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J Appl Physiol 102: 1374-1379, 2007. First published December 14, 2006; doi:10.1152/japplphysiol.01028.2006
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Markers of inflammation are inversely associated with VO2 max in asymptomatic men

Iftikhar J. Kullo,1 Mahyar Khaleghi,1 and Donald D. Hensrud2

1Division of Cardiovascular Diseases, Department of Internal Medicine, and 2Department of Nutrition and Preventive Medicine, Mayo College of Medicine, Rochester, Minnesota

Submitted 13 September 2006 ; accepted in final form 8 December 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We investigated whether markers of inflammation, including a cytokine (IL-6), acute-phase reactants [C-reactive protein (CRP) and fibrinogen], and white blood cell (WBC) count are associated with maximal O2 consumption (VO2 max) in men without coronary heart disease (CHD). In asymptomatic men (n = 172, 51 ± 9.3 yr old), VO2 max was measured during a symptom-limited graded treadmill exercise test. Physical activity level was assessed by a standardized questionnaire. IL-6 and CRP were measured by immunoassays, fibrinogen by the Clauss method, and WBC count with a Coulter counter. IL-6 and CRP were logarithmically transformed to reduce skewness. Multivariable regression was used to assess whether markers of inflammation were associated with VO2 max after adjustment for age, body mass index, CHD risk factors, and lifestyle variables (physical activity level, percent body fat, and alcohol intake). VO2 max was 34.5 ml·kg–1·min–1 (SD 6.1). Log IL-6 (r = –0.38, P < 0.001), log CRP (r = –0.40, P < 0.001), fibrinogen (r = –0.42, P < 0.001), and WBC count (r = –0.22, P = 0.004) were each correlated with VO2 max. In separate multivariable linear regression models that adjusted for age, body mass index, CHD risk factors, and lifestyle variables, log IL-6 [beta-coeff = –1.66 ± 0.63 (SE), P = 0.010], log CRP [beta-coeff = –0.99 ± 0.33 (SE), P = 0.003], fibrinogen [beta-coeff = –1.51 ± 0.44 (SE), P = 0.001], and WBC count [beta-coeff = –0.52 ± 0.30 (SE), P = 0.088] were each inversely associated with VO2 max. In conclusion, higher circulating levels of IL-6, CRP, and fibrinogen are independently associated with lower VO2 max in asymptomatic men.

fitness; interleukin-6; C-reactive protein; fibrinogen

SEVERAL PROSPECTIVE STUDIES have shown greater cardiorespiratory fitness to be associated with a lower risk of coronary heart disease (CHD) in asymptomatic individuals (3, 4, 13, 19, 31, 33). The association is independent of measures of adiposity, and a potential underlying mechanism may be that greater cardiorespiratory fitness reduces systemic inflammation (51). Atherosclerosis is recognized as a chronic inflammatory disorder, and activation of inflammatory pathways is a key event in the initiation as well as progression of atherosclerotic vascular disease (42).

Prior studies have shown acute-phase reactants, such as C-reactive protein (CRP) and fibrinogen, and white blood cell (WBC) count to be inversely related to cardiorespiratory fitness (6, 7, 21, 22, 38, 54). Whether more "proximal" mediators in the inflammatory cascade, such as the cytokines, are similarly associated with cardiorespiratory fitness is not known. Furthermore, previous studies of inflammation and cardiorespiratory fitness used treadmill time, rather than a direct measure of cardiorespiratory fitness, i.e., maximal O2 consumption (VO2 max). VO2 max is a more accurate and reproducible measure of exercise capacity than treadmill time (29) as well as a stronger predictor of cardiovascular outcomes (30, 47). Finally, adjustment for lifestyle variables, such as physical activity level, percent body fat, and alcohol intake, was not performed in the studies.

The purpose of the present study was to investigate whether several different inflammatory markers, including the cytokine IL-6, acute-phase reactants (CRP and fibrinogen), and WBC count, were associated with VO2 max in asymptomatic men after adjustment for body mass index (BMI), CHD risk factors, and lifestyle variables.


