressure and C-reactive protein 27 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: Ford ES. C-reactive protein concentration and cardiovascular disease risk factors in children: findings from the National Health and Nutrition Examination Survey Circulation 2003; 108: Alberti KGMM, Zimmer PZ, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998; 15: