Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events and osteoporosis. Increased arterial stiffness is an independent predictor of cardiovascular disease.
Objectives: We tested the hypothesis that patients with COPD would have increased arterial stiffness, which would be associated with osteoporosis and systemic inflammation.
Methods: We studied 75 clinically stable patients with a range of severity of airway obstruction and 42 healthy smoker or ex-smoker control subjects, free of cardiovascular disease. All subjects underwent spirometry, measurement of aortic pulse wave velocity (PWV) and augmentation index, dual-energy X-ray absorptiometry, and blood sampling for inflammatory mediators.
Measurements and Main Results: Mean (SD) aortic PWV was greater in patients, 11.4 (2.7) m/s, than in control subjects, 8.95 (1.7) m/s, p < 0.0001. Inflammatory mediators and augmentation index were also greater in patients. Patients with osteoporosis at the hip had a greater aortic PWV, 13.1 (1.8) m/s, than those without, 11.2 (2.7) m/s, p < 0.05. In patients, aortic PWV was related to age (r = 0.63, p < 0.0001) and log10 IL-6 (r = 0.31, p < 0.01), and inversely to FEV1 (r = –0.34, p < 0.01). The strongest predictors of aortic PWV in all subjects were age (p < 0.0001), percent predicted FEV1 (p < 0.05), mean arterial pressure (p < 0.05), and log10 IL-6 (p < 0.05).
Conclusions: Increased arterial stiffness was related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. The increased aortic PWV in patients with osteoporosis and the association with systemic inflammation suggest that age-related bone and vascular changes occur prematurely in COPD.
Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease and osteoporosis even when confounding factors are taken into account. The mechanisms linking COPD and cardiovascular disease are not known.
The excess cardiovascular risk in COPD may be due to increased arterial stiffness, which is related to airflow obstruction, systemic inflammation, and the presence of osteoporosis.
Factors underlying the relationship between airway obstruction and cardiovascular risk are unknown, but it is likely that alterations in vascular structure are involved, including atherosclerosis and loss of large artery elasticity (9). Increased arterial stiffness is associated with coronary artery disease (10), and predicts cardiovascular outcomes in various populations including healthy subjects (11–13). Arterial stiffness can be assessed noninvasively by measures including aortic (carotid–femoral) pulse wave velocity (PWV), augmentation index (AIx), and peripheral (brachial) pulse pressure (14). Aortic PWV is considered the most clinically relevant measure of arterial stiffness and independently predicts cardiovascular risk (14–18).
A factor potentially linking COPD and cardiovascular risk is the increased occurrence of osteoporosis (2), which in individuals without COPD is associated with atherosclerosis and arterial calcification (19, 20). A further potential factor is increased arterial stiffness, which is partly determined by vascular calcification (21) and is related to chronic systemic inflammation as proposed in other chronic inflammatory conditions (22). Circulating IL-6 and C-reactive protein (CRP) are increased in stable COPD over a range of severity of airway obstruction (23, 24), and both may have a role in atherosclerotic plaque formation and rupture (25).
We hypothesized that patients with COPD would have increased arterial stiffness compared with age- and sex-matched healthy smokers, and that it would be related to the severity of airway obstruction, osteoporosis, and systemic inflammation, indicating accelerated ageing associated with this lung condition. Components of the study reported here have been published in the form of abstracts (26, 27).
We recruited 75 patients with confirmed COPD when clinically stable, defined as no requirement for antibiotic or oral corticosteroid therapy and no change in respiratory symptoms beyond normal day-to-day variation in the preceding month (28, 29). We also studied 42 healthy current or ex-smoker control subjects. All subjects gave written, informed consent and the study had local research ethics committee approval. Subjects were excluded from the study if they were receiving long-term oxygen therapy or corticosteroids, or had known heart disease, malignancy, cor pulmonale, or any other inflammatory or metabolic condition.
