We investigated the relation between inflammation and incident hypertension, independent of obesity, and tested the associations of cardiorespiratory fitness (fitness) and indexes of inflammation for the development of hypertension in 2,475 normotensive men. Inflammatory markers were C-reactive protein (CRP) and fibrinogen. Fitness was directly measured by peak oxygen uptake during sign/symptom-limited treadmill exercise testing to volitional fatigue; 266 men (10.7%) developed hypertension during an average of 4 years follow-up. After adjusting for potential confounding variables, the relative risk (RR) and 95% confidence interval (CI) for incident hypertension in those in the upper tertile versus lower tertile were 1.55 (95% CI 1.15 to 2.09) for CRP and 1.51 (95% CI 1.10 to 2.06) for fibrinogen. Although the association between fibrinogen and incident hypertension persisted after adjusting for body mass index (p = 0.049), the relation between CRP and incident hypertension was no longer statistically significant (p = 0.08). Fit men had a 27% decreased (RR 0.73, 95% CI 0.56 to 0.94) risk of incident hypertension compared with unfit men in a multivariable adjusted model. In the joint analysis, unfit men with upper CRP had 1.81 times (95% CI 1.21 to 2.70) and unfit men with upper fibrinogen had 2.03 times (95% CI 1.33 to 3.12) greater risks of incident hypertension compared with fit men with low CRP and fibrinogen, respectively. However, these risks did not significantly increase in fit men with upper CRP (RR 1.12, 95% CI 0.76 to 1.63) and fibrinogen (RR 1.26, 95% CI 0.86 to 1.85) groups. In conclusion, these results suggest that heightened levels of fibrinogen, but not CRP, are associated with incident hypertension, independent of body weight, and that high fitness attenuates the risk of incident hypertension across upper levels of inflammatory markers in men.
Although the favorable effects of high fitness on the prevention of hypertension have previously been reported in normotensive populations and in subjects who are at high risk of developing hypertension, a key unanswered question is whether high fitness attenuates the likelihood of developing hypertension in subjects with elevated inflammatory markers. The purposes of the present study were (1) to investigate the association between low-grade inflammatory markers and incident hypertension, independent of obesity, and (2) to test the joint associations of fitness and inflammatory markers for the development of hypertension in men. We hypothesized that low-grade inflammatory markers would be associated with incident hypertension but that high fitness may attenuate this association.
Methods
In this study, we recruited 5,616 men who participated in 2 general health examinations during 1998 to 2009 at Samsung Medical Center, Seoul, South Korea. Of these subjects, 3,620 healthy men without hypertension, cardiovascular disease, and type 2 diabetes at baseline examination were included. An additional 1,145 men whose inflammatory markers were not measured at baseline were excluded. Accordingly, 2,475 men (aged 20 to 76 years) free of hypertension, cardiovascular disease, and type 2 diabetes, who underwent peak or symptom-limited cardiopulmonary exercise testing and whose inflammatory markers were measured at baseline, were included in the analysis. Participants were followed from 1 to 11 years after the baseline examination, over an average follow-up of 4 years. Written informed consent was obtained from all participants before health screening, and the study was approved by the Medical Center Institutional Review Board.
Cardiorespiratory fitness was directly measured by peak oxygen uptake (VO 2peak , ml/kg/min) using expired gas analysis during peak or symptom-limited exercise testing. Treadmill exercise testing was conducted using a Bruce or modified Bruce protocol. Expired gases were collected breath-by-breath through a 1-way valve and analyzed using a metabolic measurement cart (Jaeger Oxycon Delta; Erich Jaeger, Hoechberg, Germany). Oxygen uptake data were measured in 20-second intervals. VO 2peak was defined as the highest oxygen consumption recorded during peak exercise or immediate recovery. Exercise electrocardiograms were measured using 12-lead recordings (Q-4500; Quinton, Bothell, Washington). Exercise tests were stopped for any of the following reasons: a rating of perceived exertion (6 to 20 scale) >17 (very hard) and/or a respiratory exchange ratio >1.15; if the participant achieved >90% of age-predicted maximal heart rate; patient request because of volitional fatigue; attainment of a systolic blood pressure (BP) >250 mm Hg; increasing chest discomfort; threatening arrhythmias; or >1 mm of horizontal or downsloping ST-segment depression. Age-specific distributions of VO 2peak were created by the following age groups: 20 to 39, 40 to 49, 50 to 59, and ≥60. All participants were classified into fit (middle and upper tertiles) and unfit (low tertile) categories based on age-specific VO 2peak percentiles.