   METHODS
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 METHODS
RESULTS
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Study population.   Participants were asymptomatic men undergoing a screening medical evaluation at the Mayo Clinic (Rochester, MN). Between September 2003 and February 2004, 201 such men without known CHD provided written, informed consent to participate in the study and underwent assessment of VO2 max and measurement of plasma levels of inflammation markers. For the present study, the sample included 172 participants for whom data for the inflammatory markers were available. The study was approved by the Institutional Review Board of the Mayo Clinic.

CHD risk factors.   Weight was measured by an electronic balance and height by a stadiometer. BMI was calculated as kilograms per square meter. Resting blood pressure (BP) levels were measured in the right arm with a cuff sphygmomanometer after a participant had been resting for 10 min. Information about medication use, including hypertension medications, statins, oral hypoglycemic agents, and insulin, was obtained from a questionnaire completed at the time of medical examination. Diabetes was considered present if a participant was being treated with insulin or oral agents or had a fasting glucose level >125 mg/dl. Current smoking was defined as smoking in the past 30 days. History of smoking was defined as smoking >100 cigarettes in the past. The diagnosis of hypertension was determined on the basis of BP levels measured at the study visit (≥140 mmHg systolic BP or ≥90 mmHg diastolic BP) or report of a prior diagnosis of hypertension and current treatment with antihypertensive medications.

Lifestyle variables (physical activity score, percent body fat, and alcohol intake).   To assess physical activity level, the short version of the International Physical Activity Questionnaire (available at http://www.ipaq.ki.se/) with a recall period of the previous 7 days was used (10). A physical activity score was calculated on the basis of the International Physical Activity Questionnaire recommendations as 3.3 (min walked/wk) + 4.0 (min of moderate activity/wk) + 8.0 (min of vigorous activity/wk) and is considered an approximate estimate of metabolic equivalents-minutes per week. This score was divided by 7 to obtain metabolic equivalents-minutes per day. Percent body fat was estimated by the method of Pollock et al. (36) after measurement of subcutaneous fat in the axillary, triceps, and suprailiac regions by a skinfold caliper. Alcohol consumption was quantified as the number of drinks per week.

Assays.   Blood samples were obtained by venipuncture after an overnight fast. Standard enzymatic methods were used to measure total cholesterol, high-density lipoprotein (HDL) cholesterol, and plasma glucose. Plasma IL-6 was measured by a quantitative two-site high-sensitivity enzyme immunoassay (R & D Systems, Minneapolis, MN), CRP by a polystyrene particle enhanced high-sensitivity immunoturbidimetric assay (DiaSorin, Stillwater, MN), and fibrinogen by the Clauss method (Diagnostica Stago, Parsippany, NJ). Interassay coefficients of variation were 9.9–16.5% for IL-6, 1.0–8.0% for CRP, and 2.5–3.5% for fibrinogen. The WBC count was performed using a commercially available automated system (GEN·S, Coulter, Miami, FL).

VO2 max.   Symptom-limited graded exercise testing was performed on a motor-driven treadmill (Marquette Electronics, Milwaukee, WI, or Quinton Instruments, Seattle, WA) as previously described (46). A 12-lead ECG was monitored continuously, and heart rate was recorded for each minute of exercise and for ≥6 min during the recovery period. A calibrated, computerized metabolic cart (Medical Graphics, St. Paul, MN) was used for breath-by-breath analysis of expired air. O2 consumption (VO2), CO2 production, and minute ventilation were averaged during 30-s intervals. VO2 max was defined as the highest 30-s average during exercise.

Statistical methods.   Descriptive statistics are given as mean (SD) (as well as range) or frequency and percentage. IL-6 and CRP levels were logarithmically transformed to reduce skewness. Alcohol consumption, measured in drinks per week, was also skewed and logarithmically transformed after addition of 5 to avoid taking the logarithm of 0. Pair-wise correlations between log IL-6, log CRP, fibrinogen, and WBC count were assessed by Pearson's partial correlation coefficients before and after adjustment for age.

To assess whether inflammatory markers were independently associated with VO2 max after adjustment for potential confounders, including physical activity level, we performed multivariable regression analyses with stepwise backward elimination. Included in the regression models were age, BMI, CHD risk factors (systolic BP, diabetes, total cholesterol, HDL cholesterol, and current smoking), statin use, and lifestyle variables (physical activity score, percent body fat, and alcohol consumption). Variables were removed until all remaining variables were significant at P ≤ 0.10. Statistical significance was inferred at P < 0.05. Statistical analyses were performed with SAS version 8.2 (SAS Institute, Cary, NC).