Height and weight (Seca; Vogel and Halke, Hamburg, Germany) were measured and the body mass index (BMI) was determined. All subjects performed spirometry (FEV1, FVC, and FEV1:FVC ratio) (29). Static lung volumes (total lung capacity [TLC] and residual volume [RV]) (helium dilution method), carbon monoxide transfer factor (single breath hold method) (Pulmolab 501 system; Morgan Medical, Kent, UK), and arterialized ear lobe blood gases were determined in patients (30). All subjects completed a physical activity questionnaire (31).
Subjects were studied after an overnight fast and 6 hours after abstinence from caffeine, tobacco, and inhaled short-acting β2 agonists. All tests were performed after 10 minutes of supine rest. After peripheral blood pressure (BP) was measured (OMRON Corporation, Kyoto, Japan) radial artery waveforms were recorded with a high-fidelity micromanometer (Millar Instruments, Houston, TX). Pulse wave analysis (Sphygmocor; AtCor Medical, Sydney, Australia) was then used to generate a corresponding central waveform, using a validated transfer function (32). With the integral software, AIx was calculated as the difference between the second and first systolic peaks as a percentage of pulse pressure. Aortic PWV was measured with the same device by sequentially recording ECG-gated carotid and femoral artery waveforms. Wave transit time was calculated by the system software, using the R wave of a simultaneously recorded ECG as a reference frame. Aortic PWV was determined by dividing the distance between the two recording sites by the wave transit time (33).
Whole body composition and bone mineral density (BMD) at the lumbar spine and hip were determined with a Discovery bone densitometry system (Hologic, Bedford, MA). The BMD is presented as absolute figures and osteoporosis is defined by T scores (34). Fat-free mass was expressed as a height-squared ratio (FFMI), with a low FFMI defined as less than the lower 5th percentile of sex-specific control subjects (2).
Venous blood was collected for determination of glucose and lipid levels (35, 36). IL-6 and tumor necrosis factor (TNF)-α soluble receptors 1 and 2 (sr1 and sr2, respectively) were measured by ELISA (R&D Systems Europe, Abingdon, UK) (2).
Data analysis was performed with the Statistical Package for the Social Sciences (SPSS, Chicago, IL), version 10.0. Positively skewed data were log10 transformed. Analyses included the χ2 test, independent t test, Mann-Whitney U test, Pearson's correlations, one-way analysis of variance with post hoc Tukey analysis, and stepwise multiple regression analysis. p < 0.05 was considered significant.
Patients and control subjects were similar in terms of age, sex, height, and BMI (Tables 1 and 2). There was no difference in the proportion of subjects with a prior diagnosis of hypertension, or taking antihypertensive medication, among patients (34%) and control subjects (21%) (p = 0.13). Of the patients, 32 (43%) were prescribed inhaled long-acting β2 agonists, 31 (41%) an inhaled anticholinergic bronchodilator, and 35 (47%) inhaled corticosteroids (median [range] dose, 250 [0–2,000] μg betamethasone equivalent). The lipid profile and glucose were similar in patients and control subjects. More patients were current smokers and had a greater pack-year exposure than control subjects, although all had a minimum 5-pack-year smoking history.
