Rationale: Impaired vascular reactivity is an important factor in the pathogenesis of cardiovascular disease.
Objectives: We sought to assess vascular reactivity in patients with chronic obstructive pulmonary disease (COPD) and respective control subjects, and to investigate the relation between vascular function and airflow obstruction and systemic inflammation.
Methods: We studied 60 patients with stable COPD; 20 smokers with normal lung function matched for age, sex, and body weight; and 20 similarly matched nonsmokers. Patients with cardiovascular comorbidities were excluded. The endothelium-dependent and endothelium-independent function of the vasculature was measured using flow-mediated and nitrogen-mediated dilation of the brachial artery, respectively. Systemic inflammatory markers, including C-reactive protein, fibrinogen, and interleukin (IL)-6, were determined in serum.
Measurements and Main Results: Both flow-mediated and nitrogen-mediated dilation of the brachial artery were significantly lower in patients with stable COPD than in smoking and nonsmoking control subjects. Levels of inflammatory mediators such as IL-6 and fibrinogen were higher in patients than they were in control subjects. In patients with COPD, stepwise multiple regression analysis showed that age, sex, baseline brachial artery diameter, C-reactive protein level, leukocyte count, blood glucose level, and percentage of predicted forced expiratory volume in 1 s were independent predictors of flow-mediated dilation. There was no relation between flow-mediated dilation and pack-years of smoking. Baseline brachial artery diameter was the only independent predictor of nitrogen-mediated dilation in patients with COPD.
Conclusions: Both endothelium-dependent and endothelium-independent vasodilation is significantly impaired in patients with stable COPD. Airflow obstruction and systemic inflammation may increase the risk of cardiovascular disease in patients with COPD.
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk of cardiovascular disease. The mechanism for this relationship, however, remains unknown.
Impaired flow-mediated dilation was strongly related to systemic inflammation and airway obstruction, which may help explain the increased cardiovascular morbidity in patients with COPD.
Several authors have reported abnormalities in systemic vascular function in patients with COPD, providing additional support for the link between COPD and cardiovascular disease (10–12). Flow-mediated vasodilation is an endothelium-dependent function that can be measured in forearm human circulation and quantified as an index of vasomotor function (13). Flow-mediated vasodilation is an independent predictor of cardiovascular morbidity and mortality (14) and correlates well with invasive assessment of coronary artery endothelial function (15) and severity of coronary artery disease (16). Several studies have shown impaired endothelial function using this technique in conditions associated with systemic inflammation such as diabetes (17), rheumatoid arthritis (18), and polycystic ovarian syndrome (19). A recently published study furthermore suggests a relation between flow-mediated vasodilation and forced expiratory volume in 1 second (FEV1) and emphysema severity in patients with COPD (10). That report, however, did not address the role of systemic inflammation and its relation with endothelial function in COPD. This is of particular importance because there is experimental evidence on a molecular level of impaired endothelial function in response to inflammatory markers, such as C-reactive protein (20, 21). Thus, we sought to use measurements of systemic vascular function in patients with stable COPD and respective controls and to investigate the relation between airflow obstruction, systemic inflammation, and endothelium-dependent as well as endothelium-independent function of the vasculature. Some of the results of this study have been previously reported in the form of an abstract (22).
Participants were explained the study protocol and potential hazards during a personal interview. All subjects gave written informed consent. The study was approved by the Ethics Committee of the Vienna City Council.
The study population consisted of patients with stable COPD; smokers matched for age, sex, and body weight; and matched nonsmoking control subjects without airflow obstruction.
