pISSN 1738-5520 eISSN 1738-5555
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    Korean Circ J. 2007 Dec;37(12):623-629. English.
    Published online Dec 31, 2007.
    https://doi.org/10.4070/kcj.2007.37.12.623
    Copyright © 2007 The Korean Society of Cardiology
    Original Article

    Association between the JNC 7 Classification of the Stages of Systolic Hypertension and Inflammatory Cardiovascular Risk Factors

    Chan Seok Park, MD, Hee-Yeol Kim, MD, Hun-Jun Park, MD, Sung-Won Jang, MD, Sang-Hyun Ihm, MD, Jong-Min Lee, MD, Ki-Dong Yoo, MD, Doo-Soo Jeon, MD, Sang-Hong Baek, MD, Ho-Joong Youn, MD, Ki-Bae Seung, MD, Jae-Hyung Kim, MD and Kyu-Bo Choi, MD
      • Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
    • Correspondence: Hee-Yeol Kim, MD, Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Holy Family Hospital, 2 Sosa-dong, Wonmi-gu, Bucheon 420-717, Korea. Tel: 82-32-340-2018, Fax: 82-32-340-2669, Email: cumckhy@catholic.ac.kr
    Received July 12, 2007; Accepted August 14, 2007.

    Abstract

    Background and Objectives

    It is well known that the higher the blood pressure, the greater the chance of cardiovascular disease, but the factors that are responsible for this association remain largely unknown. We sought to determine whether blood pressure, in a dose-dependent way, is associated with systemic inflammation, which is a known risk factor for cardiovascular events.

    Subjects and Methods

    We analyzed the data from 5,626 participants, aged 40-65 years, of the Third National Health and Nutrition Examination Survey (NHANES III). We quantified the blood pressure by dividing the participants into the normal, pre-, stage 1 and stage 2 hypertension groups based on the Joint National Committee 7 (JNC) classification. We used multiple linear and logistic regression models to determine the relationship between blood pressure and the levels of inflammatory markers.

    Results

    After adjustments were made for various co-morbidities, participants with stage 2 systolic hypertension had higher circulating leukocyte levels [840/µL (95% confidence interval [CI], 374 to 939/µL)] and fibrinogen levels [24.5 mg/dL (95% CI, 8.9 to 31.9 mg/dL)] than those participants with normal blood pressure. They also showed higher circulating C-reactive protein levels (C-reactive protein>10.0 mg/L: p for trend=0.001). There was a dose-dependent increase for the circulating levels of the risk factors across the different levels of systolic blood pressure, but not for diastolic blood pressure.

    Conclusion

    These findings demonstrate that an elevated systolic blood pressure is an independent risk factor for systemic inflammation and this may explain why systolic hypertension is a risk factor for atherosclerosis and cardiovascular events.

    Keywords
    Hypertension; Inflammation

    Introduction

    High blood pressure (HBP) is one of the most important risk factors for cardiovascular disease (CVD). The higher the blood pressure (BP) is, the greater is the chance of developing cardiovascular disease. Data from observational studies that involved more than 1 million individuals has indicated that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mmHg systolic and 75 mmHg diastolic to higher levels.1) The increased observed risks are present for all age groups that range from 40 to 89 years of age. For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, the risk for mortality from both ischemic heart disease and stroke is doubled. In addition, longitudinal data obtained from the Framingham Heart Study has indicated that BP values in the 130 to 139/85 to 89 mmHg range are associated with a more than a 2-fold increase in the relative risk of cardiovascular disease (CVD) compared with BP levels below 120/80 mmHg.2)

    Recent evidence indicates that elevated levels of inflammation markers, and particularly C-reactive protein (CRP), are associated with a higher risk of CVD,3-5) suggesting that inflammation plays a key role in the development of CVD.6) An elevated CRP level is also related to high mortality in patients with acute aortic syndrome.7) Mild chronic inflammation may also play a significant role in the incidence of HBP.8) CRP levels in the upper ranges of the normal distribution (high-normal levels of C-reactive protein) are widely believed to reflect a state of low-grade chronic inflammation. By impairing the capacity of the endothelium to generate vasodilating factors and particularly nitric oxide (NO), elevated levels of cytokines may lead to the development of endothelial dysfunction, chronic impaired vasodilation and HBP. CRP has been shown to be associated to HBP in a few well-controlled studies.9-11) However, the results from studies on the association between fibrinogen and HBP have been contradictory.