Patients (n = 75) | Control Subjects (n = 42) | p Value | |
|---|---|---|---|
| Age, yr | 64.9 ± 9.5 | 62.0 ± 10.5 | 0.13 |
| Sex | 42 (male) | 23 (male) | 0.90 |
| Height, cm | 166.7 ± 8.6 | 167.2 ± 8.7 | 0.74 |
| Current smokers, no. (%) | 36 (48%) | 6 (14%) | < 0.0001 |
| Pack-year history, median (range) | 50 (20–90) | 15 (5–90) | < 0.0001 |
| LDL-cholesterol, mmol/L | 3.44 ± 0.47 | 3.48 ± 0.8 | 0.85 |
| Fasting glucose, mmol/L | 5.31 ± 0.53 | 5.43 ± 0.51 | 0.24 |
| Serum IL-6, pg/ml* | 2.11 ± 1.84 | 1.29 ± 1.58 | < 0.0001 |
| TNF-α sr1, pg/ml* | 1,429 ± 1.35 | 1,230 ± 1.27 | < 0.01 |
| TNF-α sr2, pg/ml* | 2,411 ± 1.36 | 2,117 ± 1.28 | < 0.05 |
| Physical activity score, median (range) | 27.7 (24.3–61.4) | 37.2 (26.5–57) | < 0.0001 |
| Epworth score, median (range) | 4 (0–10) | 4 (0–9) | 0.41 |
| Heart rate, bpm | 74.3 ± 9.4 | 64.9 ± 9.5 | < 0.0001 |
| Peripheral systolic BP, mm Hg | 144.8 ± 18.1 | 138.0 ± 12.1 | 0.017 |
| Peripheral diastolic BP, mm Hg | 82.2 ± 9.6 | 81.5 ± 7.24 | 0.67 |
| Peripheral pulse pressure, mm Hg | 62.5 ± 15.9 | 56.5 ± 11.5 | 0.02 |
| Peripheral mean arterial pressure, mm Hg | 103.9 ± 11.4 | 102.0 ± 8.1 | 0.29 |
| Augmentation index, % | 30.1 ± 8.2 | 25.9 ± 6.2 | 0.002 |
| Aortic pulse wave velocity, m/s | 11.4 ± 2.7 | 8.95 ± 1.7 | < 0.0001 |
| Aortic systolic BP, mm Hg | 133.5 ± 17.5 | 129.2 ± 12.8 | 0.13 |
| Aortic diastolic BP, mm Hg | 83.9 ± 10.6 | 82.2 ± 7.6 | 0.35 |
| Aortic pulse pressure, mm Hg | 49.5 ± 14.6 | 47.0 ± 10.9 | 0.30 |
| Aortic mean arterial pressure, mm Hg | 105.3 ± 12.5 | 101.6 ± 8.5 | 0.06 |
Patients (n = 75) | Control Subjects (n = 42) | p Value | |
|---|---|---|---|
| FEV1, L | 1.54 ± 0.7 | 2.87 ± 0.6 | < 0.0001 |
| Percent predicted FEV1 | 56.7 ± 21.1 | 107.6 ± 15.9 | < 0.0001 |
| FVC, L | 2.77 ± 1.0 | 3.7 ± 0.8 | < 0.0001 |
| Percent predicted FVC | 81.0 ± 22.5 | 111.4 ± 14.0 | < 0.0001 |
| FEV1:FVC ratio | 53.9 ± 12.1 | 77.9 ± 5.4 | < 0.0001 |
| RV:TLC, median (range)* | 48 (27–66) | ND | |
| TlCO, percent predicted* | 67.2 ± 22.7 | ND | |
| PaO2, mm Hg | 71.0 ± 8.2 | ND | |
| PaCO2, mm Hg | 35.4 ± 4.5 | ND | |
| BMI, kg/m2 | 27.6 ± 4.9 | 27.4 ± 3.9 | 0.84 |
| BMD total lumbar, g/cm2† | 0.97 ± 0.19 | 1.07 ± 0.17 | 0.003 |
| BMD total hip, g/cm2† | 0.88 ± 0.15 | 1.00 ± 0.14 | < 0.0001 |
| Total FFMI, kg/m2† | 17.5 ± 2.5 | 18.3 ± 2.5 | 014 |
There was no difference in diastolic BP or mean systemic arterial pressure (MAP) between patients and control subjects, although patients had greater systolic BP and pulse pressure, whereas aortic BP indices were similar (Table 1). Mean (SD) aortic PWV was greater in patients (11.4 [2.7] m/s) than control subjects (8.95 [1.7] m/s), p < 0.0001. The patients had a greater heart rate (p < 0.0001) and AIx (p < 0.01). Age was associated with aortic PWV in both patients (r = 0.63, p < 0.0001) and control subjects (r = 0.69, p < 0.0001). Aortic PWV was also greater in successive decades for both patients and control subjects (analysis of variance, p < 0.0001) (Figure 1). There was no relationship between age and AIx in either the patient or control group. Within the patient group, aortic PWV and AIx were not different in current and ex-smokers, nor was there a relationship between aortic PWV or AIx and pack-years of smoking. Physical activity scores were inversely related to aortic PWV in the whole population (r = –0.41, p < 0.001) and the control group (r = –0.41, p < 0.01), but not the patient group (r = –0.22, p = 0.06). There was no relationship between AIx and physical activity scores in either group. A subgroup analysis excluding subjects with hypertension demonstrated findings similar to the whole group analysis, with patients (n = 48) having a greater AIx (p < 0.01) and aortic PWV (p < 0.0001) than control subjects (n = 34).
