Cardiorespiratory Fitness, Inflammation, and Risk of Chronic Obstructive Pulmonary Disease in Middle-Aged Men: A COHORT STUDY : Journal of Cardiopulmonary Rehabilitation and Prevention

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Pulmonary Rehabilitation

Cardiorespiratory Fitness, Inflammation, and Risk of Chronic Obstructive Pulmonary Disease in Middle-Aged Men

A COHORT STUDY

Kunutsor, Setor K. PhD; Jae, Sae Young PhD; Mäkikallio, Timo H. PhD; Laukkanen, Jari A. PhD

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: September 2022 - Volume 42 - Issue 5 - p 347-351
doi: 10.1097/HCR.0000000000000674

Chronic obstructive pulmonary disease (COPD) is a respiratory condition that is characterized by chronic lung inflammation, resulting in progressive and irreversible airflow obstruction.1 The airflow obstruction is reported to result from a combination of entities such as chronic bronchitis and emphysema. As the third leading cause of death worldwide, COPD caused about 3.23 million deaths in 2019.2 It is also a major cause of disability-adjusted life years and associated with significant health costs.1 Although smoking is the principal risk factor for COPD, exposure to indoor air pollution and occupational dusts, fumes, chemicals, and infections are also recognized as important risk factors.2 Although COPD has no cure, it is preventable and treatable; hence, modulation of risk factors could be essential in preventing COPD or delaying its progression. Since COPD is mediated by a chronic inflammatory process,1 it is no surprise that elevated levels of circulating inflammatory markers such as C-reactive protein (CRP) have been demonstrated to be associated with an increased risk of COPD.3,4 Physical activity (PA) has been identified as an important predictor of COPD outcomes; lower levels of PA are associated with a higher risk of exacerbations, hospitalizations, and all-cause mortality in patients with COPD.5 Cardiorespiratory fitness (CRF), an index of cardiopulmonary function and habitual PA, is an established and independent risk marker for several vascular and nonvascular outcomes.6–8 High CRF levels have been shown to be strongly and independently associated with reduced risk of pneumonia.9 Although a previous study has shown evidence of an association between higher levels of CRF and lower long-term risk of COPD,10 the nature of the dose-response relationship and whether the association depends on inflammation are unknown. Furthermore, CRF has consistently been demonstrated to have the ability to offset the harmful effects of other risk factors11–15; however, whether high CRF levels also attenuate or offset the increased risk of COPD due to inflammation has not yet been explored. In this context, using a population-based prospective cohort of 2274 middle-aged Finnish men, we aimed to confirm the existing association between inflammation (high-sensitivity C-reactive protein [hsCRP]) and COPD risk; evaluate the nature and magnitude of the relationship between CRF and COPD risk; and evaluate the joint effects of hsCRP and CRF on the risk of incident COPD.

METHODS

STUDY DESIGN AND PARTICIPANTS

We utilized the Kuopio Ischemic Heart Disease study, an ongoing population-based prospective cohort study comprising a representative sample of middle-aged men aged 42-61 yr recruited from Kuopio, eastern Finland. Baseline examinations were carried out between March 1984 and December 1989. Of a representative sample of 3433 randomly selected men, 3235 were found to be eligible; of them, 2682 volunteered to participate, 186 did not respond to the invitation, and 367 declined to give informed consent. The data set analyzed in the present study includes 2274 men with complete information on hsCRP, CRF, relevant covariates, and COPD outcomes. The research protocol was approved by the Research Ethics Committee of the University of Eastern Finland, and all participants provided written informed consent. The investigation was concordant with the principles outlined in the Declaration of Helsinki and its future amendments.

MEASUREMENT OF COVARIATES AND OUTCOME ASCERTAINMENT

Prior to blood specimen collections, participants were instructed to fast overnight, abstain from alcohol consumption for ≥3 d, and abstain from smoking for ≥12 hr.16–20 Serum hsCRP level was measured using an Immulite High-Sensitivity immunometric CRP assay (DPC).21 Assessment of CRF was directly measured as maximal oxygen uptake (V˙o2max), using a MCG respiratory gas exchange analyzer (Medical Graphics) during cycle ergometer exercise testing.22 Repeat measurements of hsCRP and CRF levels were performed in a random subset of participants 11 yr after baseline. The assessment of age, smoking, alcohol consumption, socioeconomic status (SES), prevalent diseases, and medication history employed the use of self-administered health and lifestyle questionnaires.23 History of type 2 diabetes was defined as having a clinical diagnosis of diabetes and regular treatment with diet or medications, fasting plasma glucose ≥7.0 mmol/L, or according to self-reports. History of coronary heart disease (CHD) was based on a previous myocardial infarction, angina pectoris, the use of nitroglycerin for chest pain once a week or more frequently, or chest pain. Adulthood SES was based on a summary index that combined income, education, occupational prestige, material standard of living, and housing conditions. The composite SES index ranged from 0-25, with higher values indicating lower SES. Alcohol consumption was assessed using the Nordic Alcohol Consumption Inventory.

