Abstract
Rationale: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema.
Objectives: To identify whether the extent of arterial stiffness is associated with emphysema severity.
Methods: We performed a cross-sectional study in 157 patients with COPD.
Measurements and Main Results: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV1% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol–high-density lipoprotein ratio, and pulse oximetry oxygen saturations.
Conclusions: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.
Arterial stiffness, a marker of cardiovascular risk, is increased in patients with chronic obstructive pulmonary disease compared with matched control subjects and is associated with FEV1% predicted in healthy men. The mechanism is unknown but systemic inflammation in chronic obstructive pulmonary disease has been implicated.
Emphysema severity is associated with arterial stiffness in patients with COPD. This association is independent of airflow limitation and systemic inflammation.
The biological mechanisms responsible for the association between COPD and cardiovascular disease are poorly understood, but early studies suggest that systemic inflammation in COPD may promote atherosclerosis (6). Arterial stiffness is a useful noninvasive measure of vascular function, is associated with atheromatous plaque burden (7), and is an independent predictor of cardiovascular events in subjects with diabetes (8), renal disease (9), hypertension (10), and in the general population (11). Arterial stiffness is not simply a measure of cardiovascular risk, because reduced vascular compliance itself increases cardiac afterload and reduces coronary blood flow, and promotes myocardial ischemia (12).
Arterial stiffness is associated with airflow limitation in healthy men (13), and Sabit and colleagues recently reported increased arterial stiffness in patients with COPD compared with control subjects matched for age, sex, blood pressure, and other cardiovascular risk factors (14). Together, these studies are important because they suggest a link between pulmonary and vascular disease that may explain a proportion of the excess cardiovascular mortality in patients with COPD.
The mechanism by which arterial stiffness is increased in patients with COPD is unknown. We suspect that impaired lung function and increased arterial stiffness in COPD may both be due to increased susceptibility to degradation of connective tissue in this group of patients. In the lung, elastin degradation leads to loss of alveolar attachments, decreased compliance, and emphysema (15). While in the arteries, age-related elastin degradation is associated with increased collagen, larger, thicker arteries, and increased arterial stiffness (12). Elastin is also involved in the regulation of vascular smooth muscle cells, changes in which may also contribute to arterial stiffness (16). Elastolytic activity (matrix metalloproteinase [MMP]-9 and MMP-12) is increased in both emphysema and arteriosclerosis, and both emphysema and arterial stiffness appear to be at least partly genetically determined (15, 17). Despite smoking being by far the largest risk factor for emphysema, the severity of emphysema is highly variable among smokers (18), and mouse models also demonstrate variation in their susceptibility to emphysema (19). In the Klotho mouse (a mouse model of accelerated aging), arteriosclerosis, emphysema, and loss of skin elasticity coexist (20), whereas in Marfan's syndrome (the human autosomal dominant condition characterized by defective fibrillin synthesis), aortic root arterial stiffness is characteristic, and emphysema has been described in never-smokers (21). Loss of skin elasticity is also associated with emphysema independent of age and smoking history, providing intriguing clinical evidence for the presence of loss of elasticity systemically in patients with COPD (22).
Therefore, we hypothesize that the extent of arterial stiffness is associated with the severity of emphysema in patients with COPD.
Blood pressure and arterial stiffness were measured in 177 subjects with COPD who participated in a cohort study designed to identify prognostic markers in COPD. During recruitment, ethical approval was obtained to perform high-resolution computed tomography (HRCT) of the chest. All subsequently enrolled subjects (n = 73) had HRCT scans. All studies were approved by the Lothian Regional Ethics Committee, and all subjects gave written, informed consent.
All subjects had a clinical history compatible with COPD, a history of risk factors (history of at least 10 pack-years of smoking) and evidence of chronic airflow limitation on spirometry (post-bronchodilator FEV1/FVC < 70%) (23). Subjects were not taking oral antiinflammatory drugs, including corticosteroids. Subjects with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) were excluded. Cardiovascular comorbidity was not an exclusion criterion but was carefully recorded. Visits were performed when subjects were clinically stable (⩾4 wk since last exacerbation as defined by a worsening of symptoms requiring intervention with antibiotic therapy or oral corticosteroids).