Figure 1. Aortic pulse wave velocity (PWV) in control subjects and patients across each decade. Open columns represent control subjects; shaded columns represent patients. Error bars represent 1 standard deviation for each group. Aortic PWV was higher in patients and control subjects across each decade (analysis of variance, p < 0.0001).
[More] [Minimize]Results of pulmonary function tests are presented in Table 2. According to Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity criteria (28) the patients comprised GOLD stage I (n = 15), stage II (n = 26), stage III (n = 25), and stage IV (n = 9). The mean (SD) arterial PaO2 for patients was 71 (8.2) mm Hg, and no patient met the U.K. long-term oxygen therapy criteria (< 55 mm Hg). For analysis, patients with an FEV1 > 50% predicted (n = 41) were compared with those with an FEV1 < 50% predicted (n = 34). Both groups were similar for age, MAP, and smoking history.
Patients with an FEV1 > 50% predicted had a lower aortic PWV than those with an FEV1 < 50% predicted, p < 0.01, but a greater aortic PWV than control subjects, p < 0.01 (Figure 2). In all subjects, there was an inverse relationship between aortic PWV and FEV1 (r = –0.51, p < 0.0001) and FVC (r = –0.47, p < 0.0001). In the patient group, aortic PWV was also inversely related to FEV1 (r = –0.34, p < 0.01) and FVC (r = –0.34, p < 0.01).
Figure 2. Aortic PWV in control subjects, patients with FEV1 > 50% predicted, and patients with FEV1 < 50% predicted (age and sex matched). Open column represents control subjects; shaded column represents patients with FEV1 > 50% predicted; solid column represents patients with FEV1 < 50% predicted. Error bars represent 1 standard deviation of each group.
[More] [Minimize]The AIx was less in control subjects than in patients with FEV1 > 50% predicted (p < 0.05) or in patients with FEV1 < 50% predicted (p < 0.05). There was no difference in AIx between patients with an FEV1 > 50% and patients with an FEV1 < 50%. In all subjects, there was an inverse relationship between AIx and FEV1 (r = –0.32, p < 0.0001) and FVC (r = –0.32, p < 0.0001). A similar relationship was found in control subjects (both p = 0.001) but not patients.
In patients, aortic PWV was related to PaO2 (r = –0.34, p < 0.01). There was no relationship between AIx and other lung function.
Total BMD at the lumbar (p < 0.01) and hip (p < 0.0001) regions was less in patients than control subjects (Table 2). Patients also had a lower BMD at individual hip (all, p < 0.01) and lumbar regions (p < 0.05). More patients had osteoporosis (n = 18) than did control subjects (n = 2), χ2 < 0.001 (34). In all subjects with osteoporosis (hip or lumbar site), aortic PWV (11.6 [2.2] m/s) was greater than in subjects without osteoporosis (10.3 [2.7] m/s), p < 0.05. Those with osteoporosis at the hip had a greater aortic PWV than those without, p = 0.006, but this was not the case for osteoporosis at the spine. In the patient group, increased aortic PWV was also seen in those with osteoporosis at the hip (n = 9), p < 0.05 (Figure 3), but not in those with osteoporosis (n = 13) at the spine. Differences in aortic PWV between populations could not be accounted for by age, sex, physical activity, airway obstruction, MAP, or smoking.
Figure 3. Aortic PWV (m/s) of control subjects and patients according to their bone status at the hip. Open circles represent mean aortic PWV for subjects with no osteoporosis; solid squares represent mean aortic PWV for subjects with osteoporosis. Error bars represent 1 SEM. HS = healthy subjects.
