Extrapulmonary Effects of Chronic Obstructive Pulmonary Disease on Physical Activity

A Cross-sectional Study
Henrik Watz1, Benjamin Waschki1, Corinna Boehme1, Martin Claussen2, Thorsten Meyer3, and Helgo Magnussen1,2
1 3

Pulmonary Research Institute, 2Center for Pneumology and Thoracic Surgery, Hospital Grosshansdorf, Grosshansdorf, Germany; and Institute of Social Medicine, Medical University Luebeck, Luebeck, Germany

Rationale: Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD). COPD has a systemic component that includes signicant extrapulmonary effects that may contribute to its severity in individual patients. Objectives: To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD. Methods: In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages IIV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 010) underwent a series of tests. Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal proB-type natriuretic peptide. Mental status, metabolic/muscular status, systemic inammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/brinogen, and hemoglobin, respectively. Measurements and Main Results: In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inammation. Conclusions: Higher values of systemic inammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD. Keywords: pulmonary disease, chronic obstructive; ventricular function, left; acute phase reaction; activities of daily living

AT A GLANCE COMMENTARY
Scientic Knowledge on the Subject

Physical activity is reduced in patients with moderate to severe chronic obstructive pulmonary disease compared with healthy subjects.
What This Study Adds to the Field

Higher values of systemic inammation and left cardiac dysfunction are associated with reduced physical activity in patients with chronic obstructive pulmonary disease.

Physical activity is a parameter of increasing clinical interest. Lower levels of physical activity are associated with a higher risk for diseases such as cardiovascular disease (1), type 2 diabetes mellitus (2), mental disorders (3, 4), cancer (5), and chronic obstructive pulmonary disease (COPD) (6). In COPD, regular physical activity modies smoking-related lung function decline and is associated with lower mortality (6, 7).

COPD has been dened as a preventable and treatable disease with signicant extrapulmonary effects that may contribute to its severity in individual patients (8). Cardiovascular, mental, and musculoskeletal comorbidities, as well as elevated markers of systemic inammation and anemia, can frequently be found in patients with COPD and have an impact on mortality in this population (912). Physical activity has been shown to be reduced in patients with COPD (13, 14). We hypothesized that this reduction in physical activity may be explained by the extrapulmonary effects of COPD and its comorbidities. Thus, the rationale of our study was to assess the association of extrapulmonary effects and comorbidities in patients with COPD with reduced physical activity as measured by an accelerometer. We used multivariate linear regression analysis, the clinical stages of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (8), and the BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) index (15) to analyze the data. We previously presented the methodologic aspects of accelerometer measurement in abstract form in this journal (16).

METHODS
Study Population
One hundred seventy outpatients with stable COPD (128 male, 42 female) were studied between February and November 2006 at the Pulmonary Research Institute at Hospital Grosshansdorf, SchleswigHolstein, Germany. Patients were recruited from the institutes database that is used for clinical trials in COPD; it consists of 691 ambulatory patients with an established diagnosis of COPD (mean FEV1, 54% predicted; mean age, 62 yr). Patients were contacted by a study nurse, and those who expressed their availability and interest in the study were enrolled. Exclusion criteria were an exacerbation of COPD within the past 2 months, clinical signs of acute heart failure, and severe pain syndromes that could interfere with physical activity. The study was approved by the local ethics committee of SchleswigHolstein, and participants gave their written, informed consent.

(Received in original form July 10, 2007; accepted in nal form November 29, 2007 ) Supported by an unrestricted research grant from AstraZeneca. The funding source had no role in the study design, collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Correspondence and requests for reprints should be addressed to Prof. Dr. Helgo Magnussen, M.D., Pulmonary Research Institute at Hospital Grosshansdorf, Center for Pneumology and Thoracic Surgery, Woehrendamm 80, D-22927 Grosshansdorf, Germany. E-mail: magnussen@pulmoresearch.de This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 177. pp 743751, 2008 Originally Published in Press as DOI: 10.1164/rccm.200707-1011OC on November 29, 2007 Internet address: www.atsjournals.org

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Clinical Stages of COPD

Patients were classied according to the GOLD staging system (8) and the criteria of the BODE index (15). The BODE index was designed to predict mortality in patients with COPD and has a range of 0 to 10 points, with higher scores indicating a greater risk of death (15).

Assessment of Potential Confounders of Physical Activity

Because of the potential interaction of lifestyle with physical activity (2325), we also assessed alcohol consumption (drinks per week) and current smoking status. Educational status, which is positively correlated with leisure time physical activity (26), was also assessed. Patients quoting pain symptoms that interfered with general activity on the interference with function scale of the Brief Pain Inventory (27) were recorded. Because a history of diabetes mellitus has been shown to be a determinant of low physical activity in COPD (28), it was also recorded.