A total of 1,074 patients with COPD were screened for eligibility from the Otto-Wagner-Hospital's outpatient clinic database. Inclusion criteria for patients with stable COPD included an age of 40 to 75 years, a body mass index of less than 30 kg/m2, 20 pack-years or more of cigarette smoking, and evidence of airflow obstruction on spirometry. Our aim was to recruit an equal number of patients with mild (FEV1 predicted 50–70%), moderate (FEV1 30–50%), and severe COPD (FEV1 < 30%). Stable COPD was defined as no exacerbations during at least three visits in the previous 4 months, with no changes in respiratory medication and no symptoms of a lower respiratory tract infection. Patients included in the study were not taking oral corticosteroids or other acute or chronic medication that could influence endothelial function (e.g., statins or angiotensin-converting enzyme inhibitors). Patients with known cardiovascular comorbidities were excluded. Patients with COPD receiving long-term oxygen therapy were not excluded. (Additional details of the exclusion criteria are provided in the online supplement.) Similar criteria were applied to smoking control subjects, except for the absence of lung disease by clinical evaluation, chest radiograph, and spirometry. Inclusion criteria for nonsmoking control subjects were the same, except that these participants were life-long nonsmokers. Control subjects were recruited from the general population during a lung function day organized by the hospital. Smoking control subjects and current smokers with COPD were asked to refrain from smoking for at least 6 hours before testing (23). Abstinence from smoking was assessed by measuring expiratory carbon monoxide using a cutoff level of less than 10 ppm.
Study participants provided a detailed medical history and were given a physical examination that included blood pressure measurement, electrocardiogram, arterial blood gas analysis, lung function testing, and assessment of endothelial function of the brachial artery after reactive hyperemia. Blood samples were obtained from all participants to analyze complete blood count and systemic inflammatory markers such as interleukin-6 (IL-6), fibrinogen levels, and C-reactive protein levels. Spirometry was done according to the recommendations of the European Respiratory Society (24). Arterial blood gas was analyzed with the patients breathing room air.
Endothelium-dependent, flow-mediated dilation after reactive hyperemia, as well as endothelium-independent, nitroglycerine-mediated dilation of the brachial artery, were assessed using ultrasound according to the recommended guidelines (13). To account for differences in vessel diameter between the study groups, the ratio of flow-mediated dilation and baseline brachial artery diameter was taken as an index of diameter-independent impairment of vascular reactivity. Additional details on the method of taking these measurements are provided in the online supplement.
All data are expressed as frequencies (percentages) for normally distributed data either as (arithmetic) means ± SD or medians with interquartile range (Q1 = 25% to Q3 = 75%) for skewed distributions. Intergroup comparison of normally distributed parameters was performed using the independent t test. The Mann-Whitney U was performed for comparison of not normally distributed parameters. Depending on data distribution, either a Pearson or Spearman correlation coefficient was calculated to determine relations between ultrasound measurements, clinical characteristics, lung function parameters, and laboratory markers, both in the total sample and in patients with COPD specifically. Multivariate analyses with several potentially confounding factors were done with percentage of flow-mediated vasodilation or percentage of nitroglycerine-mediated dilation as the dependent variable, respectively. Values for P less than 0.05 were accepted statistically significant differences, with a Bonferroni correction reported for multiple comparisons. All statistics were analyzed with SPSS software (Statistical Product and Services Solutions, version 13.0; SPSS Inc., Chicago, IL).
From the database of 1,074 patients with COPD, 190 patients (17.6%) met the inclusion criteria and 884 (82.4%) were excluded (Figure 1). Of the 190 patients, 60 patients were finally included in this study.
The clinical characteristics, lung function results, and cardiovascular parameters of the study population are summarized in Table 1. The groups were well matched with respect to age, body weight, and arterial blood pressure measurements. There were statistically significant differences in lung function, heart rate, and arterial PaO2 measurements between patients with COPD and smoking and nonsmoking control subjects without airflow obstruction. Patients with COPD had a longer pack-year smoking history than did smoking control subjects (66 ± 39 pack-years versus 39 ± 23 pack-years, P < 0.001); however, the proportion of current smokers was statistically significantly lower in the patient group than it was in smoking control subjects. Smoking abstinence before testing was confirmed in all subjects: Similar carbon monoxide expiratory levels were found in smokers with COPD (n = 26; expiratory CO, 7.0 ± 2.6 ppm) and in smoking control subjects without airflow obstruction (expiratory CO, 7.7 ± 2.6 ppm). Of the patients with COPD, all were prescribed inhaled short-acting and/or long-acting bronchodilators, 45 patients (75%) were receiving inhaled corticosteroids, and 14 patients (23%) were on long-term oxygen therapy. Further information on patient characteristics are provided in Table E1 in the online supplement.
