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(Circulation. 1997;95:335-341.)
© 1997 American Heart Association, Inc.

Articles

Leisure-Time Physical Activity but Not Work-Related Physical Activity Is Associated With Decreased Plasma Viscosity

Results From a Large Population Sample

Wolfgang Koenig, MD; Malte Sund, MS; Angela Doring, MD; Edzard Ernst, MD

the Department of Internal Medicine II/Cardiology (W.K.), Ulm University Medical Center, Ulm, Germany; GSF National Research Center for Environment and Health, MEDIS Institute (M.S.) and Institute of Epidemiology (A.D.), Neuherberg, Germany; and Postgraduate Medical School (E.E.), University of Exeter, Exeter, UK.

Correspondence to Wolfgang Koenig, MD, Department of Internal Medicine II/Cardiology, University of Ulm Medical Center, Robert-Koch-Str 8, D-89081 Ulm/Germany.

	Abstract

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Background Regular leisure-time physical activity (LTPA) is inversely associated with coronary heart disease (CHD). This has been mainly explained by its impact on traditional CHD risk factors, but more recently it was also shown to lower fibrinogen, which largely determines plasma viscosity. No data on the effect of work activity (WA) on plasma viscosity have been published.

Methods and Results We studied the relationship between self-reported LTPA or WA and plasma viscosity as well as other CHD risk factors in 3522 men and women age 25 to 64 years. Physical activity was assessed by questionnaire. LTPA was inversely associated with plasma viscosity in both sexes. The unadjusted mean differences in plasma viscosity in men between no activity and the highest activity were 0.024 mPa·s (95% confidence interval [CI], 0.016 to 0.032 mPa·s, P<.001) during winter and 0.024 mPa·s (95% CI, 0.016 to 0.031 mPa·s, P<.001) during summer. After adjustment for age, cholesterol, smoking, blood pressure, body mass index, and years of education, mean differences decreased but still remained substantial and statistically significant (0.010 mPa·s; 95% CI, 0.003 to 0.018 mPa·s [P=.009] for winter activity; and 0.010 mPa·s; 95% CI, 0.002 to 0.017 mPa·s [P=.011] for summer activity). Similar results were found in women. WA showed no appreciable association with plasma viscosity after controlling for the covariates.

Conclusions LTPA is inversely associated with plasma viscosity, independent of other risk factors, whereas WA shows no material effect in men and women. Decreased plasma viscosity may represent one mechanism through which LTPA confers a decrease of CHD risk.

Key Words: exercise • risk factors • epidemiology • microcirculation • viscosity, plasma

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Regular LTPA is inversely associated with CHD,^{1 2 3 4 5 6 7} stroke morbidity and mortality,⁸ and all-cause mortality.^{9 10 11} The comparable evidence for occupational WA is less convincing: most of the data have been gathered from middle-aged men, and data for women are scarce and controversial.¹²

The manner in which the beneficial effect of regular physical activity is mediated remains unclear. Improvement of traditional risk factors¹³ or hemostatic parameters (eg, fibrinogen^{14 15} ) has been discussed. A further possibility might be an improvement in the viscosity of blood,¹⁵ which is known to contribute to the peripheral vascular resistance, thereby influencing blood flow.¹⁶

We measured plasma viscosity, which is a major determinant of microcirculatory flow, in a large sample of the population and related it to LTPA and to WA. Our hypothesis was that viscosity would be inversely related to LTPA as well as to WA.

	Methods

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The MONICA Project is a WHO-coordinated, observational long-term study. Its main objective is to measure trends in cardiovascular mortality and morbidity and to assess the extent to which these trends are related to changes in risk factor levels and/or medical care measured at the same time in different communities of different countries.^{17 18}

MONICA Augsburg Project
The first cross-sectional study of the MONICA Augsburg Project (located in southern Germany) was carried out in 1984 through 1985. Of the 5312 potentially eligible individuals (age range, 25 to 64 years) initially sampled at random from a study population of 282 279 inhabitants of a mixed urban/rural area, 4022 participated in the study (net response rate, 75%^{19 20 21} ).