Cardiovascular Status and Systemic Inammation

Echocardiography was performed to measure systolic left heart function (left ventricular ejection fraction), diastolic left heart function (deceleration time of the early transmitral ow and ratio of the peak velocity of the early E-wave to atrial A-wave), and systolic pulmonary artery pressure. N-terminal proB-type natriuretic peptide (NTproBNP) was used as a systemic biomarker of heart failure (17). Vascular Doppler sonography was performed to assess the ankle brachial index, which is an accurate measurement of peripheral arterial disease (18). High-sensitivity C-reactive protein (hs-CRP) and brinogen served as markers of systemic inammation.

Statistical Analysis
Differences between patients in different GOLD stages were analyzed by x2 test (categorical variables), Kruskal-Wallis test (ordinal or nonnormal metric variables), and analysis of variance (normally distributed metric variables). Skewed data were log transformed to yield normal distributions. Multivariate linear regression analyses were performed using either the physical activity level or steps per day as the dependent variable. It was the aim of this analysis to identify extrapulmonary factors that are associated with reduced physical activity independent of the clinical stages of COPD. Therefore, after controlling for possible confounders, a stepwise approach to model building was applied. In a rst step, age, sex, obesity (BMI > 30 kg/m2), and arterial hypertension were included in the model independent of statistical signicance. The potential confounders (drinks per week, smoking status, educational status, pain symptoms, and history of diabetes mellitus) were included in the model if they were of statistical signicance (P , 0.05). No adjustment for retirement, early retirement, or employment status was made, as these conditions could also be the result of disease severity. As a second step, GOLD stages or BODE index were included in the model. As a third step, extrapulmonary variables (left ventricular ejection fraction, deceleration time of the early transmitral ow or ratio of the peak velocity of the early E-wave to atrial A-wave, systolic pulmonary artery pressure, NTpro-BNP, ankle brachial index, brinogen or hs-CRP, nutritional depletion, muscle strength, and anemia) were added to the model if they were of statistical signicance. All extrapulmonary parameters that were shown to be signicant at this step of analysis were included in the nal multivariate regression model. For each level (confounders, disease severity represented by GOLD stages or BODE index, extrapulmonary factors), the amount of variance (R2) was calculated. Metric variables were not centered. GOLD stages were dummycoded with GOLD I as a reference category. BODE index was categorized by quintiles and dummy-coded with the rst quintile as the reference category. Data analysis was performed with the Statistical Package for Social Science, version 14.0 (SPSS, Chicago, IL).

Mental Status
The Beck Depression Inventory was used to assess depressive symptoms. Depression was dened as a Beck Depression Inventory score of 15 or greater (19).

Metabolic and Muscular Status

Body mass index (BMI; weight in kg/height in m2) and fat-free mass index (fat-free mass in kg/height in m2; measured by bioelectrical impedance analysis) were determined. Nutritional depletion was dened as a BMI of 21 kg/m2 or less or a fat-free mass index of 16 kg/m2 or less in men and 15 kg/m2 or less in women (20). Peripheral muscle strength was measured with a handgrip dynamometer.

Anemia
Hemoglobin levels were determined in tubes containing ethylenediaminetetraacetic acid. Anemia was dened as a hemoglobin level below 13 g/dl (12).

Physical Activity
Physical activity was measured over 5 to 6 consecutive days using a multisensor armband (SenseWear Pro Armband; BodyMedia, Inc., Pittsburgh, PA) that is worn on the upper right arm over the triceps muscle. It incorporates a biaxial accelerometer that records steps per day, and physiologic indicators of energy expenditure that enable the investigator to determine the physical activity level. We determined the physical activity level by dividing total daily energy expenditure by whole-night sleeping energy expenditure (21). A physical activity level of 1.70 or greater is dened as active, and a physical activity level greater than 1.78 is strongly associated with a lower risk of mortality in healthy older adults (22). A more detailed description of the applied clinical methods and the accelerometer measurement is contained in the online supplement.