    If the link between HBP and CVD risk is indeed mediated by inflammation, then one would expect to see positive associations between the levels of blood pressure and the markers correlated with systemic inflammation that are predictive of the risk of CVD, such as CRP. But this association has not yet been confirmed. In the present study, we used the population-based data from the Third National Health and Nutrition Examination Survey (NHANES III) to determine whether the stages of systolic blood pressure (SBP) and diastolic blood pressure (DBP) are associated with increased circulating levels of CRP and other inflammatory markers among apparently healthy U.S. adults.

    Subjects and Methods

    Study design

    The detailed methods for the NHANES III study have been described previously.12) Briefly, NHANES III was a cross-sectional, multistage probability sample that was recruited between 1988 and 1994, and this sample was representative of the total non-institutionalized civilian population of the United States. The NHANES III data collection included a home interview and a detailed clinical examination in a mobile examination center. We restricted our study to the 5,626 participants (age range: 40-65 years) of the NHANES III who had complete data on their blood pressure, CRP, fibrinogen and covariates.

    Blood pressure

    BP was measured three times during the home interview and three times during the clinical examination by using a standard mercury sphygmomanometer with the participant in a seated position. A participant's average BP was calculated using all the available systolic and diastolic readings. We quantified the SBP and DBP by dividing the participants into normal, prehypertension, stage 1 and stage 2 hypertension (HT) based on the Joint National Committee 7 (JNC) classification.13) Information on the current use of antihypertensive medications was also obtained.

    Laboratory measurements

    The laboratory procedures used in the NHANES III study have been described elsewhere.14) The CRP level was measured by performing latex-enhanced nephelometry. Since 3,488 (62%) of the participants had CRP values below the lowest detectable level (0.22 mg/dL), for analytic purposes, CRP was treated as a categorical variable rather than a continuous variable. CRP levels ≥0.22 mg/dL were considered "elevated," whereas those levels >1.00 mg/dL were categorized as "highly elevated". The fibrinogen levels were measured in all the participants who were 40 years of age or older by using enzyme assay methods. The serum homocysteine levels were measured via high-performance liquid chromatography. The homocysteine levels were collected between 1991 and 1994 (during phase 2 of the NHANES III), and they were available for 3,143 participants in this analysis. We included the leukocyte and platelet counts as well as the total serum cholesterol and highdensity lipoprotein (HDL) cholesterol levels in the analysis.

    Covariates

    We classified the ages (in years) into three strata: 40-49, 50-59 and 60-65. Race was divided into three categories: white, black and other. The smoking status was divided into three strata: current, former and those who had never smoked. We divided the body mass index (BMI in kg/m2) into quintiles: ≤23.5, 23.6 to 26.0, 26.1 to 28.5, 28.6 to 31.8 and ≥31.9. The presence of co-morbidities was determined by the participants' responses to the question: "Has the doctor ever told you that you had diabetes … (congestive heart failure, chronic bronchitis, etc)?" Participants were deemed to have rheumatoid arthritis or a related inflammatory disorder if they had a significantly elevated titer of rheumatoid factor (≥1 : 40) on a serum dilution latex fixation test.

    Statistical analysis

    The baseline characteristics of the study participants with pre-hypertension, stage 1 HT and stage 2 HT were compared with the participants who had normal BP by the χ2-test for binary variables and by t-tests for the continuous variables. To assess whether there was a gradient of the various baseline demographic and clinical factors across the stages of HT, we used the Mantel-Haenszel test for trends [We used multiple linear and logistic regression models to determine the relationship between the stages of systolic and diastolic HT and the levels of C-reactive protein (CRP) and fibrinogen, and the leucocyte and platelet counts]. We used multiple linear regression techniques for the data in Table 4 to estimate the independent impact of the stages of systolic and diastolic HT on the circulating levels of leukocytes, platelets, fibrinogen and homocysteine. We used a multiple logistic modeling technique to determine whether the stages of HT were associated with elevated CRP levels (Table 5) (Fig. 1). In all of these models, we adjusted for age, gender, BMI, race and co-morbidities for their potential effects on systematic inflammation. All the tests were 2-tailed in nature. Continuous variables are shown as means±SDs, unless otherwise indicated.

    Fig. 1
    Dose-response relationship between systolic hypertension and the CRP level. CRP: C-reactive protein.