Blood samples were collected in the morning after a 12-hour overnight fast and analyzed by the hospital clinical laboratory. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were analyzed by enzymatic colorimetric and liquid selective detergent methods, respectively, using a Hitachi 7600 (Hitachi Co., Tokyo, Japan) analyzer. Fasting glucose levels were determined using the Hexokinase, UV method (Hitachi 7600; Hitachi Co.). High-sensitivity C-reactive protein (CRP) was measured using a CRP (II) Latax X2 turbidimetric method (Hitachi Corporation, Tokyo, Japan). Fibrinogen was measured by a clotting method using an STA coagulation analyzer (Diagnostica Stago, Asniere, France). Inter- and intra-assay coefficients of variation were <5% for all blood variables. CRP and fibrinogen were classified into tertile categories (low, middle, and upper). Heart rate in the supine position was obtained using the electrocardiogram at rest. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m 2 ). Smoking habits (never, past, and current), alcohol consumption (none, ≥3 d/wk), and related demographic/lifestyle information were evaluated through questionnaire.
BP at rest was measured in the seated position after ≥5 minutes of quiet rest using an automated BP monitor (Dinamap PRO 100; GE Healthcare, Milwaukee, Wisconsin). The lowest reading of 2 measurements was used as the baseline value. Hypertension was defined as systolic and/or diastolic BP ≥140/90 mm Hg, diagnosed hypertension by a physician and/or the use of antihypertensive medications at baseline examination. Participants with hypertension by these criteria at baseline were excluded from the present study. The incidence of hypertension was assessed at follow-up health examinations as systolic and/or diastolic BP ≥140/90 mm Hg or diagnosed hypertension by a physician because we did not have information regarding prescribed antihypertensive medications at the follow-up examination.
Data are presented as mean ± SD or median (interquartile range) for continuous variables and proportions for categorical variables. For group comparisons by incident hypertension at follow-up, independent t tests were used to test mean differences for continuous variables, and the chi-square tests were used to test frequency differences for categorical variables. Cox proportional hazards regression was used to examine the effect of inflammatory markers and fitness on the incidence of hypertension. Relative risks (RRs) and 95% confidence intervals (CIs) for incident hypertension were estimated with adjustment for potential confounding variables with specific reference to fitness, expressed as VO 2peak and inflammatory markers (i.e., CRP and fibrinogen). We additionally investigated this association by including BMI from the earlier referenced model to determine whether inflammatory markers predict the incidence of hypertension, independent of obesity.
The joint effects of inflammatory markers and fitness on the risk of incident hypertension were examined using combined groups. Participants were divided into 6 groups based on cross-classification of inflammation levels (low, middle, and upper) and fitness status (fit and unfit). Reference groups were fit-low CRP or fit-low fibrinogen cohorts. The interactions between inflammatory markers and fitness were tested. Inspection of empirical cumulative hazard plots (log-log [survival function] vs log [time]) across exposure categories indicated that the proportional hazards assumption was appropriate. Trends across fitness, CRP, and fibrinogen were tested by treating these exposure categories as an ordinal scale. Statistical significance was set at p <0.05. All data analyses were carried out using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, version 21.0; IBM Corp., Armonk, New York).
Results
During an average 4-year follow-up, 266 men (10.7%) developed hypertension. Men who developed hypertension had greater mean BMI, heart rate at rest, systolic and/or diastolic BP at rest, total cholesterol, low-density lipoprotein cholesterol, fibrinogen, and CRP but lower VO 2peak (all p <0.05) at baseline compared with men who remained normotensive ( Table 1 ). Table 2 lists the RRs and 95% CIs of incidence of hypertension by fitness status and tertiles of inflammatory markers. Fit men had 31% lower risk of developing hypertension compared with unfit men after adjusting for potential confounding variables (model 1). The association remained unchanged after further adjustment for BMI (model 2). Men in the highest tertile of CRP had 1.55 times (95% CI 1.15, 2.09) the risk of incident hypertension than did men in the lowest tertile of CRP (model 1). Similarly, men in the highest tertile of fibrinogen had 1.51 times (95% CI 1.10, 2.06) the risk of incident hypertension compared with men in the lowest tertile of fibrinogen (model 1). The positive associations between fibrinogen and incident hypertension persisted after additional adjustment for BMI (p = 0.049) in model 2. Although further adjustment for BMI had only a modest effect on the strength of associations between CRP and incident hypertension, this association was no longer statistically significant (p = 0.08).