RESULTS
Characteristics of patients, measurements of physical activity, and extrapulmonary parameters are given in Tables 1 to 3. A

TABLE 1. PATIENT CHARACTERISTICS

Total Patients, n (%) Age, yr, mean (SD) Males, n (%) Pack-years of smoking, mean (SD) Current smokers, n (%) Regular drinkers, n (%) Drinks per week of regular drinkers, median (IQR) Retired or early retired, n (%) Unemployed, n (%) University entrance degree, n (%) 170 (100) 64.0 (6.6) 128 (75) 51.9 (24.8) 72 (42) 79 (46) 5 (212) 133 (78) 16 (9) 16 (9) GOLD I 34 (20) 66.3 (5.6) 25 (74) 46.9 (26.6) 15 (44) 17 (50) 4 (27) 27 (79) 3 (9) 3 (9) GOLD II 57 63.3 41 50.7 27 29 5 (34) (6.8) (72) (27.0) (47) (51) (210) GOLD III 43 63.2 35 55.6 23 22 5.5 (25) (7.3) (81) (23.4) (53) (51) (214) GOLD IV 36 (21) 63.7 (6.2) 27 (75) 54.0 (20.5) 7 (19) 11 (31) 9.5 (314) 33 (92) 2 (6) 2 (6) P Value* 0.15 0.74 0.44 ,0.01 0.20 0.83 0.11 0.81 0.76

40 (70) 6 (11) 7 (12)

33 (77) 5 (12) 4 (9)

Denition of abbreviations: GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; IQR 5 interquartile range. * P values were tested by analysis of variance if the variable is stated as mean (SD) or by x2 test if the variable is stated as n (%); P value for drinks per week was tested by Kruskal-Wallis test, as the variable was skewed.

Watz, Waschki, Boehme, et al.: Physical Activity in COPD TABLE 2. LUNG FUNCTION, BODE SCORE, AND PHYSICAL ACTIVITY
Total FVC, % pred, mean (SD) FEV1, % pred, mean (SD) FEV1/FVC, mean (SD) Capillary PO2, mm Hg Capillary PCO2, mm Hg BODE score, median (IQR) Steps per day, mean (SD) Physical activity level, mean (SD) Physical activity level > 1.70,x n (%) 91.9 (21.9) 56.3 (22.2) 48.0 (13.2) 68.9 (7.8) 38.3 (4.6) 2 (14) 5,882 (3,684) 1.50 (0.28) 37 (22) GOLD I 114.2 (14.8) 90.0 (8.7) 62.9 (6.7) 71.0 (6.7) 36.0 (3.8) 0 (0 - 0) 7,990 (3,370) 1.63 (0.25) 9 (26) GOLD II 96.3 63.0 53.2 71.5 37.7 1 7,160 1.62 18 (16.1) (8.1) (9.4) (7.7) (3.8) (1, 2) (3,284) (0.27) (32) GOLD III 84.7 (16.0) 40.6 (5.0) 39.1 (8.3) 69.5 (6.1) 38.0 (3.2) 3 (24) 5,126 (3,692) 1.45 (0.25) 9 (21) GOLD IV 72.8 32.8 36.2 60.4 42.6 6 2,773 1.27 1 (20.7) (11.4) (8.6) (5.8) (6.1) (47) (1,897) (0.17) (3)

745

P Value* ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.01

Denition of abbreviations: BODE 5 body mass index, airway obstruction, dyspnea, and exercise capacity; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; IQR 5 interquartile range. * P values were tested by analysis of variance if the variable is stated as mean (SD) or by x2 test if the variable is stated as n (%); P value for BODE score was tested by Kruskal-Wallis test, as the variable was skewed; P values for FEV1 and steps per day were tested by Kruskal-Wallis test, as the homogeneity of variance was not given. Data are missing for seven patients. Physical activity level is dened as total daily energy expenditure divided by whole-night sleeping energy expenditure. x Physical activity level > 1.70 is dened as active.

more detailed description of patients characteristics can be found in the online supplement (Tables E1 and E2). Twenty-two percent of the patients had a physical activity level of 1.70 or greater (Table 2). Results of the multivariate analysis for the physical activity level are given in Tables 4 and 5: The total explained variance of the physical activity level (total R2) was 37% for the model that included GOLD stages plus extrapulmonary effects and 36% for the model that included BODE score plus extrapulmonary effects. GOLD stages or BODE score accounted for two-thirds of the explained variance of the physical activity level. The extrapulmonary factors that signicantly contributed to the model independently of GOLD stage or BODE score were NTpro-BNP, diastolic left ventricular function, and systemic inammation. Together, they accounted for another third of the explained variance of the
TABLE 3. MEASUREMENTS OF EXTRAPULMONARY PARAMETERS*
Total Cardivascular disease Left ventricular ejection fraction < 50%, n (%) Deceleration time of the E-wave, ms, mean (SD) E-wave/A-wave, median (IQR) Systolic pulmonary artery pressure, mm Hg, mean (SD) NTpro-BNP, pg/ml, median (IQR) NTpro-BNP . 125 pg/ml, n (%) Ankle brachial index, mean (SD) Ankle brachial index , 0.9, n (%) Systemic inammation Fibrinogen, mg/dl, mean (SD) hs-CRP, mg/L, median (IQR) Mental status Beck Depression Inventory > 15, n (%) Metabolic status Body mass index, kg/m2, mean (SD) Fat-free mass index, kg/m2, mean (SD) Nutritional depletion, n (%) Muscle strength Handgrip strength, kg, mean (SD) Anemia Hemoglobin, g/dl, mean (SD) Hemoglobin , 13 g/dl, n (%) 5 262 0.90 30.6 67 39 0.97 43 (3) (56) (0.791.02) (7.3) (40117) (23) (0.20) (25)