Nonsmoking Control Subjects (n = 20)
Smoking Control Subjects (n = 20)
Patients with COPD (n = 60)
|Age, yr||62 ± 11||59 ± 9||62 ± 8|
|Male sex, %||35||40||55|
|Body mass index, kg/m2||25 ± 3||26 ± 3||25 ± 4|
|Current smokers, %||0||100||43*|
|Smoking history, pack-years||0||39 ± 23†||66 ± 39*‡|
|Expiratory carbon monoxide levels, ppm||4.8 ± 2.1||7.7 ± 3.6†||7.0 ± 2.6‡|
|FVC, % predicted||103 ± 16||104 ± 13||79 ± 17*‡|
|FEV1, % predicted||101 ± 16||99 ± 12||41 ± 18*‡|
|FEV1%VC, % predicted||84 ± 10||82 ± 8||43 ± 15*‡|
|Arterial blood gas analysis|
|Arterial Po2, mm Hg||84 ± 10||83 ± 7||66 ± 10*‡|
|Arterial Pco2, mm Hg||37 ± 4||36 ± 4||39 ± 5|
|Systolic blood pressure, mm Hg||126 ± 10||121 ± 12||125 ± 13|
|Diastolic blood pressure, mm Hg||75 ± 6||73 ± 9||76 ± 6|
|Mean blood pressure, mm Hg||92 ± 6||89 ± 8||92 ± 8|
| Heart rate, bpm||72 ± 13||73 ± 16||87 ± 18*‡|
The study groups were well matched with respect to traditional cardiovascular risk factors, such as cholesterol, triglyceride, and blood glucose levels (Table 2). There were no statistically significant differences in blood leukocyte counts between patients and control subjects. However, patients with COPD had statistically significantly higher plasma fibrinogen concentrations (median [interquartile range]: 426 mg/dl [range, 354–472 mg/dl]) compared with nonsmoking control subjects (382 mg/dl [range, 317–428 mg/dl], P < 0.05). Similarly, we observed that IL-6 serum levels were statistically significantly higher in patients with COPD than they were in nonsmokers. There were no statistically significant differences in these laboratory markers between patients with mild, moderate, and severe COPD (Table E2).
Nonsmoking Control Subjects (n = 20)
Smoking Control Subjects (n = 20)
Patients with COPD (n = 60)
|Traditional cardiovascular risk factors|
|Total cholesterol, mg/dl||187 ± 23||196 ± 20||187 ± 26|
|Triglycerides, mg/dl||92 ± 38||105 ± 39||103 ± 33|
|HDL, mg/dl||82 ± 18||72 ± 21||77 ± 26|
|LDL, mg/dl||113 ± 37||118 ± 28||107 ± 34|
|Glucose, mg/dl||90 ± 9||88 ± 9||92 ± 13|
|HbA1c, %||5.4 ± 0.2||5.3 ± 0.2||5.5 ± 0.4|
|Systemic inflammatory markers|
|Leukocytes, ×103/UL||7.2 (5.4–8.2)||7.5 (6.2–9.3)||7.9 (6.2–9.1)|
|Fibrinogen, mg/dl||382 (317–428)||367 (342–411)||426* (354–472)|
|C-reactive protein, mg/l||2.0 (1.0–4.8)||2.0 (1.0–4.0)||4.0 (2.0–7.0)|
| IL-6, pg/ml||1.0 (0.7–1.8)||2.1 (1.5–3.4)||2.5† (1.6–5.3)|
Ultrasound assessment of vascular reactivity was well tolerated in all subjects, none of whom had evidence of brachial artery atherosclerotic plaque on ultrasound scanning. Baseline brachial artery diameter was statistically significantly higher in patients with COPD than it was in nonsmoking control subjects (3.64 ± 0.63 mm versus 3.28 ± 0.61 mm, P = 0.031). There were, however, no statistically significant differences among patients with COPD, smokers, and nonsmokers regarding blood flow velocity through the brachial artery at rest (baseline flow), during reactive hyperemia, or after sublingual application of nitroglycerine (Table 3). This indicates that the physical stimulus for flow-mediated vasodilation and nitroglycerine-mediated dilation was comparable in all groups.