The present report is based on a subsample of 3521 subjects (1808 men and 1713 women) age 25 to 64 years. Exclusion criteria were history of cardiovascular diseases, acute or chronic infections, or inflammatory disorders and neoplasms. Furthermore, individuals with incomplete laboratory studies were not considered.

Survey Methods
All survey methods were as in the MONICA protocol.²² Participants were asked to complete a standardized questionnaire concerning medical history, attitude toward and knowledge of health, use of medical care, life style, socioeconomic variables, and a drug history of the 7 days preceding the examination.²¹ After a 30-minute interview, resting pulse rate (bpm) was taken, and BP (Hawksley random zero sphygmomanometer) was measured according to the recommendations of the MONICA Manual. Body height (in m), body weight (kg), BMI (weight/height²), smoking status (never, ex-smoker, or current smoker), and alcohol consumption (g/day) were also determined in a standardized manner.^{22 23}

Each participant was questioned regarding his or her LTPA and WA during the winter and summer. The questionnaire consisted of a four-level graded scale for LTPA during summer and winter time (0, <1, 1 to 2, and >2 h/wk) and for WA (none, light, medium, and heavy). The validity of the questionnaire was tested for winter activity in 45- to 64-year-old men against a 7-day activity diary. Efficiency (sensitivity plus specificity) and error rate of the interview data were 133.0% and 30.6% for LTPA and 165.9% and 17.0% for WA, respectively.²⁴ The effect of WA on plasma viscosity was analyzed in employed subjects only (1511 men and 828 women). Data on education were collected based on the highest level of formal education completed. From this information, the number of education years was calculated.

Laboratory Procedures
Blood samples were collected in tubes with EDTA (1.5 mg/mL), centrifuged at 3000g for 15 minutes, and maintained at 4°C for a maximum period of 4 days before measurement.²⁵ Plasma viscosity (mPa·s) was measured at 37°C in a Coulter-Harkness capillary viscometer.²⁶ Tests were done in triplicate, and the mean value was used for analysis. The measurement procedure and the sample preparation met the criteria of the International Committee for Standardization in Haematology.²⁷ For quality control, plasma viscosity measurements were compared daily with standard solutions. The coefficient of variation was 1.0%. There was no baseline shift during the 8-month data-collection period. At irregular intervals, duplicates were measured in a single-blind fashion. Their coefficient of variation was 2.0%, and 93% of the duplicates differed by <5%. Total and HDL cholesterol levels were measured by enzymatic methods. Lipid analyses were standardized at the WHO Lipid Quality Control Reference Laboratory in Prague.

Statistical Analysis
The data were analyzed by multiple linear regression techniques separately for each physical activity variable and separately for men and women. Plasma viscosity was used as the continuous dependent variable. A given physical activity variable was used as the categorical independent variable of interest. Additional independent variables used to control for possible confounding effects were the categorical covariables of age (the four 10-year age groups of the basic sampling design), BMI (according to Bray²³ ), total cholesterol (cutpoints recommended at the National Heart, Lung, and Blood Institute Consensus Conference²⁸ ), HDL cholesterol (35 and >35 mg/dL), hypertension (WHO categories), smoking status (never, ex-smoker, or current smoker), alcohol consumption (men: 0, <40, or 40 g/d; women: 0, <20, or 20 g/day), and the continuous variable years of formal education. Categorical variables were turned into 0/1 indicator variables in the usual way.

For the purpose of identifying possible effect modifiers, we used regression models, including all two-factor interactions that contained the independent variable of interest. From these models, we eliminated interaction effects in a backward-stepping manner with the usual P value of the interaction effect (Wald test) as the stepping criterion using a nominal 5% significance level.

For the computations, we used SAS software, version 6.10 for Windows 3.1.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Frequency of Reported Physical Activity
In Table 1, frequencies of the self-reported categories of LTPA are given for winter and summer and for categories of WA, separately for men and women. It can be seen that both men and women reported themselves to be nonactive much less frequently during summer than during winter (men: 28.5% versus 42.7%; women: 31.9% versus 48.2%). In both sexes, the increased summer activity resulted in a corresponding increase in the highest activity level (>2 h/wk) (38.2% of men and 26.8% of women). Men reported slightly more activity than did women in both seasons.