physical activity level. Deceleration time of the early transmitral ow had a stronger effect on the model than did the ratio of the peak velocity of the early E-wave to atrial A-wave (Tables 4 and 5). Fibrinogen had a stronger effect than hs-CRP (Tables 4 and 5). Similar results of the multivariate analysis for steps per day are given in Tables 6 and 7. Figures 1A1F depict the impact of the extrapulmonary effects that were signicant in the multivariate analysis on steps per day according to the clinical stages provided by GOLD and BODE. Arterial hypertension did not affect echocardiographic parameters of diastolic function of the left ventricle in our cohort (deceleration time of the early transmitral ow, P 5 0.72 for hypertension vs. no hypertension; log ratio of the peak velocity of the early E-wave to atrial A-wave, P 5 0.6 for hypertension vs. no hypertension).

GOLD I 3 (9) 256 (51) 0.92 (0.791.04) 29.9 (7.1) 69 (47102) 7 (21) 0.99 (0.19) 8 (24) 395 (64) 2.0 (0.94.3) 5 (15) 27.0 (4.2) 18.3 (2.5) 4 (12) 36.3 (11.8) 14.7 (1.0) 2 (6)

GOLD II 1 250 0.92 29.8 62 12 0.99 11 (2) (55) (0.841.04) (6.5) (38108) (21) (0.20) (19)

GOLD III 1 (2) 253 (48) 0.89 (0.791.05) 31.8 (6.2) 67 (36117) 10 (23) 0.97 (0.20) 10 (23) 468 (115) 4.0 (1.89.4) 8 (19) 25.0 (5.0) 17.8 (2.9) 11 (28) 36.6 (9.7) 15.1 (0.9) 0 (0)

GOLD IV 0 299 0.82 30.9 73 10 0.91 14 (0) (59) (0.700.93) (9.5) (46130) (28) (0.22) (39)

P Value 0.15 ,0.001 0.03 0.66 0.78 0.87 0.23 0.19 ,0.01 ,0.01 ,0.01 ,0.01 0.19 0.06 0.45 0.19 0.04

436 (97) 2.8 (1.26.0) 33 (19) 26.3 (5.2) 18.1 (2.7) 35 (21) 35.3 (9.6) 14.9 (1.2) 9 (5)

431 (98) 3.0 (1.66.0) 5 (9) 27.8 (5.3) 18.6 (2.7) 8 (14) 34.8 (8.7) 15.0 (1.3) 2 (4)

444 (89) 2.1 (0.854.35) 15 (42) 24.6 (5.3) 17.4 (2.8) 12 (33) 33.4 (8.5) 14.6 (1.4) 5 (14)

Denition of abbreviations: GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; hs-CRP 5 high-sensitivity C-reactive protein; IQR 5 interquartile range; NT pro-BNP 5 N-terminal proB-type natriuretic peptide. * Data are missing for the following variables: left ventricular ejection fraction (n 5 3), E-wave/A-wave (n 5 8), deceleration time of the E-wave (n 5 12), systolic pulmonary artery pressure (n 5 47), nutritional depletion (n 5 5), and handgrip strength (n 5 1). P values were tested by analysis of variance if the variable is stated as mean (SD) or by x2 test if the variable is stated as n (%); P values for E-wave/A-wave, NTproBNP and hs-CRP were tested by Kruskal-Wallis test, as the variables were skewed; P value for hemoglobin was tested by Kruskal-Wallis test, as the homogeneity of variance was not given. Nutritional depletion was dened as body mass index < 21 kg/m2 and/or fat-free mass index <16 kg/m2 in men and <15 kg/m2 in women.