[More] [Minimize]In all subjects, those with osteoporosis at the hip site had a greater AIx (p < 0.05) than those without osteoporosis, whereas in subjects with osteoporosis at the lumbar site there was no difference in AIx. Using the cutoff of a low FFMI of 17.2 kg/m2 for males and 13.7 kg/m2 for females, 14 patients had a low FFMI, 4 of whom had a low BMI and 10 of whom had a normal BMI. There was no relationship between FFMI and either aortic PWV or AIx.
Circulating IL-6 and TNF-α sr1 and sr2 were greater in patients than control subjects (Table 1). Patients with an FEV1 > 50% predicted had lower IL-6 levels than patients with an FEV1 < 50% predicted (p < 0.05), but this was still greater than in control subjects (p < 0.05). This separation was not seen for TNF-α sr1 and sr2.
Log10 IL-6 and aortic PWV were related in all subjects (r = 0.47, p < 0.0001), patients (r = 0.31, p < 0.01), and control subjects (r = 0.51, p < 0.01) (Figure 4). In addition, log10 TNF-α sr1 and sr2 were both related to aortic PWV in all subjects (p < 0.01), and control subjects (p < 0.05). In patients, aortic PWV was related to log10 TNF-α sr1 (r = 0.273, p = 0.018), but not log10 TNF-α sr2 (p = 0.16). AIx was related to log10 IL-6 (r = –0.27, p < 0.05) and log10 TNF-α sr1 (r = –0.24, p < 0.05) in patients, but not in control subjects. There was no relationship between IL-6, TNF-α sr1 and sr2, and hip or lumbar spine parameters in either patient or control group.
Figure 4. Correlation between mean aortic PWV and log10 IL-6 in patients (r = 0.31, p < 0.05) and control subjects (r = 0.51, p < 0.05). Crosses represent patients; squares represent control subjects. Continuous line represents line of best fit through patient data; interrupted line represents line of best fit through control data.
[More] [Minimize]Table 3 shows results of multiple regression analysis, investigating the relationship between aortic PWV and AIx with age, sex, BMI, percent predicted FEV1, pack-years of smoking, peripheral MAP, heart rate, glucose, low-density lipoprotein–cholesterol, IL-6, TNF-α sr1, TNF-α sr2 in all subjects and PaO2 in patients only, with age, percent predicted FEV1, peripheral MAP, and log10 IL-6 being predictive variables of aortic PWV in all subjects.
R2 | β | SE | p Value | ||
|---|---|---|---|---|---|
| All Subjects | |||||
| Aortic PWV | |||||
| Age | 0.236 | 0.513 | 0.018 | < 0.0001 | |
| Percent predicted FEV1 | 0.125 | −0.303 | 0.006 | < 0.001 | |
| Peripheral MAP | 0.018 | 0.141 | 0.016 | 0.03 | |
| Log10 IL-6 | 0.013 | 0.152 | 0.754 | < 0.05 | |
| AIx | |||||
| Sex | 0.137 | 0.375 | 1.23 | < 0.0001 | |
| Peripheral MAP | 0.073 | 0.325 | 0.06 | < 0.0001 | |
| Percent predicted FEV1 | 0.043 | −0.217 | 0.02 | 0.007 | |
| BMI | 0.036 | −0.207 | 0.14 | 0.01 | |
| Patients | |||||
| Aortic PWV | |||||
| Age | 0.313 | 0.585 | 0.026 | < 0.0001 | |
| Pack-years | 0.025 | 0.226 | 0.258 | 0.015 | |
| Log10 IL-6 | 0.026 | 0.195 | 0.958 | < 0.05 | |
| AIx | |||||
| Sex | 0.107 | 0.349 | 1.77 | 0.02 | |
| Peripheral MAP | 0.058 | 0.299 | 0.077 | 0.07 | |
| BMI | 0.034 | −0.219 | 0.183 | < 0.05 | |
The increase in aortic PWV in patients and the associated changes in peripheral pulse pressure and AIx validate our hypothesis that increased arterial stiffness is a systemic complication of COPD. Further support comes from the relationship between the severity of airway obstruction and arterial stiffness, and the further increase in those with osteoporosis. Together these changes suggest that systemic complications of COPD represent a premature ageing effect. Our finding, that patients with even mild-severity airway obstruction had increased arterial stiffness compared with control subjects, suggests that arterial stiffening occurs early in the disease process and increases with declining lung function.