Height, weight, and post-bronchodilator spirometry were measured (Alpha Spirometer; Vitalograph, Buckingham, UK) according to American Thoracic Society/European Respiratory Society standards in all subjects (24). Venous blood was sampled and stored at −80°C for subsequent analysis. Serum C-reactive protein (CRP) concentrations were measured using a highly sensitive immunonephelometric assay (Behring BN II nephelometer; Dade Behring, Marburg, Germany). Glucose and cholesterol were measured in the locally accredited clinical biochemistry laboratory (Olympus Analyzers, Center Valley, PA). Oxygen saturations were measured at rest breathing air by pulse oximetry (Nellcor Puritan Bennett Sensor; Nellcor, Pleasanton, CA). Individuals who underwent HRCT also had six-minute-walk tests in accordance with American Thoracic Society guidelines (25).
Arterial stiffness and peripheral blood pressure measurements were obtained before spirometry and venipuncture in a quiet, temperature-controlled room, with subjects resting supine at 15°. Patients had abstained from smoking, caffeine, and all medications on the day of the test. Systolic and diastolic blood pressures were measured in duplicate using an automated noninvasive oscillometric sphygmomanometer (Omron 705IT; Milton Keynes, UK) after a 10-minute rest period.
After 30 minutes of rest, arterial stiffness was measured using pulse wave velocity (PWV) by specifically trained staff. PWV measures the rate at which the systolic pressure wave travels to the peripheral vasculature. Faster wave transit times reflect stiffer arteries. We used the Q-wave of a simultaneously recorded ECG to identify the onset of the pressure wave, and used applanation tonometry (Millar Instruments, Houston, TX) at the carotid and radial arteries to record the pressure waveform at the peripheral site. The SphygmoCor system (AtCor Medical, Sydney, Australia) software applied an intersecting tangent algorithm to identify the onset of the wave. The difference in wave transit time between the carotid and radial sites was used to calculate the PWV.
Quality-control checks were made for all measurements according to manufacturer's guidelines (26). Results with a standard deviation of 15% or greater were not included in the analysis, nor were measurements with a standard deviation of 10 to 15% in which the onset of the waveform was not clearly identified.
HRCT scanning of the lungs was performed at full inspiration using a 16-slice multidetector-row CT scanner (135 kv, 20 mAs; Toshiba Aquilion, Toshiba, Japan). Patients were coached to perform full inspiration. Contrast media was not administered. Images were reconstructed with a slice thickness of 5 mm and 2.5-mm increment using an FC-03 filter (Toshiba). The calibration of air CT density measurements was made using a background air region above the sternum. Emphysema was quantified by in-house software using the 15th percentile point of the frequency distribution of lung density and pixel index for −950 and −910 Hounsfield units (27–29).
Analysis was performed using SPSS version 14 (SPSS, Inc., Chicago, IL). A univariate analysis of PWV on all variables of interest was performed in the subgroup who underwent HRCT of the chest (Pearson's correlation and independent sample t tests as appropriate). Backward multiple linear regression of PWV on the variables found to be significant (at the P < 0.1 level) in the univariate analysis was performed. Significance was taken at the P < 0.05 level. This analysis was repeated in the full cohort, including those with and without measures of emphysema (Table E2 in the online supplement).
PWV was performed in 177 patients with COPD, with satisfactory measurements obtained in 157 patients. The full cohort (n = 157) and HRCT subgroup (n = 73) were similar for all clinical, laboratory, hemodynamic, and spirometric characteristics (Table 1).