Nonsmoking Control Subjects (n = 20)
Smoking Control Subjects (n = 20)
Patients with COPD (n = 60)
|Flow-mediated dilation, %||19 ± 3||16 ± 2*||11 ± 3†‡|
|Nitroglycerine-mediated dilation, %||29 ± 7||26 ± 7||22 ± 6§|
|Baseline brachial artery diameter, mm||3.28 ± 0.61||3.49 ± 0.57||3.64 ± 0.63§|
|Flow-mediated dilation%/Baseline brachial artery diameter||0.21 ± 0.03||0.18 ± 0.02*||0.15 ± 0.04†‡|
|Baseline flow, m/s||0.8 ± 0.2||0.8 ± 0.3||0.8 ± 0.2|
|Hyperemic flow, m/s||1.7 ± 0.3||1.7 ± 0.4||1.6 ± 0.4|
|Nitrogen-induced flow, m/s||0.8 ± 0.2||0.8 ± 0.3||0.8 ± 0.2|
|Hyperemia, %||116 ± 34||98 ± 41||107 ± 47|
After release of suprasystolic compression, patients with stable COPD had a statistically significantly lower flow-mediated vasodilation response (11 ± 3%), expressed as a percentage of change over the baseline diameter, than did smokers (16 ± 2%, P < 0.005) and nonsmoking control subjects (19 ± 3%, P < 0.001) without airflow obstruction (Figure 2). Patients with COPD had a significantly lower ratio of flow-mediated dilation to baseline brachial artery diameter compared with both smoking and nonsmoking control subjects (P < 0.01 for both). Furthermore, there was a statistically significant difference in the percentage of nitroglycerine-mediated dilation between patients with COPD and nonsmoking control subjects (22 ± 6% versus 29 ± 7%, P = 0.02), but there was no statistically significant difference compared with smokers without COPD.
There were no statistically significant differences in baseline brachial artery diameter, blood flow velocity, percentage of flow-mediated vasodilation (Figure E1), or percentage of nitroglycerine-mediated dilation between patients with mild, moderate, and severe COPD (Table E3).
In the entire study population (n = 100), statistically significant relations were observed on univariate analyses between percentage of flow-mediated vasodilation and age, FEV1% predicted, FEV1%FVC (forced vital capacity), leukocyte count, C-reactive protein, IL-6, resting heart rate, percentage of nitroglycerine-mediated dilation, and baseline brachial artery diameter (Table 4). Within the patient group (n = 60), FEV1% predicted (Figure 3A), FEV1%FVC, C-reactive protein (Figure 3B), and baseline brachial artery diameter were statistically significantly related with the percentage of flow-mediated vasodilation. Despite statistical significance between percentage of flow-mediated vasodilation and total cholesterol levels in patients with COPD, there were no statistically significant relations between percentage of flow-mediated vasodilation and other cardiovascular risk factors, including pack-years of smoking (Figure E2), body mass index, triglyceride levels, or blood glucose levels. With respect to measurements of percentage of nitroglycerine-mediated dilation, on univariate analyses there were statistically significant correlations with age (r = −0.376, P < 0.001), blood glucose levels (r = −0.271, P = 0.008), FEV1% (r = 0.243, P = 0.018), and heart rate (r = −0.196, P = 0.058).