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177 TABLE 4. GOLD STAGES AND EXTRAPULMONARY PARAMETERS AS PREDICTORS OF PHYSICAL ACTIVITY LEVEL IN A MULTIVARIATE LINEAR REGRESSION ANALYSIS (n 5 158 PATIENTS)
Unstandardized Regression Coefcients Predictive Parameter Constant Female sex Age, yr Hypertension BMI > 30 GOLD stage II III IV Fibrinogen,* mg/dl log NTpro-BNP, pg/ml DcT, ms B 2.252 0.065 ,0.001 0.055 0.048 20.009 20.128 20.263 20.001 20.049 20.001 SE 0.233 0.047 0.003 0.043 0.050 0.052 0.058 0.061 ,0.001 0.022 ,0.001 95% CI Lower Bound 1.792 20.027 20.006 20.030 20.051 20.111 20.242 20.384 20.001 20.093 20.002 Upper Bound 2.712 0.157 0.007 0.139 0.146 0.093 20.014 20.142 ,0.000 20.006 ,0.000 P Value ,0.001 0.16 0.91 0.20 0.34 0.86 0.028 ,0.001 0.001 0.026 0.004 R2 0.02 R2 Change 0.02

2008

0.26

0.24

0.37

0.11

Denition of abbreviations: BMI 5 body mass index; CI 5 condence interval; DcT 5 deceleration time of the early transmitral ow; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; NTpro-BNP 5 N-terminal proB-type natriuretic peptide. The table can be interpreted as follows: Sex, age, arterial hypertension and BMI > 30 account for 2% of the variance for the physical activity level (R2 change, 0.02), GOLD accounts for 24% of the variance for the physical activity level (R2 change, 0.24), and extrapulmonary effects account for an additional 11% of the variance (R2 change, 0.11). Total explained variance of the model is 37% for physical activity level (R2, 0.37) with the parameters used in this model. A value of 0.001 for the unstandardized regression coefcient B for brinogen means that, per milligram increase of brinogen, a patient has a reduction of physical activity level of 0.001. A value of 0.001 for the unstandardized regression coefcient B for DcT means that, per millisecond increase of DcT, a patient has a reduction of physical activity level of 0.001. * log high-sensitivity C-reactive protein instead of brinogen is also signicant (unstandardized regression B, 0.068; SE, 0.024; P 5 0.005; n 5 162). log E-wave/A-wave ratio instead of DcT is also signicant (unstandardized regression B, 0.197; SE, 0.094; P 5 0.037; n 5 162).

A weak but signicant correlation between NTpro-BNP and measurements of echocardiography was for left atrial size and NTpro-BNP (r 5 0.36, P , 0.001).

DISCUSSION
The main nding of our study is that higher values of systemic inammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD, independent

of the clinical stages of COPD according to GOLD or the multidimensional BODE index. Physical activity has previously been shown to be reduced in patients with moderate to severe COPD compared with healthy subjects (13, 14). Airway obstruction, however, correlates only weakly (14) to moderately (13, 29) with physical activity, which implies that there might be additional factors inuencing physical activity in patients with COPD. Garcia-Aymerich and coworkers found further determinants of physical activity in a

TABLE 5. BODE SCORE AND EXTRAPULMONARY PARAMETERS AS PREDICTORS OF PHYSICAL ACTIVITY LEVEL IN A MULTIVARIATE LINEAR REGRESSION ANALYSIS (n 5 158 PATIENTS)
Unstandardized Regression Coefcients Predictive Parameter Constant Female sex Age, yr Hypertension BMI > 30 BODE score Quintile 2 Quintile 3 Quintile 4 Quintile 5 Fibrinogen,* mg/dl log NTpro-BNP, pg/ml DcT, ms B 2.268 0.070 0.001 0.054 0.080 20.073 20.065 20.119 20.282 20.001 20.048 20.001 SE 0.234 0.047 0.003 0.043 0.048 0.057 0.058 0.059 0.061 ,0.001 0.023 ,0.001 95% CI Lower Bound 1.807 20.023 20.005 20.032 20.016 20.186 20.181 20.235 20.403 20.001 20.093 20.002 Upper Bound 2.730 0.163 0.008 0.139 0.176 0.040 0.050 20.003 20.160 ,0.000 20.003 ,0.000 P Value ,0.001 0.14 0.75 0.22 0.10 0.21 0.27 0.044 ,0.001 ,0.001 0.035 0.002 R2 0.02 R2 Change 0.02

0.22

0.20

0.36

0.14

Denition of abbreviations: BMI 5 body mass index; BODE 5 body mass index, airway obstruction, dyspnea, and exercise capacity; CI 5 condence interval; DcT 5 deceleration time of the early transmitral ow; NTpro-BNP 5 N-terminal proB-type natriuretic peptide. * log high-sensitivity C-reactive protein instead of brinogen is also signicant (unstandardized regression B, 0.073; SE, 0.024; P 5 0.002; n 5 162). log E-wave/A-wave ratio instead of DcT is also signicant (unstandardized regression B, 0.211; SE, 0.097; P 5 0.032; n 5 162). For interpretation of the table, please refer to the footnote for Table 4. For an explanation of BODE quintiles, see the legend to Figure 1.