All Subjects | Non-HRCT | HRCT Subjects | |
|---|---|---|---|
| No. subjects | 157 | 84 | 73 |
| Age, yr | 67.9 (7.6) | 67.9 (8.0) | 67.9 (7.2) |
| Male, n (%) | 92 (59%) | 46 (55%) | 46 (63%) |
| Height, cm | 166.5 (10.0) | 165.4 (9.5) | 167.9 (10.4) |
| Weight, kg | 71.3 (18.1) | 68.32 (17.4) | 74.6 (18.4) |
| BMI, kg/m2 | 25.6 (5.6) | 24.9 (5.5) | 26.4 (5.8) |
| Clinical | |||
| Oxygen saturations* | 96 (94–97) | 96 (95–98) | 96 (94–97) |
| SGRQ total score* | 50 (33–63) | 50 (35–67) | 49 (32–61) |
| Pack-years smoking* | 40 (30–56) | 43 (25–50) | 40 (30–52) |
| Current smoker | 62 (39%) | 38 (45%) | 24 (33%) |
| Chronic bronchitis | 74 (50%) | 37 (44.6%) | 37 (58%) |
| Ankle edema | 37 (24%) | 21 (25%) | 16 (22%) |
| Inhaled corticosteroid | 103 (66%) | 54 (64%) | 49 (67%) |
| Long-acting β-agonist | 83 (53%) | 47 (56%) | 36 (49%) |
| History of ischemic heart disease | 32 (20%) | 19 (23%) | 13 (18%) |
| History of hypercholesterolemia | 21 (13%) | 11 (13%) | 10 (14%) |
| History of diabetes | 3 (2%) | 1 (1%) | 2 (3%) |
| Spirometry | |||
| FEV1, L | 1.29 (0.58) | 1.21 (0.56) | 1.37 (0.59) |
| FEV1/FVC | 49 (14) | 49 (15) | 50 (13) |
| FEV1% predicted | 51 (20) | 50 (20) | 53 (20) |
| Hemodynamic | |||
| Heart rate | 69 (11) | 69 (10) | 69 (11) |
| Systolic pressure, mm Hg | 144 (23) | 144 (24) | 144 (21) |
| Diastolic pressure, mm Hg | 81 (11) | 80 (11) | 81 (12) |
| Pulse pressure, mm Hg | 64 (19) | 64 (20) | 63 (17) |
| Mean arterial pressure, mm Hg | 102 (13) | 101 (12) | 102 (13) |
| Pulse wave velocity, m/s | 8.69 (1.51) | 8.55 (1.52) | 8.85 (1.50) |
| Laboratory | |||
| Glucose, mmol/L | 6.12 (1.28) | 6.03 (1.23) | 6.13 (1.33) |
| Cholesterol:HDL ratio | 3.74 (1.09) | 3.71 (1.14) | 3.77 (1.04) |
| White cell count, ×109/L | 7.48 (2.10) | 7.43 (2.28) | 7.55 (1.87) |
| Neutrophil count, ×109/L | 4.79 (1.67) | 4.91 (1.88) | 4.65 (1.40) |
| Platelet count, ×109/L | 262 (66) | 260 (67) | 263 (65) |
| CRP, mg/L* | 3.66 (1.87–7.25) | 3.76 (1.98–8.32) | 3.48 (1.67–6.72) |
In the full cohort, PWV was higher in men, and there were statistically significant associations (at P < 0.05) between PWV and height, oxygen saturations, FEV1% predicted, FEV1/FVC, heart rate, and blood pressure. There was no association between CRP and PWV, or between smoking pack-years and PWV (Tables 2 and 3).
All Subjects (n = 157) | HRCT Subjects (n = 73) | |||||
|---|---|---|---|---|---|---|
| r Value | P value | r Value | P value | |||
| Age | −0.013 | 0.868 | −0.137 | 0.246 | ||
| Clinical | ||||||
| Height, cm | 0.266 | 0.001* | 0.279 | 0.017* | ||
| Weight, kg | −0.020 | 0.806 | −0.332 | 0.332 | ||
| BMI, kg/m2 | −0.155 | 0.052† | −0.280 | 0.016* | ||
| Oxygen saturations | −0.167 | 0.039‡ | −0.114 | 0.336 | ||
| SGRQ total score | 0.073 | 0.366 | −0.072 | 0.547 | ||
| Pack-years smoking | −0.023 | 0.780 | −0.180 | 0.132 | ||
| Six-minute-walk distance, m | N/A | N/A | 0.074 | 0.576 | ||
| Spirometry | ||||||
| FEV1, L | −0.012 | 0.881 | 0.029 | 0.805 | ||
| FEV1/FVC | −0.295 | <0.001† | −0.419 | 0.001* | ||
| FEV1% predicted | −0.208 | 0.009† | −0.243 | 0.038‡ | ||
| Laboratory | ||||||
| Glucose, mmol/L | 0.138 | 0.085† | −0.024 | 0.843 | ||
| Cholesterol:HDL ratio | −0.048 | 0.562 | −0.082 | 0.496 | ||
| Log CRP | −0.63 | 0.435 | −0.199 | 0.093† | ||
| White cell count | 0.023 | 0.772 | 0.023 | 0.846 | ||
| Neutrophil count | 0.039 | 0.634 | −0.026 | 0.828 | ||