The relationship between the degree of arterial stiffness (aortic PWV and AIx) and severity of airway obstruction in our patients may explain the excess risk for coronary heart disease and cerebrovascular accidents in COPD, a risk that remains after controlling for confounders such as diabetes (3), tobacco exposure (4), physical inactivity (4), hypercholesterolemia (6), and hypertension (6). Increased arterial stiffness independently predicts cardiovascular and cerebrovascular events in healthy populations (12, 17, 18), as well as in patients with known cardiovascular risk factors such as end-stage renal failure (11), hypertension (13), and diabetes mellitus (16). In a longitudinal study, an increase in aortic PWV of 3.4 m/s was associated with an increased cardiovascular event risk of 16 to 20% (17). An association between FEV1, FVC, and their ratio and aortic PWV was demonstrated in a cross-sectional study of middle-aged men free of coronary heart disease, but with high proportions of hypertension and hypercholesterolemia, and diabetes mellitus in approximately 10% (37). They did not classify airway obstruction in their population and hence their results cannot be extrapolated to patients with COPD, because it is unclear what proportion of their subjects had restrictive or normal spirometry. These findings provide added support for epidemiologic data linking reduced lung function and cardiovascular morbidity and mortality (3, 6, 8).
Increased arterial stiffness has important hemodynamic consequences. The increased velocity of the reflected pressure wave augments aortic pressure in late systole, causing an increase in pulse pressure, due to increased systolic BP and decreased diastolic BP. As a consequence, myocardial oxygen demand and left ventricular afterload are increased, whereas coronary perfusion is reduced, leading to subendocardial ischemia (13). Furthermore, increased left ventricular afterload promotes left ventricular hypertrophy, a recognized independent cardiovascular risk factor (38). In the vasculature, increased pulse pressure alters the cyclical dynamics of the arterial wall connective tissues, promoting vascular remodeling, an increase in arterial wall thickness, and plaque formation (39). Thus, arterial stiffness may be both a marker for and a cause of cardiovascular disease.
Patients with osteoporosis had the greatest arterial stiffness. Osteoporosis and less severe bone thinning occur in COPD, even in mild disease, and are generally clinically occult (2). The reciprocal association between osteoporosis and arterial stiffness is supported by the relationship between bone mineral loss and each of vascular calcification, atherosclerosis, and cardiovascular disease (19, 40). Vascular calcification can occur in either the intimal or medial layer of the arterial wall. Intimal calcification is associated with advanced atherosclerosis, whereas medial calcification is associated with arteriosclerosis and is a consequence of deposition of calcium in elastic fibers. Medial calcification, seen in ageing, diabetes, and renal disease, has been shown to contribute to arterial stiffness in both animal and human studies (41, 42). The parallel increase in aortic calcium deposition and decrease in bone mineral density, described in a longitudinal study by Schultz and coworkers (20), lends further support to the link between osteoporosis and vascular calcification. Furthermore, studies have demonstrated that vessel wall calcification shares many similarities with osteogenesis, with the expression of many bone and mineralization regulatory factors in calcified lesions (43). The relationship between osteoporosis at the hip, but not at the lumbar spine, and aortic PWV may reflect an apparent maintenance of lumbar bone mineral density due to overlying vascular calcification or vertebral body collapse, and was reported in a larger non-COPD population study (19).
