Cardiorespiratory Fitness and C-Reactive Protein Among a Tri-Ethnic Sample of Women
Background— Elevated C-reactive protein (CRP) is associated with increased coronary heart disease (CHD) risk. Cardiorespiratory fitness (“fitness”) is related with lower CHD risk; however, its relationship with CRP is relatively unknown.
Methods and Results— Cross-sectional associations between fitness and plasma CRP were examined among 135 African American (AA), Native American (NA), and Caucasian (CA) women (55±11 year; 28±6 kg/m2). Fitness was assessed with a maximal treadmill exercise test. Plasma CRP concentrations were determined with the Dade Behring high-sensitivity immunoassay. Geometric mean CRP levels were 0.43, 0.25, and 0.23 mg/dL, and average maximal MET levels of fitness were 7.2, 9.1, and 10 METs for AA, NA, and CA, respectively. CRP decreased across tertiles of fitness (P=0.002), increased across tertiles of BMI (P=0.0007), and varied by race (P=0.002). After adjustment for covariates, lower CRP (P<0.05) was observed across tertiles of fitness among NA and CA, but not AA. Among all women, after adjusting for race and covariates, the odds of high-risk CRP (>0.19 mg/dL) were 0.67 (95% CI=0.19 to 2.4) among fit (>6.5 METs) versus unfit women.
Conclusions— The health benefits from enhanced fitness may have an antiinflammatory mechanism.
Received April 17, 2002; accepted May 21, 2002.
C-reactive protein (CRP) is a marker of subclinical inflammation. Elevated CRP is associated with a 2- to 5-fold increased risk of coronary events.1,2⇓ CRP is inversely related with insulin sensitivity,3 directly related with type 2 diabetes risk,4 and elevated among individuals with excessive body fat.3–5⇓⇓ Fewer data exist on CRP and health for women and race-ethnic minorities, among whom CHD, diabetes, and obesity incidence is rising.6 Also, few studies2,4⇓ have considered the influence of physical activity on associations between CRP and health outcomes.
Regular physical activity is associated with lower CHD and diabetes risk.7 Self-reported physical activity is inversely related with CRP concentrations.8,9⇓ Cardiorespiratory fitness (“fitness”), assessed with maximal exercise testing, is stronger than self-reported physical activity as a predictor of several health outcomes.7,10⇓ We showed higher fitness correlates with lower CHD risk factors.11–13⇓⇓ Blair and associates observed lower cardiovascular mortality14 and type 2 diabetes15 rates with higher fitness, irrespective of obesity status. Data on fitness and health parameters are particularly sparse among women and minorities.7,10,12,13⇓⇓⇓ In the present study, we describe the cross-sectional association between fitness and CRP in a tri-ethnic sample of healthy women.
Informed consent was obtained from 44 African American (AA), 45 Native American (NA), and 46 Caucasian (CA) women who volunteered to be in the Cross-Cultural Activity Participation Study (CAPS). The aim of CAPS was to develop physical activity surveys for diverse populations of women.11,13,16,17⇓⇓⇓ CAPS inclusion criteria were self-reported: AA, NA, or CA ethnicity, absence of symptomatic disease, and the absence of conditions that would preclude daily physical activity. Interview-based health histories, body mass index (BMI, kg/m2), waist girth (cm), and resting blood pressure measures have been described.11,13,16,17⇓⇓⇓
After a 12-hour fast and 24-hour abstinence from exercise and smoking, antecubital blood was collected in EDTA, centrifuged, and frozen at −80°C until analysis. Plasma CRP concentrations were measured with the Dade-Behring high-sensitivity immunoassay (detection range=0 to 6.5 mg/dL).1,2⇓ Additional CHD risk factor concentrations were obtained with standard automated assay procedures described elsewhere.11,13,17⇓⇓
Fitness was quantified as the duration of a maximal treadmill exercise test consisting of 2-minute stages graded by 1 MET (1 MET=3.5 mL O2 · kg−1 · min−1) per stage.13 Exercise tests were conducted in the presence of a physician, and maximal exertion was seen as achieving ≥85% age-predicted maximal heart rate and perceived exertion ≥17 on a 20-point Borg scale.13,14⇓
Summary statistics (mean, SD, frequency, Pearson correlation) were computed for variables in general accord with the assumptions of normal distribution. CRP values were skewed; therefore, log transformed values are included in all analyses and geometric means are reported descriptively. Differences in CRP concentrations across categories of race, fitness, and BMI were analyzed with the general linear model. Fitness was quantified as treadmill exercise times that were adjusted for age with linear regression. Fitness varied by race (P<0.0001); therefore, race-specific treadmill time distributions were used to categorically define fitness as low (<33rd percentile), moderate (33rd to 67th percentile), and high (>67th percentile).13 BMI and waist girth were defined categorically as 18.5 to 24.9, 25 to 29.9, and ≥30 kg/m2, and <88 or ≥88 cm, respectively.11 For the entire sample, multiple logistic regression was used to model the race and covariate adjusted association between fitness (fit, >6.5 METs versus unfit, ≤6.5 METs) and high-risk CRP (>0.19 mg/dL).2 METs were estimated from maximal treadmill speed and grade11 and used to standardize fitness scores. Women in the upper 75th percentile of maximal METs were defined as fit.14 Probability values are two-sided with an α rate of 0.05.