| Variable | No Hypertension (n=2209) | Hypertension (n=266) | P values |
|---|---|---|---|
| Age (years) | 48.3 (5.9) | 48.6 (6.6) | 0.333 |
| Body mass index (kg/m 2 ) | 24.4 (2.4) | 25.2 (2.3) | <0.001 |
| Current smoker | 39.2 % | 43.2 % | 0.057 |
| Alcohol intake ( ≥ 3 day/week) | 8.1 % | 7.5 % | 0.702 |
| Resting heart rate (bpm) | 62.5 (8.7) | 64.1 (9.0) | 0.006 |
| Systolic blood pressure (mmHg) | 116.1 (11.9) | 123.3 (10.4) | <0.001 |
| Diastolic blood pressure (mmHg) | 73.7 (8.6) | 78.6 (7.1) | <0.001 |
| Total cholesterol (mg/dl) | 201.4 (32.6) | 206.7 (35.9) | 0.014 |
| High-density lipoprotein cholesterol (mg/dl) | 48.7 (11.2) | 48.9 (11.9) | 0.866 |
| Low-density lipoprotein cholesterol (mg/dl) | 130.7 (29.3) | 135.1 (32.3) | 0.020 |
| Triglycerides (mg/dl) | 143.2 (76.3) | 144.0 (71.1) | 0.871 |
| Glucose (mg/dl) | 94.5 (9.7) | 95.5 (10.1) | 0.117 |
| Fibrinogen (mg/dl) | 278.2 (54.6) | 290.4 (54.3) | 0.001 |
| C-reactive protein (mg/dl) ∗ | 0.07 (0.04-0.12) | 0.09 (0.05-0.15) | <0.001 |
| VO 2peak (ml/kg/min) | 34.6 (5.0) | 33.8 (4.8) | 0.027 |
| Variables | N | No. of Incident n (%) | Unadjusted RR (95% CI) | Model 1 RR (95% CI) | Model 2 RR (95% CI) |
|---|---|---|---|---|---|
| VO 2peak (ml/kg/min) | |||||
| Per 1 METs increment | 0.87 (0.80-0.95) | 0.89 (0.81-0.97) | 0.91 (0.83-0.99) | ||
| Unfit (29.8, 27.7-31.3) | 826 | 104 (12.6) | 1 (ref) | 1 (ref) | 1 (ref) |
| Fit (36.4, 34.4-39.2) | 1649 | 162 (9.8) | 0.67 (0.53-0.86) | 0.69 (0.53-0.89) | 0.73 (0.56-0.94) |
| P -value | 0.002 | 0.004 | 0.015 | ||
| C-reactive protein (mg/dl) | |||||
| Per 1 SD increment | 1.06 (0.97-1.17) | 1.03 (0.94-1.13) | 1.01 (0.92-1.11) | ||
| Low (<0.05) | 949 | 77 (8.1) | 1 (ref) | 1 (ref) | 1 (ref) |
| Middle (0.06-0.10) | 738 | 79 (10.7) | 1.22 (0.90-1.68) | 1.19 (0.86-1.63) | 1.12 (0.81-1.54) |
| Upper (>0.11) | 788 | 110 (14.0) | 1.60 (1.19-2.14) | 1.55 (1.15-2.09) | 1.41 (1.03-1.93) |
| P -value | 0.006 | 0.014 | 0.08 | ||
| Fibrinogen (mg/dl) ∗ | |||||
| Per 1 SD increment | 1.17 (1.05-1.31) | 1.21 (1.07-1.36) | 1.19 (1.06-1.34) | ||
| Low (<253) | 857 | 71 (8.3) | 1 (ref) | 1 (ref) | 1 (ref) |
| Middle (254-294) | 775 | 86 (11.1) | 1.29 (0.94-1.77) | 1.27 (0.93-1.75) | 1.27 (0.92-1.74) |
| Upper (>295) | 839 | 107 (12.8) | 1.46 (1.08-1.98) | 1.51 (1.10-2.06) | 1.48 (1.08-2.02) |
| P -value | 0.045 | 0.037 | 0.049 |
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