All incident cases of COPD occurring from study entry to 2014 were included. No losses to follow-up were recorded in the Kuopio Ischemic Heart Disease study. Participants (using Finnish personal identification codes) were under continuous annual surveillance for the development of new events including COPD. Information on COPD was collected by linkage to the National Hospital Discharge Register and comprehensive review of hospital records. The diagnoses of COPD were made by qualified physicians based on the International Classification of Disease codes. The Independent Events Committee, masked to clinical data, performed classification of outcomes.

STATISTICAL ANALYSIS

Baseline characteristics were presented as means ± SD or median (IQR) for continuous variables and percentages for categorical variables. The HR with 95% CI for incident COPD were calculated using Cox proportional hazard models. The HR were adjusted for in two main models: model 1—age; and model 2—model 1 plus smoking status, history of type 2 diabetes, prevalent CHD, history of asthma, history of chronic bronchitis, history of tuberculosis, alcohol consumption, energy intake, and SES. In a third model, there was mutual adjustment for each exposure. To explore a potential nonlinear dose-response relationship between CRF and COPD risk, we constructed a multivariable restricted cubic spline (RCS) with knots at the 5th, 35th, 65th, and 95th percentiles of the distribution of CRF as recommended by Harrell.24 These knots offer an adequate fit of the model for most data sets and are a good compromise between flexibility and loss of precision caused by overfitting a small sample.24 These pre-specified knots also ensure that there are enough observations in each interval to estimate the cubic polynomial. We tested for potential nonlinearity by using a likelihood ratio test comparing the model with only a linear term against the model with linear and cubic spline terms.25,26 Although generalized additive models (GAMs) use automatic smoothness selection methods to estimate nonlinear trends compared with RCR,27 both approaches perform quite similarly in modeling nonlinear relationships. In addition to modeling CRF as a continuous variable, hsCRP was categorized into normal (≤3 mg/L) and high levels (>3 mg/L) and CRF was categorized into low and high levels based on the median value to maintain consistency with previous reports.11,19,28 To quantify and correct for within-person variability (regression dilution bias) in levels of the exposures (hsCRP and CRF), which is the extent to which measurements of these exposures vary for an individual around the long-term average exposure levels (“usual levels”),29 adjusted regression dilution ratios (RDRs) were calculated by regressing available repeat measurements of the exposures on baseline values.9,30–32 This involved dividing the estimated disease association (log HR and 95% CI) by the RDR.29 The formula [(1/RDR) − 1] × 100 was used to estimate the percent underestimation of the association, when baseline values of the exposures are used. For the evaluation of the joint associations, study participants were divided into four groups according to median cutoffs of hsCRP and CRF: normal hsCRP-low CRF; normal hsCRP-high CRF; high hsCRP-low CRF; and high hsCRP-high CRF. All statistical analyses were conducted using Stata version MP 16 (Stata Corp).

RESULTS

The overall age and CRF of men at baseline were 53 ± 5 yr and 30.3 ± 8.0 mL/kg/min, respectively. The median level of hsCRP was 1.24 (0.69, 2.36) mg/L (Table 1). Repeat measurements of hsCRP and CRF taken 11 yr after baseline were available in a random sample of 692 and 564 men, respectively. The overall age-adjusted RDR of hsCRP was 0.57 (95% CI, 0.50-0.64), suggesting that the association of hsCRP with COPD risk using baseline measurements of hsCRP only could underestimate the risk by [(1/0.57) − 1] × 100 = 75%. The overall age-adjusted RDR of CRF was 0.58 (95% CI, 0.53-0.64), suggesting that using baseline measurements of CRF to assess the association between CRF and COPD risk could underestimate the risk by [(1/0.58) − 1] × 100 = 72%.