Participants were middle-aged, overweight, and had relatively low CHD risk factors (Table 1). Among all women, CRP correlated significantly (P<0.05) with fitness (r=−0.25), BMI (r=0.25), waist girth (r=0.21), insulin (r=0.26), and triglyceride (r=0.27). Higher CRP (P<0.05) was observed among CA estrogenic medication users and NA diabetics. Age-adjusted maximal treadmill exercise times were higher (P<0.0001) for both CA and NA compared with AA, and for CA compared with NA. Table 2 shows CRP varied by race (P=0.002), decreased across tertiles of fitness (P=0.002), and increased with higher BMI (P=0.0007) and waist girth (P=0.004). After adjusting for BMI, smoking, diabetes, and estrogen status, lower CRP (P<0.05) was observed across tertiles of race-specific treadmill times among NA and CA, but not AA (Table 3). This association persisted among women with higher than race-specific median levels of insulin, triglyceride, and low-density lipoprotein cholesterol (LDL-C), and waist girth ≥88 cm in NA and CA (data not shown). Although not statistically significant, after adjusting for race, BMI, insulin, and triglyceride, the odds of high-risk CRP (>0.19 mg/dL [prevalence=46%]) were 0.67 (95% CI=0.19 to 2.4) among fit (>6.5 METs) versus unfit women.
Inverse associations have been reported between inflammatory markers, like plasma CRP and fibrinogen, and self-reported physical activity.8,9⇓ Cardiorespiratory fitness is an objective measure of recent physical activity.7,10,12⇓⇓ Reports on fitness and inflammatory markers are sparse. Haddock et al18 showed fitness was an independent determinant of fibrinogen among postmenopausal Caucasian women. Significantly higher submaximal fitness and lower CRP concentrations were recently reported among 14 German men after 9 months of exercise training.19 Our cross-sectional data showed that CRP and fitness are inversely related even after accounting for BMI and other covariates among NA and CA women. The lack of association between fitness and CRP among AA was consistent with the pattern of association between fitness and the other CHD risk factors (data not shown). The restricted variation in treadmill exercise time among AA (Table 1) might have been a contributory factor. The fact that the highest level of fitness among AA was generally less than the lowest fitness score among NA and CA implies that a cardioprotective threshold level of fitness might exist.7,10⇓ The race and covariate adjusted odds of CRP >0.19 mg/dL among all women were 0.67 for fit versus unfit women; however, this association did not reach statistical significance (95% CI=0.19 to 2.4), possibly due to sample size limitations. Prospective studies are needed to determine whether the cardioprotective effect of fitness is mediated through inflammatory pathways.