All Subjects (n = 100)
Subjects with COPD (n = 60)
|r Value||P Value||r value||P Value|
|Body mass index, kg/m2||−0.002||0.986||−0.048||0.716|
|Smoking, pack-years (n = 80)||−0.163||0.149||−0.013||0.919|
|Inhaled corticosteroid use, yes/no||n.a.||n.a.||−0.183||0.161|
|Inhaled corticosteroid use, puffs/d||n.a.||n.a.||−0.064||0.625|
|Lung function parameters|
|FEV1, % predicted||0.609||< 0.001||0.302||0.024|
|Leukocyte count (G/L)||−0.194||0.051||−0.233||0.075|
|C-reactive protein, mg/l||−0.383||< 0.005||−0.376||0.003|
|Interleukin-6, pg/ml||−0.294||< 0.005||−0.128||0.337|
|Heart rate, beats/min||−0.270||0.005||−0.168||0.215|
|Systolic blood pressure, mm Hg||−0.136||0.177||−0.198||0.129|
|Nitroglycerine mediated dilation, %||0.700||< 0.001||0.636||< 0.001|
| Brachial artery diameter, mm||−0.435||< 0.001||−0.494||< 0.001|
Associations between percentage of flow-mediated vasodilation and percentage of nitroglycerine-mediated dilation as the dependent variables and age, sex, body mass index, pack-years of smoking, FEV1% predicted, baseline brachial artery diameter, total cholesterol, triglyceride levels, blood glucose levels, leukocyte cell count, blood fibrinogen, C-reactive protein, IL-6, systolic blood pressure, heart rate, inhaled corticosteroid use, and long-term oxygen therapy use were further investigated using stepwise multiple regression analyses in patients with COPD. Table 5 shows the results of multiple regression analyses for the flow-mediated vasodilation response. The following factors were independently associated with percentage of flow-mediated vasodilation in the patient group: age (P < 0.001), sex (P = 0.001), brachial artery diameter (P < 0.001), C-reactive protein levels (P = 0.001), leukocyte count (P = 0.004), blood glucose levels (P = 0.014), and FEV1% predicted (P = 0.046). The strongest independent predictor of the postocclusion nitroglycerine-mediated dilation response in the patient group was the baseline brachial artery diameter (Table E4).
|Age, yr||−0.501||0.059||< 0.001|
|Body mass index, kg/m2||0.014||0.108||0.899|
|Brachial artery diameter, mm||−0.530||0.832||0.001|
|FEV1, % predicted||0.225||0.022||0.046|
|Leukocyte count, G/L||−0.310||0.186||0.004|
|C-reactive protein, mg/l||−0.402||0.088||0.001|
|Interleukin 6, pg/ml||0.167||0.161||0.226|
|Blood glucose, mg/dl||0.306||0.035||0.014|
|Heart rate, beats/min||−0.218||0.025||0.079|
|Systolic blood pressure, mm Hg||0.001||0.031||0.993|
|Inhaled corticosteroid use||−0.097||1.039||0.416|
|Long-term oxygen therapy use||−0.116||0.925||0.320|
The present study investigated systemic vascular function of the brachial artery in patients with stable COPD and smokers and nonsmokers without COPD matched for age and body mass index. We found statistically significantly differences in baseline brachial artery diameter and endothelium-dependent and -independent vasodilation in patients with COPD compared with the respective control groups. We also saw statistically significant relations between flow-mediated dilation with markers of systemic inflammation and severity of airflow obstruction, both in the total sample and in patients with COPD, specifically. The reported findings in patients with COPD were independent of smoking history.
The principle of flow-mediated vasodilation is an increase in flow through the brachial artery, which is induced by causing postischemic (nitric oxide–mediated) vasodilatation in the downstream vascular bed of the distal forearm. Flow-mediated vasodilation has been shown to correlate well with invasive use of acetylcholine infusion to assess coronary artery endothelial function (15). A reduction in the flow-mediated vasodilation response suggests the presence of endothelial dysfunction. Endothelial dysfunction, in turn, is a key early event in atherogenesis and an independent predictor of cardiovascular diseases appearing long before the formation of structural atherosclerotic changes (25). Changes in vessel wall in early atherosclerosis, however, may not be limited to the endothelium and a reduction in vasodilation in response to endothelium-derived and exogenous sources of nitric oxide (NMD) may also be mediated by changes in vascular smooth muscle function. Adams and coworkers have previously shown that smooth muscle dysfunction becomes apparent with increasing number of cardiovascular risk factors, resulting in an impaired NMD response independently from endothelial dysfunction (26).
