Introduction

Hypertension is a serious public health problem in the world because of its high prevalence and consequently increased risk of cardiovascular disease. As the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)1 defined prehypertension as a systolic blood pressure (SBP) of 120–139 mm Hg and/or a diastolic blood pressure (DBP) of 80–89 mm Hg, some researchers focused interest on the relationship between prehypertension and cardiovascular disease. Although prehypertension has not currently been categorized as a disease, some evidence have documented that people with prehypertension have more cardiovascular risk factors,2 increased risks of hypertension3 and cardiovascular events compared with those with normal BP.4, 5, 6

Inflammation and endothelial dysfunction are novel risk factors for atherosclerosis and clinical cardiovascular disease.7 Several previous studies have showed that an elevated level of C-reactive protein (CRP) is associated with increased risk of hypertension.8, 9, 10 Several studies reported that CRP, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) were related to prehypertension.11, 12, 13, 14 However, most of these studies were conducted in Western populations. The association of inflammation and endothelial dysfunction with prehypertension has been poorly studied in Asian populations.

In the present study, we examine the association between plasma levels of CRP, sICAM-1, sE-selectin and angiotensin II and the risk of prehypertension in a Mongolian population from China.

Methods

Study participants

We conducted a cross-sectional study between 2002 and 2003 in Inner Mongolia, an autonomous region in north China that borders Mongolia and Russia. The detailed methods for the study participant selection and data collection are presented elsewhere.15 Briefly, the study participants aged 20 years and older were recruited from 32 villages in 2 adjacent townships located in Kezuohou Banner (county) and Naiman Banner in Inner Mongolia. The majority of local residents were Mongolians who had lived there for many generations and maintained a traditional diet and lifestyle. The study population consisted of both farmers and herdsmen whose diets were high in fat and salt. There were a total of 3475 Mongolian people aged 20 and older living in these villages; among them, 2589 persons participated in the study.

This study was approved by the Soochow University Radiation Medicine and Public Health School institutional review board. Written informed consent was obtained from all study participants.

Data collection

Data on demographic information, lifestyle risk factors, family history of hypertension and personal medical history were obtained using a standard questionnaire administered by trained staff. Cigarette smoking was defined as having smoked at least one cigarette per day for 1 year or more. The information regarding amount and type of alcohol consumed during the past years was collected, and alcohol drinking was defined as consuming at least 50 g distillate spirits (∼50% alcohol concentrate, namely, 25 g alcohol) per day for 1 year or more.

Three sitting BP measurements were taken by trained observers using a standard mercury sphygmomanometer according to a standard protocol, after the subjects had been resting for 30 min, and there were 30 s intervals between two BP measurements. The first and fifth Korotkoff sounds were recorded as SBP and DBP, respectively. The mean of the three BP measurements was used in the analysis. Hypertension was defined as SBP ⩾140 mm Hg and/or DBP ⩾90 mm Hg and/or use of antihypertensive medication in recent 2 weeks. Participants who had mean SBP/or DBP within the range of 120–139/80–89 mm Hg and have never been told that they have hypertension were defined as prehypertensives.1 Body height and weight, waist circumference and hip circumference were measured by trained staff using a balance beam scale after subjects removed their shoes and were wearing light clothing. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Waist circumference and hip circumference were measured at the level of 1 cm above the umbilicus. Waist circumference and hip circumference ratio (WHR) was calculated as the ratio of waist circumference to hip circumference. For this analysis, high BMI was defined as ⩾24 kg m−2 and high WHR was defined as ⩾0.9 based on the recommendations of the Working Group on Obesity in China.16