    Table 4
    Crude and multivariate regression analyses as adjusted by the changes in inflammatory factors

    Table 5
    Relative odds of having an elevated level of circulating CRP

    Results

    There were 5,626 participants in this analysis (47.8% were male and 68.7% were white). The average age and BMI of the participants were 51.7±6.7 years and 28.2±4.9 kg/m2, respectively. The baseline characteristics and laboratory profiles, based on the JNC 7 report, are summarized in Table 1. Old age, male-gender and an increased BMI were positive risk factors for prehypertension and hypertension, whereas being of the white race was inversely correlated with the risk of HT. Diabetes was more prevalent among the pre-HT and HT participants and the fasting sugar levels were also increased in these groups. Congestive heart failure, stroke and rheumatoid arthritis were more prevalent in the stage 1 and 2 HT groups based on the JNC 7 classification. Compared to the control group, the total cholesterol levels were increased and the HDL-cholesterol levels were decreased in the pre-HT and stage 1 HT groups.

    Table 1
    The baseline characteristics and laboratory profiles

    Relationship between the stages of hypertension and the inflammatory markers

    The laboratory profiles of the inflammatory markers were classified according to the JNC 7 report, and they are presented in Table 2. Participants with "elevated" and "highly elevated" CRP levels were more common in the pre-, stage 1 and stage 2 HT groups. The fibrinogen levels and leukocyte counts were also increased in the pre-, stage 1 and stage 2 HT groups. The homocysteine levels were also increased in the stage 1 and stage 2 HT groups; however, the difference was not statistically significant in the pre-hypertension group compared to the control group. There was no significant difference in the platelet count on comparison between the groups. However, the participants with an elevated platelet count were more common in the prehypertension and stage I hypertension groups.

    Table 2
    Levels of circulating inflammatory markers

    Table 3 shows the crude and adjusted changes in blood pressure by the increasing levels of the inflammatory markers. The systolic blood pressure was significantly elevated in patients with elevated levels of CRP as well in those patients with elevated leukocyte and platelet counts. This was observed after adjustment for age, gender, race, body mass index, the systolic or diastolic BP and the use of anti-hypertensive medication (CRP≥2.2 mg/L, elevation of SBP by 2.04 mmHg, p=0.001; CRP>10.0 mg/L, elevation of SBP by 3.24 mmHg, p=0.002; elevated leukocyte count, elevation of the SBP by 2.54 mmHg, p=0.002; elevated platelets count, elevation of the SBP by 1.80 mmHg, p=0.021). However, no association was detected between the DBP and the circulating levels of inflammatory factors.

    Table 3
    Crude and adjusted changes in blood pressure by the increasing levels of inflammatory factors

    The levels of inflammatory markers in the pre-hypertension and hypertension groups were increased more than those in the normal group (Table 4). After adjustments for age, gender, body mass index, race and various co-morbidities, the participants with stage 2 systolic hypertension had circulating leukocyte, platelet and fibrinogen levels that were 840/µL [95% confidence interval (CI): 374 to 939/µL], 637/µL (95% CI: 1 840 to 19 341/µL) and 24.5 mg/dL (95% CI: 8.9 to 31.9 mg/dL), respectively, which were all higher levels than those of the participants with normal BP. However, the homocysteine level did not increase in association with the stages of HT. Only the fibrinogen level and the leukocyte count had a linear trend across the stages of systolic BP. Table 5 and figure 1 show the odds ratios and 95% confidence intervals for "elevated" and "highly elevated" CRP levels according to the stage of hypertension as classified by the JNC 7 classification. After adjustments for age, gender, body mass index, race and various comorbidities, the participants with stage 2 systolic HT were also more likely to have an elevated circulating CRP level [CRP≥2.2 mg/L, Odds ratio: 2.32, 95% confidence interval (CI): 1.43 to 2.32; CRP>10.0 mg/L, Odds ratio: 4.36, 95% C: I 2.21 to 8.59]. Both the stage 1 HT and pre-HT participants were associated with smaller but still significant increases in these levels. There was also a dose-dependent increase in the circulating levels of CRP across the stages of systolic BP (CRP≥2.2 mg/L, p for trend=0.002, CRP>10.0 mg/L, p for trend=0.001).

    Discussion

    Using a large representative sample of the U.S. population, this study identified a positive, independent and dose-response relationship between inflammatory markers and the degree of systolic blood pressure as classified according to the JNC 7 report. Especially, an elevated CRP level had a more significant linear trend across the stages of hypertension. The fibrinogen and leukocyte levels also showed significantly positive trends after adjustments were made for age, gender, race, body mass index, diastolic BP, the smoking status, diabetes, aspirin use and various co-morbidities. Moreover, increased CRP levels and an increased leukocyte count predicted elevation of the systolic blood pressure.