A possible pathophysiologic relationship between bone loss and COPD may be through heightened systemic inflammation. Although a relationship between systemic inflammation and bone loss was not demonstrated in our study, it is possible that levels of circulating inflammatory markers may not reflect levels and bioactivity of inflammatory cytokines at the tissue level. In patients without COPD IL-1, IL-6, IL-11, and TNF-α stimulate osteoclast development with subsequent increased bone resorption leading to osteoporosis (44). Meanwhile, increased arterial stiffness in COPD may be due to a number of factors, including chronic systemic inflammation (2, 23, 24). C-reactive protein is related to and is a predictor of cardiovascular risk (45). We measured IL-6, a regulator of CRP production and secretion, and TNF-α soluble receptors, as an indicator of possible TNF-α bioactivity, because all are increased in COPD. In both patients and control subjects inflammatory mediators and arterial stiffness were related, with IL-6 predicting aortic PWV in multivariate analysis. This is supported by the relationship between CRP and aortic PWV but not AIx in healthy adults (32) and between increased levels of CRP, IL-6, and TNF and both aortic PWV and AIx in healthy subjects and patients with chronic inflammatory conditions (46, 47). The mechanism linking systemic inflammation and arterial stiffening is unknown, but its association with endothelial dysfunction may increase arterial stiffness due to reduced nitric oxide bioavailability (48), vascular smooth muscle proliferation, atherogenesis, and increased synthesis of less elastic structural proteins including collagen (49). Atherosclerotic plaques may contribute to circulating inflammatory mediators such as IL-6, raising the possibility of a vicious cycle in the vasculature (50). Whether systemic inflammation is a risk factor or a risk marker for cardiovascular disease in COPD is unknown, but the clear association demonstrated here is open to further investigation. The importance of the association with a low PaO2 is unclear, but hypoxemia may influence arterial stiffness by its effect on systemic inflammation (51).
An important factor influencing arterial stiffness is age, which was strongly related to aortic PWV and in multiple regression was the strongest predictor in both the patients and control subjects. However, AIx, which was increased in patients compared with control subjects, was not related to age. This apparent divergence may be explained by the fact that AIx, a less robust and indirect surrogate measure of arterial stiffness (14), is dependent on multiple components of the arterial pressure wave and exhibits different age-related changes relative to aortic PWV (52). Changes in AIx are more prominent in younger individuals, whereas changes in aortic PWV are more prominent in those more than 50 years old, which is relevant to this study, in which the median age of subjects was 63 years.
None of our patients had a history of ischemic heart disease or symptoms at baseline, although increased arterial stiffness may reflect underlying hidden or subclinical cardiovascular disease. The increased arterial stiffness in patients within each decade is similar to changes in type I diabetes mellitus (53) and suggests that age-related vascular changes occur prematurely in COPD compared with disease-free individuals. However, unlike diabetes mellitus, the risk of premature, excess cardiovascular disease in COPD is not appreciated. The links between FEV1, arterial stiffness, and osteoporosis suggest possible common degenerative changes occurring in connective tissues as part of natural ageing.
The smoking history of our patient and control groups was different, yet this is unlikely to account for the increased arterial stiffness seen in patients with COPD, and was adjusted for in our regression analysis. Within our patient group, current smokers and those with a higher pack-year history did not have a higher AIx or aortic PWV. In addition, there was a difference in aortic PWV between GOLD stage I and II and GOLD stage III and IV patients with COPD, who were similar in terms of current smokers and the pack-years of smoking. Zureik reported similar aortic PWV in never-smokers, current smokers, and ex-smokers in their general population (p = 0.75) (37). Other studies support the lack of separation in aortic PWV between smokers and nonsmokers, but report acute and chronic effects of smoking on AIx (54, 55).
The cross-sectional nature of this study does not allow causal relationships between COPD, systemic inflammation, arterial stiffness and cardiovascular disease to be inferred, but has shown strong relationships that could be explored further. In addition, this study was not powered to test the relationship between aortic PWV and a large number of independent variables. The inclusion of patients and control subjects with hypertension, taking vasodilating drugs, may also be criticized, although the subgroup analysis with exclusion of hypertensive patients and control subjects did not alter our findings.
Increased arterial stiffness was present in patients with COPD over a wide range of severity of airway obstruction and was greatest in those with osteoporosis. Our findings indicate vascular changes predictive of cardiovascular disease occur and remain undetected in mild or early lung disease and may underlie the excess cardiovascular risk in COPD.
The authors thank Dr. Lisette Nixon for work with biochemical assays, Mrs. Maggie Munnery and Mr. Barry McDonnell for practical advice and assistance, and the Lung Function Department staff at Llandough Hospital for training, and for access to their facilities. We also thank North Cardiff Medical Centre and the Consultant Respiratory Physicians at Llandough Hospital for the inclusion of their patients in this study.
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