Another important observation from our data was the variation in plasma CRP by race (Table 2). Geometric mean CRP concentrations were significantly higher among AA (0.43 mg/dL) compared with NA (0.25 mg/dL) and CA (0.23 mg/dL) women. This relationship was maintained after controlling for BMI, insulin, TG, smoking, and diabetes. Higher CRP concentrations have been reported among AA versus CA adults.5,9⇓ Potential mechanisms for racial differences in CRP are unknown. In our study, AA women had higher BMI and insulin levels and were less fit than CA and NA. Barinas-Mitchell et al7 found the effect of race on CRP was strongest among estrogen users who had lower BMI, fasting glucose, and physical activity levels compared with women not using estrogen. We found estrogen use was similar between AA and CA, but only related with CRP among CA. Studies are needed to understand the effects of race and estrogenic medication on CRP.
Our data confirm a significant association between CRP and adiposity measures. The correlation for CRP with BMI (r=0.25) and waist girth (r=0.21) was similar to previous reports.3,5,8,9⇓⇓⇓ CRP concentrations rose sharply across higher BMI and waist categories (Table 2). The inverse association between CRP and fitness (Table 3) seen in our study persisted in models adjusted for race, BMI, and waist girth. This relationship suggests fitness may be an important determinant of plasma CRP even among women with increased body fat, and carries important public health implications given the recent increase in CHD, obesity, and type 2 diabetes rates among women and minorities.6
Several mechanisms could account for lower CRP in active and fit individuals. Significant reductions in CRP and other inflammatory markers have been shown among individuals completing prolonged exercise training.19,20⇓ Elevated CRP has been associated with infectious viral pathogens1; however, enhanced natural killer cell activity may confer a resistance to acute infections in fit individuals.7 Higher levels of physical activity and fitness are associated with improved insulin sensitivity and lower levels of body fat and oxidized LDL-C.7,11–13,15,20⇓⇓⇓⇓⇓ These factors may be noninfectious triggers for elevated CRP.1,3–5⇓⇓⇓ Higher fitness levels appear to have an antiinflammatory effect that may be a mechanism for lowering CHD and type 2 diabetes risk.
This pilot study was conducted to provide data in an important area where data currently do not exist. The relatively small sample and cross-sectional design restricted the power of our statistical analyses and, therefore, limited the conclusions that could be drawn. We observed lower CRP concentrations among CA and NA women with higher fitness levels. This relationship was not observed among AA women for reasons not fully understood.
This work was supported by NIH WHI-SIP No. 22W-U48/CCU409664 awarded to Dr Ainsworth.
- ↵Muhlestein JB, Horne BD, Calrquist JF, et al. Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation. 2000; 102: 1917–1923.
- ↵Festa A, D’Agostino R, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome. The Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000; 102: 42–47.
- ↵Barinas-Mitchell E, Cushman M, Meilahn EN, et al. Serum levels of C-reactive protein are associated with obesity, weight gain, and hormone replacement therapy in healthy postmenopausal women. Am J Epidemiol. 2001; 153: 1094–1101.
- ↵Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular disease in the United States. Circulation. 2000; 102: 3137–3147.
- ↵US Dept of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, Ga: Centers for Disease Control and Prevention; 1996
- ↵Geffken DF, Cushman M, Burke GL, et al. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol. 2001; 153: 242–250.
- ↵Irwin ML, Mayer-Davis EJ, Addy CL, et al. Moderate-intensity physical activity and fasting insulin levels in women. Diabetes Care. 2000; 23: 449–454.
- ↵LaMonte MJ, Eisenman PA, Adams TD, et al. Cardiorespiratory fitness and coronary heart disease risk factors: the LDS Hospital Fitness Institute Cohort. Circulation. 2000; 102: 1623–1628.
- ↵LaMonte MJ, Durstine JL, Addy CL, et al. Physical activity, physical fitness, and Framingham 10-year risk score: the Cross-Cultural Activity Participation Study. J Cardiopulm Reehab. 2001; 21: 63–70.
- ↵Ainsworth BE, Irwin ML, Addy CL, et al. Moderate physical activity patterns of minority women: the Cross-Cultural Activity Participation Study. J Women’s Health. 1999; 8: 805–813.
- ↵Drowatzky KL, Durstine JL, Irwin ML, et al. The association between physical activity, cardiorespiratory fitness, and lipoprotein(a) concentrations in a tri-ethnic sample of women: the Cross-Cultural Activity Participation Study. Vascular Med. 2001; 6: 15–21.