Blood samples were collected in the morning after at least 8 h of fasting. All plasma and serum samples were frozen at −80 °C until laboratory testing. Fasting plasma glucose (FPG) was measured using a modified hexokinase enzymatic method; hyperglycemia was defined as FPG⩾6.1 mmol l−1.17 Concentrations of total cholesterol (TC), high-density lipoprotein–cholesterol and triglycerides (TGs) were assessed enzymatically on a Beckman Synchrony CX5 Delta Clinical System (Beckman Coulter, Fullerton, CA, USA) using commercial reagents, and low-density lipoprotein–cholesterol (LDL–C) concentration was calculated by means of the Friedewald equation for participants who had less than 400 mg per 100 ml TGs.18 Dyslipidemia was defined as TC⩾5.72 mmol l−1 and/or TG ⩾1.69 mmol l−1 and/or LDL–C ⩾3.64 mmol l−1 and/or high-density lipoprotein–cholesterol <0.91 mmol l−1.19 CRP was determined by an immunoturbidimetric assay on a Beckman Synchron CX5 Delta Clinical System using commercial reagents. sE-selectin and sICAM-1 were measured by an enzyme-linked immunosorbent assay assay (R & D Systems, Minneapolis, MN, USA) that employs the quantitative sandwich enzyme immunoassay technique. Angiotensin II concentration was measured by radioimmunoassay after separation by high-performance liquid chromatography.

Statistical analysis

The unadjusted means and s.d.s of continuous variables and prevalence of categorical variables were calculated for hypertensive, prehypertensive and normotensive individuals, respectively. For the biomarkers, the mean and s.d. of sICAM-1 were calculated for the three groups because of normal distribution; comparison between the three groups was conducted by using analysis of variance models. Medians and interquartile ranges of CRP, sE-selectin and angiotensin II were calculated for the three groups because of non-normal distribution; comparison between the three groups was conducted by using Wilcoxon rank-sum test.

To assess whether inflammation or endothelial dysfunction was associated with prehypertension and hypertension, logistic regression was used to calculate the odds ratio (OR) for prehypertension and hypertension associated with elevated plasma concentrations of each biomarker, respectively. The dependent variable (prehypertension or hypertension) and independent variables were binary, and elevated plasma concentrations of biomarkers were defined as a measurement in the upper quartile of the values for this study population. The first logistic regression model included only biomarker; age and gender were added in the second model. In the third model, BMI, WHR, FPG, smoking, alcohol drinking, LDL–C, TC, TG and family history of hypertension were also included in the analysis. All P-values were two tailed, and a significance level of 0.05 was used. Statistical analysis was conducted using SAS statistical software (version 9.1; SAS Institute Inc, Cary, NC, USA).

Results

Baseline characteristics of Mongolians according to BP status

A total of 2589 participants aged 20–84 years, including 1064 men and 1525 women, were included in the analysis. There were 968 (37.39%) hypertensives, 994 (38.39%) prehypertensives and 627 (24.22%) normotensives among the participants. Baseline characteristics of study participants according to BP status are shown in Table 1. The results showed that the hypertensives tended to have older age and greater BMI, WHR, FPG, TG, TC and LDL–C levels, and higher rates of male, family history of hypertension, cigarette smoking, alcohol drinking compared with prehypertensives and normotensives (P<0.05). Prehypertensives likely had older age and greater BMI, WHR, FPG, TG, TC and LDL–C levels, and higher rates of male, family history of hypertension, alcohol drinking compared with normotensives (P<0.05). There were no statistical differences for high-density lipoprotein–cholesterol concentrations among the three groups (P>0.05).

Table 1 Baseline characteristics of 2589 Mongolians according to BP status in Mongolia, China

Inflammatory and endothelial biomarkers according to BP status

The median (interquartile range) for CRP, sE-selectin and angiotensin II, and the mean (s.d.) of sICAM-1 are shown in Table 2. Levels of CRP, sE-selectin, angiotensin II and sICAM-1 were higher in hypertensives than those in prehypertensives or normotensives, respectively (P<0.05). The prehypertensives also have higher CRP and sICAM-1 levels compared with normotensives (P<0.05). There was no statistical difference for sE-selectin and angiotensin II levels between prehypertensives and normotensives (P>0.05).