Table 1 - Baseline Characteristics of Study Participants (n = 2274)a
Characteristics
hsCRP, mg/L 1.24 (0.69, 2.36)
CRF, mL/kg/min 30.3 ± 8.0
Questionnaire/prevalent conditions
Age, yr
Alcohol consumption, g/wk
Total energy intake, kJ/d
History of type 2 diabetes
Current smoking
History of CHD
History of asthma
History of chronic bronchitis
History of tuberculosis
53 ± 5
31.9 (6.4, 91.5)
9904 ± 2572
76 (3.3)
710 (31.2)
535 (23.5)
76 (3.3)
163 (7.2)
86 (3.8)
Physical measurements
BMI, kg/m2
SBP, mm Hg
DBP, mm Hg
Socioeconomic status
26.9 ± 3.5
134 ± 17
89 ± 10
8.41 ± 4.24
Blood biomarkers
Total cholesterol, mmol/L
HDL-C, mmol/L
Fasting plasma glucose, mmol/L
5.91 ± 1.07
1.29 ± 0.30
5.33 ± 1.19
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRF, cardiorespiratory fitness; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; SBP, systolic blood pressure.
aData are presented as mean ± SD, median (IQR), or n (%)

During a median follow-up of 26.0 (18.5, 28.1) yr, 116 incident cases of COPD were recorded. Compared with men with normal hsCRP levels, high hsCRP level was associated with an increased risk of COPD following adjustment for age, smoking status, prevalent type 2 diabetes, histories of CHD, asthma, chronic bronchitis, and tuberculosis, alcohol consumption, energy intake, and SES, 1.94 (95% CI, 1.31-2.89), and the association was minimally attenuated after further adjustment for CRF, 1.79 (95% CI, 1.20-2.68) (Table 2).

Table 2 - Separate and Joint Associations of hsCRP and CRF With Risk of Chronic Obstructive Pulmonary Disease
Exposure Categories Events/Total Model 1b Model 2c Model 3d
HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value
hsCRP, mg/L
Normal hsCRP (≤3)
High hsCRP (>3)
74/1837
42/437
ref
3.15 (2.16-4.61)
<.001 ref
1.94 (1.31-2.89)
.001 ref
1.79 (1.20-2.68)
.005
CRF, mL/kg/min
Per 1-SD increasea
Low CRF (6.36-30.05)
High CRF (30.06-65.40)
116/2274
75/1137
41/1137
0.60 (0.48-0.74)
ref
0.51 (0.35-0.76)
<.001
.001
0.72 (0.57-0.91)
ref
0.65 (0.43-0.98)
.006
.04
0.75 (0.60-0.95)
ref
0.68 (0.45-1.03)
.018
.07
hsCRP, mg/L, and CRF, mL/kg/min, combination
Normal hsCRP-low CRF
Normal hsCRP-high CRF
High hsCRP-low CRF
High hsCRP-high CRF
44/829
30/1008
31/308
11/129
ref
0.56 (0.35-0.90)
2.66 (1.68-4.22)
1.92 (0.98-3.75)
.018
<.001
.058
ref
0.67 (0.41-1.08)
1.80 (1.12-2.89)
1.35 (0.68-2.69)
.10
.016
.39
NA
NA
NA
NA
Abbreviations: CRF, cardiorespiratory fitness; hsCRP, high-sensitivity C-reactive protein; ref, reference.
aThe SD of CRF is 8.0.
bModel 1: Adjusted for age.
cModel 2: Model 1 plus smoking status, history of type 2 diabetes, prevalent coronary heart disease, history of asthma, history of chronic bronchitis, history of tuberculosis, alcohol consumption, energy intake, and socioeconomic status.
cModel 3: Model 2 plus CRF for hsCRP or hsCRP for CRF.

A multivariable RCS curve showed that the risk of COPD decreased linearly with increasing CRF across the range 31-43 mL/kg/min (P value for nonlinearity = .94) (Figure 1). The HR for COPD per 1-SD increase in CRF in analysis adjusted for age, smoking status, prevalent type 2 diabetes, histories of CHD, asthma, chronic bronchitis, and tuberculosis, alcohol consumption, energy intake, and SES was 0.72 (95% CI, 0.57-0.91). On further adjustment for inflammation (hsCRP), a potential mediator of the association, the HR remained similar 0.75 (95% CI, 0.60-0.95). Comparing high versus low CRF, the corresponding adjusted HRs were 0.65 (95% CI, 0.43-0.98) and 0.68 (95% CI, 0.45-1.03), respectively. Correction for regression dilution bias strengthened the respective associations (see Supplemental Digital Content, available at: https://links.lww.com/JCRP/A357).

F1
Figure 1.:
Restricted cubic spline of the HRs of incident COPD with CRF. Reference value for CRF is 17 mL/kg/min; dashed lines represent the 95% CI for the spline model (solid line). Models were adjusted for age, smoking status, history of diabetes, prevalent coronary heart disease, history of asthma, history of chronic bronchitis, history of tuberculosis, total cholesterol, alcohol consumption, and socioeconomic status. Abbreviations: COPD, chronic obstructive pulmonary disease; CRF, cardiorespiratory fitness.