   RESULTS
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The age of the 172 study participants was 51.1 yr (SD 9.3) (range 26–84 yr; Table 1), 51 subjects (29.6%) were hypertensive, 56 (32.6%) were on statins, and 73 (42%) were past or current smokers (9.9% current smokers). Log IL-6 was significantly correlated with log CRP, fibrinogen, and WBC count before and after adjustment for age (Table 2).


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  		Table 1. Subject characteristics

 

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  		Table 2. Correlation between log IL-6, log CRP, fibrinogen, and WBC count

 
Significant correlations of log IL-6 (r = –0.38, P < 0.001), log CRP (r = –0.40, P < 0.001), fibrinogen (r = –0.42, P < 0.001), and WBC count (r = –0.22, P = 0.004) with VO2 max are shown in Fig. 1. After adjustment for age, variables inversely related to VO2 max were log IL-6, log CRP, fibrinogen, WBC count, BMI, systolic BP, current smoking, and percent body fat; variables positively related to VO2 max were physical activity score and HDL cholesterol (Table 3).


Figure 1
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  		Fig. 1. Scatter plots depicting correlation between log IL-6, log C-reactive protein (CRP), fibrinogen, and WBC count with maximal O2 consumption (VO2 max).

 

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  		Table 3. Variables associated with VO2 max after adjustment for age

 
After adjustment for age, BMI, CHD risk factors, and lifestyle variables, three of the four markers of inflammation, log IL-6 (P = 0.010), log CRP (P = 0.003), and fibrinogen (P = 0.001), remained significantly, inversely related to VO2 max, while WBC count was related inversely in a borderline-significant manner (P = 0.088). The inflammatory markers explained 2–7% of the variation in VO2 max (Table 4). A unit increase in log IL-6, log CRP, and fibrinogen was associated with a decrease of 1.66, 0.99, and 1.51 ml·kg–1·min–1, respectively, in VO2 max (Table 4).


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  		Table 4. Association of inflammatory markers with VO2 max after adjustment for age, BMI, CHD risk factors, and lifestyle variables

 
In a multivariable regression model that included age, BMI, CHD risk factors, lifestyle variables, and all four inflammatory markers, the following variables were significantly associated with VO2 max after stepwise backward elimination: age, BMI, physical activity score, current smoking, percent body fat, systolic BP, and fibrinogen. The model explained 54% of the interindividual variation in VO2 max (Table 5). The main determinants of interindividual variation in VO2 max were age and BMI followed by smoking status and plasma fibrinogen level.


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  		Table 5. Predictors of VO2 max: multivariable regression model with backward stepwise elimination

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
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The main finding of the present study was that, in asymptomatic men, the cytokine IL-6 and acute-phase reactants (CRP and fibrinogen) were inversely related to VO2 max, even after adjustment for potential confounders such as age, BMI, CHD risk factors, lifestyle variables, and, particularly, physical activity level. Although previous studies have reported an inverse association between inflammatory markers and cardiorespiratory fitness, the present study is the first to 1) demonstrate an independent association between a cytokine (IL-6) and VO2 max, 2) use a direct measure of cardiorespiratory fitness (VO2 max), rather than treadmill time, and 3) adjust for several lifestyle variables, including physical activity level, alcohol intake, and percent body fat.

Adiposity and physical activity are important confounders in the study of the association between inflammatory markers and cardiorespiratory fitness. Adipose tissue is an important source of IL-6 (9, 43), and increased adiposity is known to be associated with reduced cardiorespiratory fitness. Similarly, lower physical activity level is associated with higher levels of IL-6 (8, 35, 40), as well as with reduced cardiorespiratory fitness. In the present study, the association between VO2 max and IL-6 was independent of adiposity and physical activity. Whether exercise lowers levels of IL-6 cannot be confirmed by our cross-sectional study; however, several prospective studies of exercise training have demonstrated significant reductions in inflammatory markers (15, 28, 32, 48, 52). It has been reported that a single bout of exercise actually increases plasma levels of IL-6 and IL-1 (34), whereas repeated exercise training lowers the levels of these cytokines (49). There are several plausible mechanisms by which exercise could reduce inflammation independent of a reduction of adiposity (14). Long-term exercise or physical training has been noted to significantly elevate antioxidant capacity in humans as well as experimental animals (2, 25, 37, 45), reduce the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation (44), lessen age-related impairment in nitric oxide availability (50), improve endothelial dysfunction (16), and decrease the expression of adhesion molecules on leukocytes (18).