| Platelet count | −0.042 | 0.615 | <0.001 | >0.999 | ||
| Hemodynamic | ||||||
| Heart rate | 0.246 | 0.002* | 0.231 | 0.049‡ | ||
| Systolic pressure, mm Hg | 0.180 | 0.024† | 0.125 | 0.293 | ||
| Diastolic pressure, mm Hg | 0.403 | <0.001* | 0.367 | 0.001* | ||
| Mean arterial pressure, mm Hg | 0.332 | <0.001* | 0.282† | 0.016‡ | ||
| Pulse pressure, mm Hg | −0.027 | 0.740 | −0.095 | 0.423 | ||
| Emphysema indices | ||||||
| −950 HU pixel index | N/A | N/A | 0.471 | <0.001* | ||
| −910 HU pixel index | N/A | N/A | 0.476 | <0.001* | ||
| 15th Percentile density, HU | N/A | N/A | −0.409 | <0.001* | ||
Full Cohort (n = 157) | HRCT Subgroup (n = 73) | |||||
|---|---|---|---|---|---|---|
| m/s | P Value | m/s | P Value | |||
| Gender | 0.783 | 0.001† | 0.99 | 0.006‡ | ||
| Current smoking | 0.181 | 0.464 | 0.30 | 0.418 | ||
| Chronic bronchitis | 0.338 | 0.173 | 0.25 | 0.509 | ||
| Ankle edema | 0.369 | 0.195 | 0.05 | 0.906 | ||
| Inhaled corticosteroid | 0.023 | 0.929 | 0.42 | 0.322 | ||
| Long-acting β-agonist | 0.156 | 0.521 | 0.47 | 0.182 | ||
| Ischemic heart disease | 0.351 | 0.242 | 0.34 | 0.480 | ||
| Hypercholesterolemia | 0.591 | 0.095§ | 0.80 | 0.124 | ||
In the subgroup of patients who underwent HRCT, height, body mass index (BMI), heart rate, diastolic pressure, FEV1% predicted (Figure 1), and FEV1/FVC, were associated with PWV on univariate analysis (Table 2). PWV was higher in patients with severe and very severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage 3 and 4) than in those with mild and moderate disease (GOLD stage 1 and 2; 9.05 vs. 8.37 m/s, P = 0.004), and was greater in men than women (0.99 m/s, P = 0.006), but there was no difference in PWV between subjects with or without a history of ischemic heart disease or between current and ex-smokers (Table 3). Pack-years of smoking history was not associated with PWV (r = −0.180, P = 0.132), or with emphysema severity (r = −0.96, P = 0.428, Figure E1). No relationship was found between high-sensitivity CRP (hsCRP) and PWV, or between leukocytes and PWV (Table 2). There was a robust and highly significant correlation between PWV and severity of emphysema regardless of which measure was used (P < 0.001; Table 2, Figure 1).
Figure 1. Associations between emphysema severity, FEV1% predicted and arterial stiffness in the high-resolution computed tomography subgroup. Scatter plots of pulse wave velocity on emphysema severity (A), and airflow limitation (B). Scatter plot of emphysema severity on airflow limitation (C). Bar chart of percentage change between first quartile of pulse wave velocity and higher quartiles in terms of airflow limitation (1 − FEV1% predicted) and emphysema severity (pixel index 910) (D).
[More] [Minimize]After multiple linear regression modeling, severity of emphysema (r2 = 0.13, P = 0.002) and mean arterial pressure (r2 = 0.08, P = 0.043) were the factors most closely associated with PWV, with BMI and gender almost reaching statistical significance (Table 4). The full model, prior to the removal of any variables, has been included on the online supplement (Table E1). In the full cohort of 157 patients including those with and without emphysema measures, height, BMI, diastolic blood pressure, and heart rate were found to be independently associated with PWV on backward multiple linear regression (Table E2).