In the present study we observed an impairment in both FMD and NMD response in patients with COPD compared with smoking and nonsmoking control subjects, suggesting an increased cardiovascular risk in this population (25, 26). In fact, a recent health care database cohort study of more than 10,000 patients reported that patients with COPD were two to four times more likely to die of cardiovascular disease at 3-year follow-up than were age- and sex-matched control subjects without COPD (27). Furthermore, there is epidemiologic evidence of a link between FEV1 and cardiovascular mortality (28, 29).
We have to acknowledge, however, that our findings were largely influenced by differences in baseline brachial artery diameter between the study groups (30). We have no immediate explanation for the differences in vessel size; however, Holubkov and coworkers (31) observed that a large size of the resting brachial artery diameter itself serves as an independent predictor of angiographically verified coronary artery disease. We further observed statistically significant differences in the ratio of flow-mediated dilation to baseline brachial artery diameter between the groups, suggesting that there is a diameter-independent impairment of vascular reactivity in patients with COPD over and above the impairment related to smoking. It appears, however, that this occurs at smooth muscle rather than endothelial level, as the response of the brachial artery to nitroglycerin (NMD) was also impaired, and hence that the smooth muscle response to endogenous and exogenous sources of nitric oxide was decreased (26).
Few recent studies similarly investigated systemic vascular function as a surrogate of cardiovascular risk in patients with COPD. Sabit and colleagues (11) studied arterial stiffness using pulse wave velocity in 75 clinically stable patients with COPD and 43 healthy smoking control subjects free of cardiovascular disease. The authors observed pronounced arterial stiffness in patients compared with control subjectss and statistically significant relationships between pulse wave velocity and percentage predicted FEV1, suggesting increased cardiovascular risk with increasing airflow obstruction in COPD. McAllister and coworkers (12) extended these findings by demonstrating that in addition to FEV1, emphysema severity based on quantitative CT scans was revealed as the most powerful predictor of arterial stiffness. The latter reports support our observations as the underlying pathology of arterial stiffness includes endothelial and vascular smooth muscle dysfunction, as well as elastin loss and thus increased vessel lumen size (32).
Barr and colleagues (10) studied flow-mediated dilation in 107 former smokers, including 42 patients with mild to severe COPD. Consistent with our findings, Barr and colleagues found a statistically significant relation between flow-mediated vasodilation and FEV1; however, the corresponding mean flow-mediated vasodilation was much lower in Barr and colleagues' report (flow-mediated vasodilation, 3.8 ± 3.1%) as opposed to the values in our work (flow-mediated vasodilation, 11 ± 3%). It is noteworthy that the authors measured the flow-mediated vasodilation response to forearm occlusion in contrast to placing the cuff around the upper arm, as was done in our study. Studies have variably used either upper arm or forearm cuff occlusion, and there is no consensus as to which technique is more accurate or more precise. When the cuff is placed on the upper part of the arm, reactive hyperemia typically elicits a greater percentage of change in diameter compared with the change produced by placement of the cuff on the forearm (13). Because of these methodologic differences, it is difficult to directly compare our findings with those of Barr and colleagues (10); however, the consistent relation observed between flow-mediated vasodilation and FEV1 in both studies suggests a link between vasodilator reactivity of the vasculature and COPD pathology. The precise mechanisms for this relation, however, are not clear.
Smoking is a major risk factor for endothelial dysfunction and COPD. Studying current and former smokers without evidence of other cardiovascular risk factors, Celermajer and colleagues (33) demonstrated a dose-dependent inverse relation between pack-years of smoking and flow-mediated vasodilation. The authors further observed overall higher flow-mediated vasodilation in former smokers compared with current smokers, suggesting some degree of reversibility of the adverse effects of cigarette smoke on the endothelium. This is why we sought to ensure abstinence from acute smoking and to adjust our results for pack-years of smoking. Consistent with previous reports, however, we did not find a relation between smoking pack-years and systemic vascular abnormalities in patients with COPD (11, 12). We therefore assume that factors other than smoking exert greater influences on systemic vascular function in patients with COPD.