View this table: [in this window] [in a new window]   Table 1. Plasma Viscosity Means in Physical Activity Categories With Frequencies and Mean Resting Pulse Rate

For WA, the most frequent category was "medium" in both sexes, with women reporting it more frequently than men (30.9% of men versus 40.8% of women). The least frequent category was "heavy," with men reporting it almost twice as often as women (15.5% of men versus 8.7% of women).

Resting Pulse Rate and Reported Physical Activity
Table 1 shows that in men, the mean resting pulse rate (bpm) was highest in those reporting no LTPA or <1 h/wk (75.5 and 75.4 bpm in winter and in summer, respectively). It was lowest in the most active men reporting >2 h/wk (70.8 and 71.6 bpm). In women, this association was less consistent, although for LTPA during winter, again, those reporting to be most active (>2 h/wk) showed the lowest mean resting pulse rate (73.3 bpm).

For WA in men, the lowest mean resting pulse rates were seen in those reporting "no" or "light" intensity (72.7 and 72.6 bpm, respectively), and the highest rate was seen in those with "heavy" activity during work (75.7 bpm). In women, there was no clear relation between intensity of reported WA and mean resting pulse rate.

Plasma Viscosity and LTPA
Plasma viscosity mean values for LTPA were highest in those reporting no activity (Table 1) (men: 1.275 and 1.276 mPa·s; women: 1.260 and 1.266 mPa·s in winter and summer, respectively). They were lowest in the most active subjects reporting >2 h/wk (men: 1.251 and 1.252 mPa·s; women: 1.232 and 1.237 mPa·s). Note that the winter and the summer values were very close to each other. Moderate LTPA (<1 and 1 to 2 h/wk) was associated with intermediate mean values, which were identical or almost identical for a given activity variable. In men, the intermediate activity levels showed substantially lower mean values in winter than in summer. In women, this effect was less pronounced.

Tables 2 and 3 provide the differences in plasma viscosity mean values between the "nonactive" category and the category listed for men and women, respectively. Unadjusted differences are followed by differences that are regression adjusted for age and by differences that are regression adjusted for all covariables. The tables include SEM values, P values, and 95% confidence limits of the differences.

View this table: [in this window] [in a new window]   Table 2. Plasma Viscosity Mean Differences Between the `Nonactive' Physical Activity Category and the Categories Listed, Crude and Adjusted for Age and for All Covariables for Men

Plasma viscosity differences in men (Table 2) decreased appreciably when adjustment was made for age alone, both in winter and in summer. Adjustment for all covariables decreased the differences still further but left substantial differences of the same order of magnitude (close to 0.010 mPa·s) in all except one comparison. P values remained sufficiently small for all groups except for the summer "1 to 2 h/wk" group. In both seasons, those reporting >2 h/wk activity had plasma viscosity mean values that were lower than that of the nonactive group by 0.010 mPa·s (P=.009 in winter, P=.011 in summer). In women (Table 3), the results were essentially the same as in men.

View this table: [in this window] [in a new window]   Table 3. Plasma Viscosity Mean Differences Between the `Nonactive' Physical Activity Category and the Categories Listed, Crude and Adjusted for Age and for All Covariables for Women

Plasma Viscosity and WA
WA in men yielded almost identical plasma viscosity mean values in the top two categories (1.267 mPa·s in the "medium" category and 1.265 mPa·s in the "heavy" category), which were substantially larger than in the two bottom categories (1.255 mPa·s in both categories). In women, there was a graded increase from 1.232 to 1.248 mPa·s (Table 1).

Plasma viscosity differences became negligible and statistically highly nonsignificant in both sexes after controlling for all covariables (Tables 2 and 3).

Effect Modifiers
No meaningful effect modifiers were obtained for either physical activity variable.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We investigated the association between plasma viscosity and physical activity in a large random sample of the general population. Although we analyzed a subsample of the original sample, it seems safe to neglect potential selection bias since basic distributional statistics of the variables used in our study, published elsewhere,²⁹ did not materially deviate from those of the original random sample.²¹

LTPA
Our findings suggest that LTPA in both sexes is inversely associated with plasma viscosity independent of classic cardiovascular risk factors.