Table 2 Mean (s.d.) or median (IQR) of inflammatory and endothelial biomarkers according to BP status

ORs of prehypertension and hypertension associated with biomarkers of inflammation and endothelial dysfunction

The ORs of prehypertensives and hypertensives associated with elevated biomarkers of inflammation and endothelial dysfunction are presented in Table 3. Compared with normotensives, elevated CRP (all P<0.05 in three models) and angiotensin II (all P<0.05 in three models) were associated with increased risk of hypertension, and elevated sICAM-1 was associated with increased risk of hypertension under unadjusted for other factors or after adjusted for age and gender (both P<0.05 in models 1 and 2). Inversely, hypertension was not significantly associated with increased risk of elevated sE-selectin (P>0.05 for three models).

Table 3 ORs and 95% CIs of prehypertension and hypertension associated with biomarkers of inflammation and endothelial dysfunction

Similarly, compared with normotensives, elevated CRP (all P<0.05 in three models) was associated with increased risk of prehypertension, and elevated sICAM-1 was associated with increased risk of prehypertension under unadjusted for other factors or after adjusted for age and gender (both P<0.05 in models 1 and 2). Inversely, prehypertension was not significantly associated with increased risk of elevated sE-selectin or angiotensin II (P>0.05 for three models). ORs of prehypertension were weaker than those of hypertension.

Discussion

In this cross-sectional study among a Mongolian population, we found that plasma levels of CRP and sICAM-1 were positively and significantly associated with hypertension and prehypertension. Individuals with higher levels of CRP and sICAM-1 probably were at an increased risk of hypertension and prehypertension compared with those with normal levels of CRP and sICAM-1. These data provide further support that inflammation and endothelial dysfunction may have a role in the development from prehypertension to hypertension.

Several prospective cohort studies have indicated that CRP levels were predictive of the risk of myocardial infarction, ischemic stroke and vascular death.20 There was also evidence to suggest that CRP may have a direct role as a mediator in atherogenesis by inducing intracellular adhesion molecule expression.7, 21 Our previous study and other studies showed that CRP may be an independent risk factor for hypertension.8, 9, 10 Sesso et al.22 reported that elevated CRP was associated with an increased risk of incidence of hypertension in a cohort study that included people with baseline BP in the prehypertension range. Possible mechanisms for this association include oxidative stress23 and interactions with adhesion molecules, plasminogen activator inhibitor-1 and LDL–C uptake.21, 24, 25

Data of NHANES III11 showed that prehypertensives had a higher prevalence of elevated CRP (>3.0 mg l−1) than normotensives (27.4 vs. 19.8%). After adjustment for multivariable, participants with SBP of 120–139 mm Hg or DBP of 80–89 mm Hg were more likely to have elevated CRP than those with SBP <120 mm Hg or DBP <80 mm Hg. Their findings were consistent to ours, in which elevated CRP associated with increased risk of hypertension (OR: 1.50, 95% confidence interval (CI): 1.07, 2.11) and prehypertension (OR: 1.38, 95% CI: 1.02, 1.85), respectively, adjusted for multivariable.

Chrysohoou’s study12 revealed an association between prehypertension and inflammatory markers (CRP, WBC counts, tumor necrosis factor-α, amyloid-a and homocysteine) among cardiovascular disease-free adults, independent of other coexisting risk factors or unhealthy lifestyle behavior, suggesting that prehypertension might be a proinflammatory condition. In this work, inflammation seems to have a critical role in the development of hypertension, as these prehypertensives with increased CRP seem to be more vulnerable in developing hypertension during the 5 years of follow-up.

In our relatively large population-based study, plasma levels of sICAM-1, but not sE-selectin and angiotensin II, were significantly higher in prehypertensives than that in normotensives. In addition, we only found the rude OR and age- and gender-adjusted OR of prehypertension for higher sICAM-1 were statistically significant. Our findings were similar to DeSouza's findings, in which 11 hypertensive subjects had higher plasma levels of sICAM-1 and soluble vascular cell adhesion molecule-1 but not sE-selectin compared with 10 normotensive controls,26 and univariate analysis revealed a positive correlation between sICAM-1 and both SBP (r=0.50, P=0.02) and DBP (r=0.49, P=0.03). Hlubocka reported that 22 hypertensive patients had significantly higher levels of sICAM-1 but not soluble vascular cell adhesion molecule-1, sE-selectin and soluble P-selectin compared with 22 normotensive subjects.27