HRCT Subjects (n = 73)* | Regression Coefficient | Standard Error | Partial r2 | t Statistic | P Value |
|---|---|---|---|---|---|
| Constant | 6.730 | 1.311 | |||
| Male gender | 0.610 | 0.339 | 0.05 | 1.78 | 0.077 |
| Body mass index, kg/m2 | −0.053 | 0.028 | 0.08 | −1.90 | 0.061 |
| Mean arterial pressure, mm Hg | 0.026 | 0.013 | 0.08 | 2.06 | 0.043 |
| Emphysema pixel index −950 | 4.648 | 1.331 | 0.15 | 3.49 | 0.001 |
We have shown that emphysema severity is associated with arterial stiffness independent of cigarette smoking. The association is also independent of age, sex, blood pressure, hsCRP, dyslipidemia, inflammation, hypoxemia, and airflow obstruction. Arterial stiffness increases cardiac afterload, impairs coronary blood flow (12), and is associated with increased cardiovascular risk in a number of conditions as well as in the general population (7–11). As such, the association between emphysema and arterial stiffness is likely to be clinically significant, as well as highly statistically significant.
The association that we found between arterial stiffness and emphysema severity was independent of low BMI, airflow limitation, and the subject's six-minute-walk distance, all of which are markers of COPD severity (30). No marker of cardiovascular risk has been validated in a COPD population. However, because arterial stiffness has previously been shown to be higher in patients with COPD than in control subjects (14), and because we have shown that that severity of emphysema is associated with arterial stiffness independent of COPD severity, longitudinal studies are now required to identify whether patients with COPD with an emphysematous phenotype are at increased cardiovascular risk compared with patients with a nonemphysematous phenotype.
In a previous study, by Sabit and colleagues, PWV was associated with IL-6, and the authors postulated that the increased systemic inflammation seen in COPD may be responsible for the observed increase in arterial stiffness (14). In a larger cohort, we did not find any association between PWV and hsCRP, whose release is stimulated by IL-6. Nor did we find a relationship between emphysema severity and hsCRP. As such, our results do not support the hypothesis that systemic inflammation is an important cause of arterial stiffness in patients with COPD. Nonetheless, we used a different measure of PWV than Sabit and colleagues (14), and there may be other circulating inflammatory factors, oxidized lipids or proteins that, through their effect on endothelium and smooth muscle, link the lung inflammation and oxidative stress that are found in patients with emphysema to the development of arterial stiffness.
Another possible mechanism to explain the association between emphysema severity and arterial stiffness is hypoxia. We did not find an association between pulse oximetry oxygen saturations and arterial stiffness after controlling for other variables. Although pulse oximetry does not directly measure tissue hypoxia, it seems unlikely, given the relatively large regression coefficient we found, that tissue hypoxia could completely account for the observed association between emphysema and PWV, even with a measure such as mixed venous oxygenation.
There are a number of pathologic features common to arterial stiffness and emphysema, which suggest that, in some individuals with COPD, there may be an acquired or inherited tendency to develop emphysema and arterial stiffness. Elastin loss (15) and increased alveolar septal thickening (31) occur in emphysema, whereas in stiff arteries, elastin fragmentation is found, together with increased numbers of collagen fibers, and increased vessel lumen size and thickness (12). In humans, a polymorphism in gelatinase B (MMP-9) is associated with increased risk of arterial stiffness (32, 33) as well as upper zone emphysema (34). In Marfan's syndrome, increased aortic root stiffness is well described and has important clinical consequences, but these patients may also develop emphysema even in the absence of cigarette smoke exposure (21).
Increased levels of MMP-9 are found both in bronchoalveolar lavage (35) and sputum (36) in subjects with emphysema, and levels of MMP-9 are increased in the serum of subjects with arterial stiffness (37). MMP-12 (macrophage elastase) knockout mice are protected against cigarette smoke–induced emphysema compared with wild-type mice (38), and MMP-12/apoE–deficient mice are protected against elastin degradation in atherosclerosis compared with single-deficiency apoE mice (39). Finally, the Klotho mouse (a model of accelerated aging) develops early emphysema, loss of skin elasticity, and increased arterial stiffness (20). Subjects with an emphysematous phenotype of COPD may therefore have a systemic susceptibility to lung, skin, and arterial connective tissue damage.