    Serum fibrinogen may promote hemostasis by increasing blood viscosity and acting as a cofactor for platelet aggregation.15) A high fibrinogen level has been shown to be an independent predictor of the progression of atherosclerosis.16) It also provides additive value to the risk associated with the high-sensitivity CRP (hs-CRP) and other traditional risk factors for predicting CVD events.17) In addition, an elevation of the fibrinogen level has been shown to predict future increases in blood pressure.18) The leukocyte count is associated with several components of metabolic syndrome.19) The elevation of the leukocyte count is a marker for an increased risk of CVD.20), 21) In addition, it is associated with hypertension and this is independent of smoking and the other traditional cardiovascular risk factors.22)

    Increased levels of homocysteine have also been implicated in the pathogenesis of atherosclerosis.23) CRP is a marker of chronic inflammation, and it is known to be positively associated with the systolic blood pressure and hypertension.9-11) An elevated CRP level is associated with a higher risk of CVD.3-5) However, several studies did not show a positive correlation between the CRP levels and systolic blood pressure.24), 25) Obesity is associated with increased plasma levels of proinflammatory cytokines, including interleukin-6 and tissue necrosis factor α, which increase the levels of circulating CRP; hence, obesity has been suggested to be a major potential confounder of the association of CRP with blood pressure in prior studies.25-27) However, our results showed a positive relationship between inflammatory markers, including CRP, and the stages of HT after adjustment for the body mass index.

    Pre-HT is a novel classification introduced by the JNC 7 report (BPs ranging from 120 to 139 mmHg systolic and/or 80 to 89 mmHg for the diastolic blood pressures). This stage was introduced based on the increased mortality from ischemic heart disease and stroke for the subjects in this category.1), 2) Inflammatory markers such as CRP, fibrinogen and the leukocyte counts were elevated in the pre-HT stage in our study. These findings suggest that chronic inflammation is present from a very early stage of hypertension and so intervention at an earlier stage should be considered.

    Our study demonstrated a significant dose-related relationship between inflammatory markers and the systolic blood pressure; however, a similar association was not present for the diastolic blood pressure. Although high BP is an important cardiovascular risk factor, current evidence shows that an increase in the SBP is more deleterious than an increase in the DBP. Isolated systolic hypertension is currently considered a major risk factor for stroke in elderly subjects.28) Effectively treating subjects who suffer with isolated systolic hypertension reduces the total mortality, the cardiovascular mortality, stroke and heart failure events.29), 30) Increased CRP levels and leukocyte counts predicted elevation of the systolic blood pressure in our study. Therefore, even though there were no significant correlations between inflammatory markers and the diastolic blood pressure, the results of this investigation showed a correlation of the systolic blood pressure with inflammation and cardiovascular events.

    This study has several strengths, but it also has some limitations. One of the strengths was the use of data from a nationally representative sample; therefore, the results can be generalized to the entire U.S. population. Second, we used the standardized classification of the grades of hypertension that was introduced by the JNC 7 report, which is based on numerous studies on the pathogenesis, therapies and prognosis of hypertension. Several limitations of this study should be considered. First, the current study used a cross-sectional design, which did not allow us to determine the temporal relationship between BP and the elevation of inflammatory markers. The second limitation of our analysis was the dates of the NHANES III survey, which was conducted between 1988 and 1994; this was before the high-sensitivity assay for CRP became widely available. Therefore, 62% of the cohort in this study was categorized as having undetectable CRP levels(<2.2 mg/L). Consequently, we could not examine the relationship between BP and the CRP levels as a continuous variable. Prospective studies would be more likely to identify a putative causal relationship between inflammatory markers and hypertension. In addition, prospective, placebo-controlled intervention trials are needed to document that reducing the levels of inflammatory markers, such as CRP by pharmacological treatment, might lead to a reduced risk for the development of hypertension, This would provide new insight into the correlation between inflammatory markers and BP.

    In conclusion, the findings of this study showed that an elevated systolic BP was an independent risk factor for systemic inflammation; this was noted from the very early stages of BP elevation. In addition, the results suggest that systolic BP, in a dose-dependent fashion, promotes the systemic inflammatory response. These observations support using the classification system of hypertension that was introduced by the JNC7 report, and our findings link systolic BP with the risk of CVD, and this is mediated by inflammation.

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    MeSH Terms
    Atherosclerosis
    Blood Pressure
    C-Reactive Protein
    Cardiovascular Diseases
    Classification*
    Fibrinogen
    Hypertension*
    Inflammation
    Joints
    Leukocytes
    Logistic Models
    Nutrition Surveys
    Risk Factors*
    Metrics
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