In an observational study in Taiwan,13 there were 20 prehypertensives and 41 hypertensives without other risk factors (for example, diabetes mellitus, dyslipidemia and obesity) and 17 normotensive controls. Hypertensive patients had significantly higher circulating levels of sICAM-1 compared with normotensive controls (P=0.009). The mean sICAM-1 level was significantly higher in the prehypertensives than that in the normotensive controls (P=0.03). No significant differences in levels of soluble vascular cell adhesion molecule-1 and sE-selectin were found between the two groups. In a community-based study including 664 men and women living in England, Miller et al. reported that plasma level of sE-selectin was significantly associated with elevated BP in women but not in men.14 Additionally, sICAM-1 was not significantly associated with elevated BP in either women or men. The relationship between biomarkers of inflammation and endothelial dysfunction and elevated BP varies with gender, age and abdominal obesity,3, 14 which may partially explain previous inconsistencies in the literature. In our analysis, we adjusted for these confoundings to estimate the ORs of hypertension or prehypertension for the biomarkers. Under adjusted for only age and gender, sICAM-1 was significantly associated with both hypertension and prehypertension; the OR of both hypertension or prehypertension for sICAM-1 tended to be statistically significant because those low limits of 95% CI for OR were near to 1, although the ORs did not reach level of significance after adjusting for multivariate. Whether adjusted for only age and gender or multivariate, the ORs of both hypertension and prehypertension for CRP were statistically significant. Therefore, we believe that there is probably a certain extent of inflammation and endothelial dysfunction in the phase of prehypertension; inflammation and endothelial dysfunction may promote prehypertension progressing to hypertension.

Besides its role as a vasoconstrictor, angiotensin II also induces endothelial dysfunction and inflammation, resulting in accelerated progression of atherosclerosis.28, 29 Angiotensin II may have a direct role in inducing hypertension by increasing oxidative stress and inflammation.30, 31 In our study, an increased angiotensin II level was found among individuals with hypertension but not prehypertension.

The present study found that concentrations of all the four biomarkers of inflammation and endothelial dysfunction in hypertensives were significantly higher than that in prehypertensives, and that CRP and sICAM-1 of the four biomarkers of inflammation and endothelial dysfunction in prehypertensives were significantly higher than that in normotensives; the ORs of hypertension associated with the biomarkers were significantly greater than the ORs of prehypertension associated with the biomarkers. These findings indicated that the progression to hypertension from prehypertension could be the results of gradual accumulation of inflammatory reaction and endothelial dysfunction, and accumulation of some traditional cardiovascular risk factors. In previous paper,15 we have reported that prevalence of some traditional cardiovascular risk factors and number of the risk factors in prehypertensives are similar to that in hypertensives, but weaker than hypertensives, which imply that prehypertension had the same risk factors as hypertension and some cardiovascular risk factors have existed in the stage of prehypertension.

Several limitations of this study should be mentioned. First, this was a cross-sectional study, therefore a causal relationship between inflammatory and endothelial biomarkers and the risk of hypertension could not be established. Secondly, ∼25% of the eligible population from these villages did not choose to participate, which may have introduced some selection bias. However, we believe this bias is minimal because it is unlikely that participants did not choose to participate because of their BP or biomarkers levels that they did not know. Furthermore, several important biomarkers of inflammation and endothelial dysfunction were not measured in our study. There were several important strengths of our study that deserve to be mention too. This is the largest study to examine the association between the biomarkers of inflammation and endothelial dysfunction and hypertension or prehypertension in an Asian population. The study participants were homogeneous regarding their genetic background and environmental exposures. The study data were collected with rigid quality control, and important covariables were measured and controlled in analysis.

In conclusion, our study indicated that higher plasma levels of CRP and slCAM-1 were associated with not only hypertension but also prehypertension. These data support the hypotheses that inflammation and endothelial dysfunction might have an important role in the etiology of hypertension. Future prospective cohort studies and clinical trials should be conducted to test the causal relationship between inflammation and endothelial dysfunction and the risk of hypertension.