Cumulative hazard curves showed a heightened risk of COPD among men with high hsCRP-low CRF compared with other groups (P value for the log-rank test <.001 for all; Figure 2). Compared with men with normal hsCRP-low CRF, high hsCRP-low CRF was associated with an increased risk of COPD in multivariable analysis, 1.80 (95% CI, 1.12-2.89), with no evidence of an association for high hsCRP-high CRF and COPD risk, 1.35 (95% CI, 0.68-2.69).

F2
Figure 2.:
Cumulative Kaplan-Meier curves for COPD during follow-up according to joint categories of hsCRP and CRF. Abbreviations: COPD, chronic obstructive pulmonary disease; hsCRP, high-sensitivity C-reactive protein; CRF, cardiorespiratory fitness; CRP, C-reactive protein.

DISCUSSION

Consistent with previous reports,3,4 we have confirmed the independent associations of elevated levels of hsCRP with an increased risk of COPD. In this general population-based cohort of middle-aged White men, the results demonstrate a strong inverse linear dose-response relationship between objectively measured CRF and future risk of COPD. The association was independent of several risk factors including lifestyle factors and comorbidities. The association was also independent of inflammation, when CRF was appropriately modeled as a continuous variable. It should be noted that since COPD is characterized and mediated by chronic inflammation,1 our adjustment for hsCRP may represent an overadjustment. New findings based on the joint associations of hsCRP and CRF with the risk of COPD showed that the risk of COPD was increased in men with elevated hsCRP and low CRF levels, but the increased risk of COPD due to elevated levels of hsCRP was attenuated by increased levels of CRF. These findings add to the accumulating literature on the beneficial effects of CRF on chronic diseases and align with previous reports showing higher CRF levels attenuate or offset the increased risk of adverse outcomes due to other risk factors.12,13

Although smoking is the major risk factor for COPD, only 20-25% of smokers develop COPD.1 COPD is characterized by a chronic inflammatory process that persists after smoking cessation. The main inflammatory mediators involved in COPD include tumor necrosis factor alpha (TNF-α), interleukin-1, interleukin-6, reactive oxygen species, and proteases.1 During the process of inflammation, CRP, an acute-phase protein, is produced by the liver in response to stimulation by inflammatory cytokines such as interleukin-6 and TNF-α.33 A distinct feature of COPD is the presence of acute exacerbations, which are typically associated with increased inflammation and are triggered by infections and environmental factors.1 It has been demonstrated that consistently elevated levels of circulating CRP in the early stages of respiratory tract infections increase the risk of progression to severe disease.33 The mechanistic pathways that underlie the association between high levels of CRF and reduced incidence of COPD are not well understood but may be via the effects of habitual PA, which confers good CRF, an index of better cardiopulmonary function. The protective effects of PA on COPD may be exerted via the anti-inflammatory effects of regular PA.34 High levels of PA may reduce lung function decline, hence preventing or delaying the onset of COPD.35 The increasing demand of ventilation during progressive PA may mechanically improve and increase the amount of ventilation in pulmonary airways, bronchioles, and alveoli. Further research is needed to elucidate the mechanistic pathways underlying the relationship between CRF and COPD risk and if there is a causal relevance.

There are several strengths of the current evaluation. These include the population-based prospective cohort design, large sample size, the long-term follow-up, the use of the direct gold standard measure of CRF, and ability to evaluate the dose-response relationship between CRF levels and COPD risk and to correct for within-person variability in levels of both exposures. The limitations included the use of a relatively homogeneous population consisting of predominantly White males, which precluded generalization to women or other populations, repeat measurements of the exposures were only available in a subset of the study participants, and potential for biases such as reverse causation and residual confounding.

CONCLUSIONS

In a middle-aged Finnish male population, both hsCRP and CRF are each independently associated with the risk of COPD. The relationship between CRF and COPD risk is consistent with a graded dose-response relationship at CRF levels ranging from 31-43 mL/kg/min. However, high levels of CRF attenuate the increased risk of COPD related to high hsCRP levels.

ACKNOWLEDGMENTS

The authors thank the staff of the Kuopio Research Institute of Exercise Medicine and the Research Institute of Public Health and University of Eastern Finland, Kuopio, Finland, for the data collection in the study.

This work was supported by the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. S.K.K. is funded by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol (BRC-1215-20011). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, and decision to publish or preparation of the manuscript.

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Keywords:

cardiorespiratory fitness; chronic obstructive pulmonary disease; cohort study; inflammation

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