Increased systemic inflammation may have an effect on the relation between systemic vascular function and COPD (11). There is cumulating evidence that systemic inflammation in COPD may play an important role in the pathogenesis and prediction of cardiovascular disease (9, 34). In patients with COPD, one mechanism for this may be an increase in proatherogenic markers such as circulating levels of IL-6, fibrinogen, and C-reactive protein (1, 2, 7, 35). Among these, C-reactive protein has emerged as one of the most important predictors of myocardial infarction, stroke, and vascular death in several settings (36). C-reactive protein, however, is not only a marker but also a mediator of atherogenesis. C-reactive protein, at concentrations known to predict vascular disease, directly stimulates diverse early atherosclerotic processes, including endothelial cell adhesion molecules (37) and macrophage low-density lipoprotein uptake (38). In addition, there have been recent reports of a direct effect of C-reactive protein on endothelial function (20, 21). Verma and colleagues (21) demonstrated down-regulation of endothelial nitric oxide synthase in endothelial cells that had been incubated with C-reactive protein, resulting in a statistically significant reduction in basal and stimulated nitric oxide release. A reduction in vascular nitric oxide bioavailability, in turn, is associated with impaired endothelium-dependent vasodilation, one of the earliest detectable vascular changes before atherosclerotic plaque development (39).
Several clinical reports support the observed relation between C-reactive protein and impaired flow-mediated dilation in our report (40–42). Studying 128 smokers without airflow obstruction, Verma and associates (40) observed a statistically significant relation between C-reactive protein and vascular endothelial function. Studying 88 patients with peripheral arterial disease, Brevetti and associates (41) similarly observed that flow-mediated vasodilation correlated negatively with circulating concentrations of C-reactive protein and fibrinogen, but the authors found no association with traditional cardiovascular risk factors. These findings may suggest that the influence of systemic inflammation in conditions such as COPD (but also including other chronic inflammatory diseases such as diabetes and rheumatoid arthritis) may exceed that of traditional risk factors in affecting endothelial function (43). The absence of a relation between flow-mediated vasodilation with pack-years of smoking, body mass index, and triglyceride and cholesterol levels reported here may support such a view. The lack of a correlation, however, also may be attributed to the study, which had a stringent selection process that basically excluded all patients with clinically or laboratory-diagnosed cardiovascular risk factors.
We also identified age and sex as independent predictors of flow-mediated vasodilation, both in the total sample and in patients with COPD. These observations confirm previously reported age- and sex-related differences in the endothelium-dependent vascular response (44). The latter phenomenon may be explained by a steep decline in the female endothelial function commencing at around the time of menopause, thus suggesting a protective effect of estrogens on the vessel wall (45).
Another important limitation of our study is the potential confounding effect of pulmonary hypertension in patients with COPD. Peinado and coworkers (46) reported impaired endothelial-dependent relaxation of the pulmonary arteries in resected lung specimens and suggested that this might contribute to the development of pulmonary hypertension in COPD. It is likely that some of our patients had secondary pulmonary hypertension; however, it would have had required catheterization of the right side of the heart to rule out pulmonary hypertension in these patients, because the sensitivity of less-invasive diagnostic methods such as echocardiography in patients with COPD is rather low (47).
In conclusion, we observed impaired endothelial-dependent and endothelium-independent vascular function in patients with COPD compared with control subjects. The association between systemic inflammation, airway obstruction, and abnormal systemic vascular function may provide an explanation for the increased risk of cardiovascular disease in patients with COPD.
The authors are grateful to Ralf Zwick for his help in conducting the study. The authors thank Prof. Celermajer for his helpful comments. They further acknowledge Brigitte Konta and Wilhelm Frank for their assistance in statistical analysis. They appreciate the help by Prof. Bettelheim and the laboratory staff from the Otto-Wagner-Hospital.
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