Lung and artery susceptibility to connective tissue damage could be due to congenital variation in the synthesis, destruction, and/or repair of extracellular matrix. Factors we were unable to measure, such as low birth weight, poor diet, recurrent infection, and environmental pollution, might plausibly increase the susceptibility of both the lung and vasculature to connective tissue destruction, particularly in early life (40–43). Furthermore, recent evidence that COPD may have an autoimmune component characterized by an abnormal immune response to elastin (44) is of interest, as an autoimmune mechanism linking arterial stiffness to emphysema might be amenable to therapeutic intervention. Further work is needed to elucidate these potential mechanisms, and to identify whether there are similar associations between loss of lung tissue and arterial stiffness in individuals without COPD.
In this study, we performed PWV measurement using the carotid–radial method, which is associated with coronary artery plaque burden, and increases linearly with age (45, 46). Using this technique allowed us to perform PWV with subjects lying supine at 15°, which meant we could include patients with severe dyspnea. However, carotid–femoral PWV (in which the tonometer is placed over the femoral artery), rather than carotid–radial PWV, is now the recognized “gold standard” measure of arterial stiffness (47). Carotid–femoral PWV has been shown to predict cardiovascular risk in longitudinal studies, and because it measures stiffness in the central arteries, which have comparatively little smooth muscle, carotid–femoral PWV is largely unaffected by changes in smooth muscle remodeling and vascular tone (47). No measure of arterial stiffness has been validated as a marker of cardiovascular risk in a COPD population. However, if we had shown an association between emphysema severity and arterial stiffness using carotid–femoral rather than carotid–radial PWV, a stronger case could have been made for emphysematous patients being at increased cardiovascular risk.
Nevertheless, in this cohort, using carotid–radial PWV we replicated the findings reported previously that arterial stiffness is higher in patients with severe COPD than in patients with mild and moderate COPD (14), and that FEV1 is associated with arterial stiffness after adjusting for age and height (13). The mean difference we found was smaller, and the association with FEV1 we demonstrated was weaker, than was previously described using carotid–femoral PWV (13, 14). Despite this, we found a strong association between emphysema severity and arterial stiffness (r = 0.47, P < 0.001). Consequently, had we used carotid–femoral PWV rather than carotid–radial PWV, it seems likely that we would have found an even stronger association between arterial stiffness and emphysema severity.
Other noninvasive measurements that we could have used without subjects lying completely flat include time to wave reflection and augmentation index. However, these measures of arterial stiffness are more vulnerable to the effects of heart rate, and are less useful in elderly populations (45, 48).
Ideally, we would have performed HRCT in all patients. Nevertheless, there was no evidence of selection bias in the patients undergoing CT (Table 1), and the association between PWV and emphysema severity was highly statistically significant even in this smaller sample.
In previous studies, increased BMI has been associated with increased arterial stiffness (49), presumably as a result of the effects of obesity and the metabolic syndrome. We instead found that low BMI was associated with increased PWV on univariate testing, and approached significance on multivariable testing (Table 4). However, low BMI is a marker of more severe COPD (30) and is likely to reflect a more catabolic state, which may explain this apparently contradictory finding, as well as explain why other metabolic factors such as hyperglycemia and hypercholesterolemia were not significantly associated with PWV in our cohort.
Cigarette smoke exposure has a causal relationship with both emphysema and cardiovascular disease. It was therefore important to control for smoking in our analysis. Pack-years is the most widely used measure for assessing smoke exposure retrospectively and is vulnerable to inaccuracy, but not bias (50). In 157 patients with COPD, we found no relationship between PWV and smoking pack-year history, nor did we find any relationship between smoking pack-years and emphysema severity in the HRCT subgroup. In previous work, there was no association between smoking pack-years and PWV (14), and in a recently published study on 274 subjects with COPD who underwent HRCT, there was no relationship between severity of emphysema (scored visually) and smoking pack-year history (18). We did not find a difference in PWV between current and ex-smokers, which is consistent with previous findings in a COPD population (14). Therefore, it seems reasonable to conclude that total cigarette smoke exposure is not an important determinant of emphysema or arterial stiffness severity within a group of patients with COPD, who have in effect been selected as a result of their relative susceptibility to cigarette smoke. As such, we can be reasonably confident that the association between emphysema and PWV is not due to confounding from cigarette smoke exposure.