The scale for self-reported intensity of LTPA comprised the four categories 0, 0 to 1, 1 to 2, and >2 h/wk with separate recordings of winter and summer activities. We kept these variables separate because data were gathered during winter time and therefore the responses regarding winter LTPA might be more reliable than those collected for summer LTPA.

The unadjusted plasma viscosity mean values in these categories seemed to suggest a graded response, perhaps with similar intermediate categories. However, the significance levels for the differences of adjacent categories were much too large to support this observation. After adjustment for age and even more so after adjustment for all covariables, the differences of adjacent mean values became too small and the associated P values too large to warrant the distinction between the second through fourth categories.

This lack of a graded response might indicate the lack of sensitivity of the questionnaire in discrimination between subtle differences in self-reported LTPA. Formal validation of the questionnaire against a 7-day activity diary in 45- to 64-year-old men was done only for LTPA during winter. Mean resting pulse rate, as a surrogate marker of physical fitness,³ was slightly lower with increasing duration of LTPA in men in both seasons (P<.0005 for linear trend), which would support the validity of the questionnaire. In women, however, such an inverse association was less clear during winter LTPA (P=.10), and no such relation could be seen for summer LTPA (P=.34). For WA in men, there was a positive association between categories of increasing activity and resting pulse rate (P<.005 for linear trend), whereas in women, no association was found (P=.32).

The amount by which plasma viscosity mean values in our data were found to be lower in physically active subjects than in nonactive ones (0.01 mPa·s) could have considerable implications for public health strategies. In men, according to data from the Caerphilly and Speedwell studies,³⁰ a difference of 0.010 mPa·s is associated with a change of 4% in CHD incidence with the use of their model 2 results excluding fibrinogen and white blood cell count (personal communication, P.M. Sweetnam, MRC Epidemiology Unit, Llandough Hospital, Penarth, South Glamorgan, CF64 2XW, UK). A study in which MONICA Augsburg data were compared with data from the Glasgow MONICA²⁹ resulted in an adjusted plasma viscosity mean difference between the West of Scotland and Augsburg of 0.064 mPa·s (95% confidence interval, 0.056 to 0.071 mPa·s). At about the same time that these data were collected, men in the Glasgow MONICA area had approximately twice as high a risk of CHD than did men in the Augsburg region. With simple linear interpolation, one would be led to estimate the effect of a reduction of plasma viscosity by 0.010 mPa·s as a reduction of CHD incidence by almost 16%.

Similar effects of LTPA can be found on fibrinogen. Several large cross-sectional studies^{14 15 31 32 33 34} have all reported an inverse association between LTPA and plasma fibrinogen, the main determinant of plasma viscosity. Smaller longitudinal studies in healthy adults,^{35 36} claudicants,³⁷ and patients after coronary artery surgery³⁸ have supported these findings. Therefore, results from fibrinogen studies may be used to support plasma viscosity findings.

Thus, Connelly et al¹⁴ found that men reporting strenuous exercise and men not exercising differed by an amount of fibrinogen (0.10 g/L) that according to results from the Northwick Park Heart Study³⁹ would alter the risk of a major event of ischemic heart disease by 15%.

In women, fewer data on the association between regular LTPA and fibrinogen levels have been published,³² and no data on LTPA and plasma viscosity are available. The present data indicate that the direction and the magnitude of the effect of exercise on plasma viscosity are as large as in men.

Mechanisms of Action
The beneficial effect of regular LTPA on plasma viscosity is the result of several mechanisms. Physical exercise is known to lead to an expansion of plasma volume.^{40 41 42} The lack of an inverse association of total serum protein and hemoglobin with LTPA in our study population (data not presented) suggests that chronic hemodilution is not the major contributor to the reduction of plasma viscosity. However, both parameters might have been less sensitive than plasma viscosity, and the range of physical activity was relatively small. Furthermore, hemodilution may have been counteracted by a simultaneous increase in hematopoesis during long-term training. Regular physical activity is associated with a degree of red blood cell destruction that could stimulate hematopoesis.⁴³

A decrease in fibrinogen has also been observed with regular endurance training in several studies.^{14 15 32 34 35} This would inevitably lead to a decrease in plasma viscosity. In the final analysis, the mechanism or mechanisms by which endurance exercise leads to decreased fibrinogen remain unclear. Finally, a more speculative alternative hypothesis includes the presence of less inflammatory activity in active persons. This notion is supported by the fact that regular activity is associated with decreased leukocyte counts.⁷

WA
In employed men (n=1511) and women (n=828), WA was associated with increased plasma viscosity in unadjusted analyses. Although this effect was of a graded nature in unadjusted analyses in women, this was not the case in men. After adjustment for all covariables, no material mean differences remained between those reporting any category of WA and those being physically inactive during work.