Our finding that higher levels of acute-phase reactants (CRP and fibrinogen) and higher WBC count are associated with lower VO2 max is consistent with the results of previous studies. CRP and fibrinogen levels have been found to be inversely associated with cardiorespiratory fitness independent of BMI (6, 7, 54). Two previous reports have examined the association between WBC count and VO2 max (17, 21). Kim et al. (21) reported an independent association between WBC count and fitness in 8,241 apparently healthy Korean men. In our study, WBC count was inversely associated with VO2 max after adjustment for age (P = 0.002), but the strength of association was attenuated after adjustment for age, BMI, current smoking, percent body fat, and systolic BP (P = 0.057) and additional adjustment for physical activity (P = 0.088).

In a multivariable regression analysis that included all four markers of inflammation, fibrinogen, but not IL-6 or CRP, remained significantly associated with VO2 max (Table 5). Although IL-6 is a major inducer of fibrinogen gene expression (11, 39), cytokines other than IL-6, such as oncostatin M (53), may induce fibrinogen biosynthesis. Fibrinogen is not only an inflammatory marker, but it is also the main determinant of plasma viscosity (26, 27). In one study (5), plasma viscosity was significantly and inversely associated with VO2 max in middle-aged men, and serum total protein and plasma fibrinogen concentrations accounted for most of the interindividual variation in plasma viscosity. The significant, independent, inverse association between fibrinogen and VO2 max may be attributable to fibrinogen being a marker of systemic inflammation as well as a surrogate for blood viscosity.

Limitations of the present study include the relatively small sample size and cross-sectional design. Our study sample consisted predominantly of middle-aged white men (88% of the participants were 40–70 yr old), and the extent to which our findings may be generalizable to women and to subjects of other ethnic backgrounds is not known. LaMonte et al. (23) found CRP to be related to cardiorespiratory fitness in a triethnic sample of 135 women. However, the association was significant in Native American and Caucasian but not African-American women. Although physical activity was significantly associated with markers of inflammation in several studies (number of participants per study = 3,075–5,888) (1, 8, 14, 20), we did not find such an association (analyses not shown) possibly because of the relatively small sample size in our study. We did not have data on levels of other inflammatory mediators, such as IL-1, TNF-{alpha}, and adhesion molecules, which may have provided further insight into the relation between inflammation and cardiorespiratory fitness. Further work is needed to identify which inflammatory pathways are linked to cardiorespiratory fitness and to determine the pathophysiological mechanisms underlying such an association. Finally, nearly one-third of the study participants were on statins, and these medications may have anti-inflammatory effects (41). However, we did not find an interaction between statin use and any of the inflammatory markers in the prediction of VO2 max (analyses not shown).

The results of our study have implications for public health and also suggest avenues for further research. The fact that cardiorespiratory fitness is inversely associated with inflammatory markers, independent of BMI, emphasizes the importance of regular exercise, regardless of the level of adiposity. Increasing exercise capacity by regular exercise is likely to have significant health benefits, even without a reduction in weight (12, 24). Therefore, individuals should be encouraged to achieve and maintain a high level of physical fitness. Further investigation is needed to assess whether levels of inflammatory mediators represent a marker for effectiveness of exercise programs and whether exercise can be used as a therapeutic modality for patients with heightened inflammatory status.

In conclusion, a cytokine (IL-6) and acute-phase reactants (CRP and fibrinogen) were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO2 max) in asymptomatic men, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness. The improved cardiovascular outcomes of fit vs. nonfit individuals may be due to a favorable inflammatory profile in the former.


   GRANTS
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This work was supported by National Center for Research Resources Grant RR-17720 (to I. J. Kullo) and funds from the Mayo Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. J. Kullo, Div. of Cardiovascular Diseases, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: kullo.iftikhar{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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