We have shown for the first time that, in patients with COPD, severity of emphysema correlates with a measure of arterial stiffness. This association may be due to the systemic effects of COPD (inflammation, oxidative stress, and hypoxia), to environmental factors such as pollution, or to a shared susceptibility to degradation of elastin and other components of the extracellular matrix in both systemic arteries and the lung. Studies that explore a mechanism for the shared susceptibility hypothesis are now required, and may provide insights into the search for distinct phenotypes in patients with COPD as well as future therapeutic strategies to reduce cardiovascular risk in COPD.
The authors thank Joyce Barr and Andrew Deans, and the staff at the Royal Infirmary of Edinburgh Clinical Research Facility for help with data collection, and Dr. Sarah Wild and Cat Graham for advice in data analysis.
| 1. | Anthonisen NR, Connett JE, Enright PL, Manfreda J. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med 2002;166:333–339. |
| 2. | Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789. |
| 3. | Hozawa A, Billings JL, Shahar E, Ohira T, Rosamond WD, Folsom AR. Lung function and ischemic stroke incidence: the Atherosclerosis Risk in Communities Study. Chest 2006;130:1642–1649. |
| 4. | Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313:711–715. |
| 5. | Schunemann HJ, Dorn J, Grant BJ, Winkelstein W Jr, Trevisan M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 2000;118:656–664. |
| 6. | Sin DD, Man SFP. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519. |
| 7. | van Popele NM, Mattace-Raso FU, Vliegenthart R, Grobbee DE, Asmar R, van der Kuip DA, Hofman A, de Feijter PJ, Oudkerk M, Witteman JC. Aortic stiffness is associated with atherosclerosis of the coronary arteries in older adults: the Rotterdam Study. J Hypertens 2006;24:2371–2376. |
| 8. | Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation 2002;106:2085–2090. |
| 9. | Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434–2439. |
| 10. | Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39:10–15. |
| 11. | Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, Asmar R, Reneman RS, Hoeks AP, Breteler MM, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006;113:657–663. |
| 12. | Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:932–943. |
| 13. | Zureik M, Benetos A, Neukirch C, Courbon D, Bean K, Thomas F, Ducimetière P. Reduced pulmonary function is associated with central arterial stiffness in men. Am J Respir Crit Care Med 2001;164:2181–2185. |
| 14. | Sabit R, Bolton CE, Edwards PH, Pettit RJ, Evans WD, McEniery CM, Wilkinson IB, Cockcroft JR, Shale DJ. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:1259–1265. |
| 15. | Shifren A, Mecham RP. The stumbling block in lung repair of emphysema: elastic fiber assembly. Proc Am Thorac Soc 2006;3:428–433. |
| 16. | Brooke BS, Bayes-Genis A, Li DY. New insights into elastin and vascular disease. Trends Cardiovasc Med 2003;13:176–181. |
| 17. | Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension 2005;45:1050–1055. |
| 18. | Makita H, Nasuhara Y, Betsuyaku T, Onodera Y, Hizawa N, Nishimura M. Characterization of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease. Thorax 2007 [E-pub ahead of print 15 June 2007.] |
| 19. | Guerassimov A, Hoshino Y, Takubo Y, Turcotte A, Yamamoto M, Ghezzo H, Triantafillopoulos A, Whittaker K, Hoidal JR, Cosio MG. The development of emphysema in cigarette smoke-exposed mice is strain dependent. Am J Respir Crit Care Med 2004;170:974–980. |
| 20. | Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, et al. Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45–51. |
| 21. | Pyeritz RE. The Marfan syndrome. Annu Rev Med 2000;51:481–510. |
| 22. | Patel BD, Loo WJ, Tasker AD, Screaton NJ, Burrows NP, Silverman EK, Lomas DA. Smoking related COPD and facial wrinkling: is there a common susceptibility? Thorax 2006;61:568–671. |
| 23. | GOLD Executive Committee. Global strategy for the diagnosis, management, and prevention of COPD [Internet] [accessed on 11 July 2007]. Available from: http://www.goldcopd.com |