Watz, Waschki, Boehme, et al.: Physical Activity in COPD TABLE 6. GOLD STAGES AND EXTRAPULMONARY PARAMETERS AS PREDICTORS OF STEPS PER DAY IN A MULTIVARIATE LINEAR REGRESSION ANALYSIS (n 5 158 PATIENTS)
Unstandardized regression coefcients Predictive Parameter Constant Female sex Age, yr Hypertension BMI > 30 GOLD stage II III IV Fibrinogen,* mg/dl log NTpro-BNP, pg/ml DcT, ms B 20,726 518 259 501 2859 2939 22,714 24,272 27 2677 215 SE 2,936 587 41 537 630 652 729 774 3 277 5 95% CI Lower Bound 14,925 2642 2141 2561 22,104 22,226 24,155 25,801 212 21,225 224 Upper Bound 26,528 1,678 23 1,563 385 349 21,273 22,742 22 2130 26 P Value ,0.001 0.38 0.16 0.35 0.18 0.15 ,0.001 ,0.001 0.006 0.016 0.001 R2 0.04 R2 Change 0.04

747

0.32

0.28

0.41

0.09

For denition of abbreviations, see Table 4. * log high-sensitivity C-reactive protein instead of brinogen is also signicant (unstandardized regression B, 767; SE, 299; P 5 0.011). log E-wave/A-wave ratio instead of DcT is also signicant (unstandardized regression B, 2,993; SE, 1,179; P 5 0.012; n 5 162). For interpretation of the table, please refer to the legend for Table 4.

cohort of 346 patients with severe COPD (FEV1, 35% predicted) (28). Using the Minnesota Leisure Time Physical Activity Questionnaire, they found that socioeconomic status, history of diabetes, health-related quality of life, and long-term oxygen therapy were independently associated with a low level of physical activity. Our study extended these observations by objectively quantifying systemic components of COPD (10) and their associations with reduced physical activity. Left heart failure is present in 20% of elderly patients with COPD (30). In about 50% of these patients, left ventricular diastolic dysfunction causes the symptoms of heart failure (30). Even without symptoms of heart failure, diastolic dysfunction of the left ventricle in COPD is a frequently reported echocardiographic observation (31). Here we show for the rst time that echocardiographic parameters indicating impaired diastolic

lling processes of the left ventricle are associated with reduced physical activity in patients with COPD. Twenty-three percent of our cohortnearly 30% of the patients with GOLD stage IV diseasehad NTpro-BNP levels greater than 125 pg/ml, which is an accepted threshold that indicates potential heart failure in patients with COPD (17). NTpro-BNP values showed a weak correlation with left atrial size, which is known in patients with stable chronic left heart failure (32) and may reect chronic left ventricular lling pressure (33). An increased left ventricular lling pressure leads to an increase in left ventricular wall stretch, which is the predominant pathophysiologic process underlying increased circulating levels of NTpro-BNP (34). Higher levels of NTproBNP were associated with reduced physical activity in our patients.

TABLE 7. BODE SCORE AND EXTRAPULMONARY PARAMETERS AS PREDICTORS OF STEPS PER DAY IN A MULTIVARIATE LINEAR REGRESSION ANALYSIS (n 5 158 PATIENTS)
Unstandardized Regression Coefcients Predictive Parameter Constant Female sex Age, yr Hypertension BMI > 30 BODE score Quintile 2 Quintile 3 Quintile 4 Quintile 5 Fibrinogen,* mg/dl log NTpro-BNP, pg/ml DcT, ms B 20,175 600 252 514 2589 2982 21,365 22,646 24,874 28 2617 214 SE 2,833 570 40 524 588 693 710 711 745 2 273 4 95% CI Lower Bound 14,575 2527 2132 2522 21,751 22,352 22,767 24,052 26,346 213 21,158 223 Upper Bound 25,774 1,727 28 1,549 574 388 38 21,240 23,401 24 277 25 P Value ,0.001 0.30 0.20 0.33 0.32 0.16 0.06 ,0.001 ,0.001 0.001 0.025 0.002 R2 0.04 R2 change 0.04

0.35

0.31

0.45

0.10

For denition of abbreviations, see Table 5. * log high-sensitivity C-reactive protein instead of brinogen is also signicant (unstandardized regression B, 869; SE, 284; P 5 0.003). log E-wave/A-wave ratio instead of DcT is also signicant (unstandardized regression B, 2,698; SE, 1,168; P 5 0.022; n 5 162). For interpretation of the table, please refer to the legend for Table 4. For explanation of BODE quintiles, see the legend to Figure 1.