There is no clear explanation for these findings. Results from a longitudinal study in the same cohort showed that higher WA was not associated with decreased incidences of myocardial infarction and total mortality.⁴⁴ One might speculate that psychosocial stress, resulting in an increased vasomotor tone, might lead to a constriction of plasma volume, thereby increasing plasma viscosity.⁴⁵ However, this mechanism would result in an increase in hematocrit (or hemoglobin), and this was not observed in our study. Job strain (eg, high demand, low control) has been found to be associated with increased levels of plasma fibrinogen.⁴⁶

The validity of the questionnaire assessing WA had been tested against a 7-day activity diary. Although it consisted of only one question, the agreement between both instruments was judged to be satisfying.²⁴ However, it cannot be excluded that distinguishment by type of activity might have influenced our results.

Regular Physical Activity and Cardiovascular Risk
In a meta-analysis, a protective effect of regular LTPA on morbidity and mortality of CHD could be shown.⁴⁷ Less convincing data are available for WA; this might be due to measurement problems (eg, only 6 of 18 occupational studies had high-quality scores in contrast to all of the nonoccupational studies).⁴⁷

The mechanisms through which the positive effect of endurance exercise on cardiovascular morbidity and mortality^{1 2 3 4 5 6 7 8} as well as on total mortality^{9 10 11 48 49} are mediated remain speculative. Recent data from the 23-year follow-up of the Honolulu Heart Program¹³ suggest that the impact of physical activity on CHD may be exclusively attributable to its effects on smoking, hypertension, diabetes, cholesterol, and BMI, yet in the Lipid Research Clinics Mortality Follow-up Study,³ adjustment for conventional cardiovascular risk factors only slightly reduced the relative risk of death from cardiovascular causes. This suggests that other factors, possibly thrombotic or rheological mechanisms, might play a role.

Increased levels of fibrinogen as well as plasma viscosity are positively associated with various cardiovascular risk factors^{50 51 52 53} ; furthermore, both variables have been shown to predict cardiovascular mortality and morbidity independent of other risk factors.^{30 54 55}

Conclusions
The results of the present study have shown an inverse association between LTPA and plasma viscosity. Because plasma viscosity has been found to be predictive of CHD morbidity and mortality, its decrease may at least in part account for the beneficial effect of regular LTPA observed in several longitudinal studies.

	Selected Abbreviations and Acronyms

 

BMI = body mass index BP = blood pressure CHD = coronary heart disease LTPA = leisure-time physical activity MONICA Project = Multinational Monitoring of Trends and Determinants in Cardiovascular Disease WA = work activity WHO = World Health Organization

Received June 26, 1996; revision received August 26, 1996; accepted September 4, 1996.

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51. Folsom A. Epidemiology of fibrinogen. Eur Heart J. 1995;16(suppl A):21-24.

52. Koenig W, Sund M, Ernst E, Keil U, Rosenthal J, Hombach V. Association between plasma viscosity and blood pressure: results from the MONICA-Project Augsburg. Am J Hypertens. 1991;4:529-536.[Medline] [Order article via Infotrieve]

53. Koenig W, Sund M, Ernst E, Mraz W, Hombach V, Keil U. Association between rheology and components of lipoproteins in human blood: results from the MONICA-Project Augsburg. Circulation. 1992;85:2197-2204.[Abstract/Free Full Text]

54. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993;118:956-963.[Abstract/Free Full Text]

55. Koenig W, Hombach V, Ernst E, Sund M, Mraz W, Keil U. Plasma viscosity as a cardiovascular risk factor. Circulation. 1992;85:1045. Letter.

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