| 24. | Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al. Standardisation of spirometry. Eur Respir J 2005;26:319–338. |
| 25. | American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–117. |
| 26. | AtCor Medical. Measuring pulse wave velocity [Internet] [accessed on 11 July 2007]. Available from: http://atcormedical.com |
| 27. | Bergin C, Müller N, Nichols DM, Lillington G, Hogg JC, Mullen B, Grymaloski MR, Osborne S, Paré PD. The diagnosis of emphysema: a computed tomographic–pathologic correlation. Am Rev Respir Dis 1986;133:541–546. |
| 28. | Gevenois PA, de Maertelaer V, De Vuyst P, Zanen J, Yernault JC. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1995;152:653–657. |
| 29. | Gevenois PA, De Vuyst P, Sy M, Scillia P, Chaminade L, de Maertelaer V, Zanen J, Yernault JC. Pulmonary emphysema: quantitative CT during expiration. Radiology 1996;199:825–829. |
| 30. | Celli BR, Cote CG, Marin JM, Casanova C, Montes DO, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005–1012. |
| 31. | Lang MR, Fiaux GW, Gillooly M, Stewart JA, Hulmes DJ, Lamb D. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994;49:319–326. |
| 32. | Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 2004;24:1479–1484. |
| 33. | Zhou S, Feely J, Spiers JP, Mahmud A. Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension. J Hum Hypertens 2007;21:861–867. |
| 34. | Ito I, Nagai S, Handa T, Muro S, Hirai T, Tsukino M, Mishima M. Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema. Am J Respir Crit Care Med 2005;172:1378–1382. |
| 35. | Finlay GA, Russell KJ, McMahon KJ, D'Arcy EM, Masterson JB, FitzGerald MX, O'Connor CM. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997;52:502–506. |
| 36. | Boschetto P, Quintavalle S, Zeni E, Leprotti S, Potena A, Ballerin L, Papi A, Palladini G, Luisetti M, Annovazzi L, et al. Association between markers of emphysema and more severe chronic obstructive pulmonary disease. Thorax 2006;61:1037–1042. |
| 37. | Yasmin SW, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, Ashby MJ, Cockcroft JR, Wilkinson IB. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:372. |
| 38. | Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:2002–2004. |
| 39. | Luttun A, Lutgens E, Manderveld A, Maris K, Collen D, Carmeliet P, Moons L. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 2004;109:1408–1414. |
| 40. | Cheung YF, Wong KY, Lam BC, Tsoi NS. Relation of arterial stiffness with gestational age and birth weight. Arch Dis Child 2004;89:217–221. |
| 41. | Martyn CN, Greenwald SE. Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet 1997;350:953–955. |
| 42. | Kajekar R. Environmental factors and developmental outcomes in the lung. Pharmacol Ther 2007;114:129–145. |
| 43. | Mills NL, Törnqvist H, Robinson SD, Gonzalez M, Darnley K, MacNee W, Boon NA, Donaldson K, Blomberg A, Sandstrom T, et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation 2005;112:3930–3936. |
| 44. | Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, Green L, Hacken-Bitar J, Huh J, Bakaeen F, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med 2007;13:567–569. |
| 45. | McEniery CM, Yasmin SW, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005;46:1753–1760. |
| 46. | McLeod AL, Uren NG, Wilkinson IB, Webb DJ, Maxwell SR, Northridge DB, Newby DE. Non-invasive measures of pulse wave velocity correlate with coronary arterial plaque load in humans. J Hypertens 2004;22:363–368. |
| 47. | Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588–2605. |
| 48. | Sakurai M, Yamakado T, Kurachi H, Kato T, Kuroda K, Ishisu R, Okamoto S, Isaka N, Nakano T, Ito M. The relationship between aortic augmentation index and pulse wave velocity: an invasive study. J Hypertens 2007;25:391–397. |
| 49. | Mitchell GF, Guo CY, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D. Cross-sectional correlates of increased aortic stiffness in the community: the Framingham Heart Study. Circulation 2007;115:2628–2636. |
| 50. | Bernaards CM, Twisk JW, Snel J, Van Mechelen W, Kemper HC. Is calculating pack-years retrospectively a valid method to estimate life-time tobacco smoking? A comparison between prospectively calculated pack-years and retrospectively calculated pack-years. Addiction 2001;96:1653–1661. |