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Figure 1. (A) Steps per day according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages and brinogen level. The mean brinogen level in our cohort was 436 mg/dl. Two-way analysis of variance (ANOVA): main effect GOLD, P , 0.001; main effect brinogen, P 5 0.02; interaction effect GOLD 3 brinogen, P 5 0.57. (B) Steps per day according to BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) score and brinogen level. BODE quintile 1: BODE score 0, n 5 41 (24%); BODE quintile 2: BODE score 1, n 5 33 (19%); BODE quintile 3: BODE score 2, n 5 31 (18%); BODE quintile 4: BODE score 3 1 4, n 5 32 (19%); BODE quintile 5: BODE score 510, n 5 33 (19%). Twoway ANOVA: main effect BODE, P , 0.001; main effect brinogen, P , 0.01; interaction effect BODE 3 brinogen, P 5 0.90. (C) Steps per day according to GOLD stages and N-terminal proB-type natriuretic peptide (NTpro-BNP) level. The median NTpro-BNP level in our cohort was 67.3 pg/ml. Two-way ANOVA: main effect GOLD, P , 0.001; main effect NTpro-BNP, P 5 0.04; interaction effect GOLD 3 NTpro-BNP, P 5 0.80. (D) Steps per day according to BODE score and NTpro-BNP level. See (B) for explanation of BODE quintiles. Two-way ANOVA: main effect BODE, P , 0.001; main effect NTpro-BNP, P 5 0.04; interaction effect BODE 3 NTpro-BNP, P 5 0.76. (E) Steps per day according to GOLD stages and

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We did not nd a relationship between physical activity and systolic pulmonary artery pressure estimated by Doppler echocardiography. Doppler echocardiography, however, is of limited value in accurately assessing pulmonary hypertension in patients with advanced lung diseases (35). Furthermore, we could only measure systolic pulmonary artery pressure in 72% of our patients (see Table 3 and the online supplement). The ankle brachial index is a noninvasive, reliable measure of peripheral arterial disease (18) and is a strong predictor for cardiovascular morbidity and mortality in the general population (36). Values less than 0.9 indicate peripheral arterial disease (18). In patients with values less than 0.5, physical activity is reduced, whereas mild to moderate peripheral arterial disease (ankle brachial index, 0.50.9) is not associated with reduced physical activity (18). On the basis of the values less than 0.9, we observed a frequency of peripheral arterial disease of 25% in our cohortnearly 40% in patients with GOLD stage IV. Only 3% of our patients had values less than 0.5. The presence of peripheral arterial disease was not associated with reduced physical activity in our cohort. Systemic inammation is present in patients with COPD and has an impact on mortality in this population (37, 38). Furthermore, higher values of hs-CRP are associated with a reduced exercise capacity in patients with COPD (39, 40). It is known from epidemiologic studies that people who report less physical activity have higher values for markers of systemic inammation (41). Here we conrm with accelerometer data the association between physical inactivity and systemic inammation. Depression is a frequent comorbidity in patients with COPD (19). We found depression to be prevalent in nearly 20% of our patients according to the Beck Depression Inventory42% of patients with GOLD stage IV disease. Our prevalence data are similar to those from a previous study using the same test (19). Depression was not associated with reduced physical activity in our cohort. The frequency of nutritional depletion in our cohort paralleled GOLD stages, with an overall prevalence of 21%. In a previous study, which included patients with GOLD stages II and III COPD, the prevalence of nutritional depletion was 27% (20). Nutritional depletion was not associated with reduced physical activity in our cohort. Peripheral muscle weakness in COPD is considered to be related to loss of fat-free mass (20), muscle atrophy, and deconditioning (42). We found no relationship between physical activity and peripheral muscle strength. This result has to be discussed in the context of existing data concerning peripheral muscle weakness in COPD. Pitta and coworkers showed that both handgrip muscle strength and quadriceps muscle strength correlated moderately with physical activity in a bivariate model (14). We cannot conrm the association of handgrip muscle weakness with reduced physical activity in our multivariate model. In a landmark study investigating the effect of peripheral muscle weakness on exercise limitations, it was isometric quadriceps force, not handgrip force, that remained a signicant predictor of exercise limitations in a stepwise multiple regression analysis (43). In a small study of 16 patients with COPD, impaired endurance time of the quadriceps muscle was shown to be related to physical inactivity (44). Therefore, it seems possible that physical activity may be affected by quadriceps

muscle strength, which was not assessed in our study due to the lack of adequate equipment. Preliminary evidence suggests that anemia in patients with COPD may be more prevalent than expected and may be related to systemic inammation (45). Anemia is associated with reduced functional exercise capacity and a higher mortality rate in patients with COPD (12). The prevalence of anemia in our cohort was 5%, which is less than that reported in a cohort of patients with COPD (mean FEV1, 43% predicted) attending a Veterans Administration clinic (12). The prevalence of 14% in our GOLD stage IV patients, however, was comparable to the reported data in patients with COPD receiving long-term oxygen therapy (46). The presence of anemia was not associated with reduced physical activity in our cohort. Physical activity is dened as any bodily movement produced by skeletal muscles that results in energy expenditure beyond resting energy (1). The gold standard to assess total energy expenditure under free-living conditions is the doubly labeled water method (22). This methodology, however, is limited by cost and by its unavailability outside specialized centers. Simple accelerometers are inaccurate at estimating total daily energy expenditure from body movement counts only (47, 48). The SenseWear Pro Armband incorporates several other physiologic sensors that, in conjunction with the accelerometer recordings, give a more valid estimate of total daily energy expenditure (49). The physical activity level, which is dened as total daily energy expenditure divided by resting energy expenditure, is the equivalent of any physical activity performed during the day and has been shown to be a predictor of mortality in a healthy elderly population (22). At present, only limited data about the physical activity levels in COPD are available. Slinde and coworkers determined the physical activity levels in 10 underweight patients with COPD using the doubly labeled water method and indirect calorimetry (50). Physical activity levels ranged from 1.15 to 1.8, which are comparable to the range of physical activity levels found in our cohort. Of interest, only 22% of our patients had a physical activity level of 1.70 or greater, which suggests that most patients with COPD have a sedentary lifestyle. This observation conrms a previous nding that patients with COPD are markedly inactive in daily life (14). In our multivariate analysis, the explained variance of physical activity by the BODE index was similar to the explained variance by GOLD stages. Furthermore, extrapulmonary effects remained signicant when added to the BODE index. This is a surprising result, as the BODE index incorporates functional exercise capacity and dyspnea, two parameters that are affected by pulmonary and cardiac function (51). A possible explanation could be the fact that our cohort had a median of only 2 BODE points. The BODE index is potentially superior to GOLD stages in predicting physical activity in a cohort of patients with more severe COPD and a higher BODE score. This possibility, however, is subject to further studies. Our study has limitations that need to be addressed. Because it was a cross-sectional study, no causality or directionality of the ndings can be inferred. Furthermore, a selection bias has to be considered, as we recruited our patients from an existing database of patients with COPD who were willing to participate in clinical projects. Therefore, the prevalence and magnitude of observed extrapulmonary effects, which clearly affected statistical

deceleration time of the early transmitral ow. The mean deceleration time in our cohort was 262 ms. Two-way ANOVA: main effect GOLD, P , 0.001; main effect deceleration time, P , 0.01; interaction effect GOLD 3 deceleration time, P 5 0.23. (F) Steps per day according to BODE score and deceleration time of the early transmitral ow. See (B) for explanation of BODE quintiles. Two-way ANOVA: main effect BODE, P , 0.001; main effect deceleration time, P , 0.01; interaction effect BODE 3 deceleration time, P 5 0.15. In AF, bars represent mean values; horizontal lines represent standard error.

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analysis in our study, have to be seen in context with other studies and larger epidemiologic cohorts. In summary, this study provides cross-sectional evidence that reduced physical activity in patients with COPD is associated not only with clinical stages of COPD severity but also with left heart dysfunction and systemic inammation.
Conict of Interest Statement: None of the authors has a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The authors thank Dr. Stephanie Bitter-Suermann, Dr. Christine Otten, Dr. Margret Jandl, Dr. Frank Kanniess, Ms. Ines Zimmermann, Ms. Jeanette Kotzur, and Ms. Diana Knut-Rehr for their help collecting patients data. They thank Prof. Dr. Heiner Raspe for the academic discussions about the topic of the study, and Dr. Olaf Holz and Ms. Mary McKenney for the critical review of the manuscript.

17.

18.

19. 20.

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