Subclinical cardiovascular changes in chronic obstructive pulmonary disease patients: Doppler ultrasound evaluation

Introduction: Chronic obstructive pulmonary disease (COPD) is a disease characterized by progressive poorly reversible airway obstruction. COPD is associated with chronic systemic inflammation, hypercoagulable status, platelet activation, and oxidative stress. These factors may result in subclinical cardiovascular diseases (CVD): for example, carotid atherosclerosis, peripheral arterial diseases, and coronary artery diseases. Aims: The aim of this case-control study was the detection of subclinical CVD in COPD patients. Settings and design: This was a case-control study. Materials and methods: A total of 62 COPD patients and 62 healthy volunteers were enrolled in the present study. All patients were subjected to full medical history and clinical examination, chest radiography, arterial blood gas analysis, laboratory assessment of C-reactive protein, complete blood count, lipid profile, spirometry, transthoracic echocardiography, carotid Doppler ultrasound, and measurement of ankle-brachial index. A comparison between COPD and control groups regarding different parameters was performed, and a comparison between different stages of COPD regarding different parameters was also performed. Results: The carotid intima-media thickness and carotid plaques were significantly higher, whereas the ankle-brachial index was significantly lower in COPD patients compared with the control group, with no differences observed in different stages of COPD. Pulmonary hypertension and right ventricular dilatation were significantly common in COPD patients compared with the control group, and they were significantly increased with progressive stages of COPD. Pulmonary artery systolic pressure and carotid intima-media thickness showed a significant negative correlation with PaO 2 , but showed a significant positive correlation with PaCO 2 . Conclusion: COPD is a risk factor for subclinical CVD, mainly carotid artery atherosclerosis and peripheral arterial diseases.


Introduction
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease that is characterized by progressive and persistent air fl ow limitation with an enhanced infl ammatory response to noxious gases both in the airways and the lungs. Th e disease severity is exaggerated by exacerbations and comorbidities [1]. Th e WHO predicts that COPD will become the third leading cause of death and the fi fth leading cause of disability by 2020 [2]. Extrapulmonary manifestations of COPD include weight loss, nutritional abnormalities and skeletal mass dysfunction, cardiovascular diseases (CVD), osteoporosis, anxiety and depression, lung cancer, infections, metabolic syndrome, and diabetes [3].
Smoking, which is a risk factor for both COPD and CVD, leads to oxidative stress, which directly aff ects the endothelium, causing both humeral and cellular systemic infl ammation and activation of coagulation factors, leading to cardiovascular complications [4]. Extrapulmonary manifestations are more common in patients with COPD than in smokers without COPD, which suggests that COPD may be an independent risk factor for these manifestations [5]. Th e specifi c cellular mechanisms by which systemic infl ammation plays a role in the pathogenesis of CVD are complex. However, some studies revealed the importance of systemic infl ammation in plaque initiation, development, and rupture. Th e atherosclerotic process starts with injury to the vascular endothelium, which becomes more permeable by a variety of factors, including systemic infl ammation and oxidative stress [6]. In addition to the role of proteases in the pathogenesis of COPD, extracellular proteases cause breakdown of the vascular endothelia, leading to vascular remodeling and development of atherosclerosis. Elastin degradation and disorders of elastic fi bers increase with aging, resulting in atherosclerosis and nonvascular diseases, mainly emphysema [7]. 10.0 MHz (Aloka Echo Camera SSD-3500; Aloka Pro-sound; Japan ultrasound) the carotid intima-media thickness (CIMT) was considered abnormal if it is 1 mm or more. Th e extent, the location, and the characteristics of atherosclerotic plaques in the common carotid artery and the internal carotid artery were documented with gray-scale imaging [8]. (7) Assessment of the ankle-brachial index (ABI) was performed using a bidirectional blood fl ow meter with a wave form display of 8 MHz and a precalibrated mercury sphygmomanometer. Th e ABI was calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. Th e ABI was calculated for each leg, and the lower value was the patient's overall ABI. An abnormal value in either leg indicates peripheral artery disease. Diagnostic criteria for the ABI were standardized as follows: most healthy adults have a value greater than 1.0; a value of less than 0.91 is consistent with signifi cant peripheral artery disease and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 refl ects noncompressibility of the leg arteries and is not diagnostic [9]. (8) Laboratory evaluation including a complete blood count, C-reactive protein (CRP), and lipid profi le including LDL, HDL, cholesterol, and triglyceride were measured.

Exclusion criteria
(1) Patients with known cardiac disease, for example, cardiomyopathy, valvular heart diseases, and coronary artery diseases. (2) Patients with hypertension and/or dyslipedemia.
(3) Patients with respiratory disorders other than COPD.

Statistical analysis
We used the SPSS statistical software, 16.00 (Lead Technologies Inc., Chicago, Illinois, USA) for statistical analyses. Diff erent numeric variables were expressed as mean ± SD; COPD patients and healthy control groups were compared regarding diff erent parameters using the t-test. Also, diff erent stages of COPD were compared with regard to CIMT, ABI, and echocardiographic parameters. Categorical variables were expressed as absolute numbers and percentages. Comparisons between two groups were analyzed by the independent-sample t-test for continuous variables a nd the χ 2 -test for discrete variables. A Spearman rank univariate correlation study was conducted for correlation between two continuous variables.

Materials and methods
Th e present case-control observational study was conducted in the Departments of Chest Diseases, Internal Medicine, and Radiology, Faculty of Medicine, Assiut University Hospital, where 62 patients with COPD and 62 healthy volunteers were included.
Written informed consents were obtained from all participants according to national Ethics Committee.
Individuals of both groups were subjected to the following: (1) Detailed history and physical examination.
(2) Chest radiography.  [10]. Even in the absence A P-value of less than 0.05 was considered to be statistically signifi cant.

Results
Th e mean age of our COPD patients was 61.6 ± 9.1 years: 90.3% of them were male (Table 1).
Regarding cardiovascular risk factors, COPD patients had signifi cantly higher total cholesterol, LDL, triglyceride, and CRP levels. In contrast, there was an insignifi cant diff erence between both groups with regard to the smoking index and th e hemoglobin level. Most of our COPD patients were classifi ed as GOLD III (45.16%) and IV (32.26%), whereas none was classifi ed as GOLD I. We observed that COPD patients had a higher CIMT and lower ABI in comparison with the control group. Carotid plaques were observed in 22.6% of the COPD patients; the control group had no carotid plaques (Table 2 and Fig. 1). Th e PASP was signifi cantly higher in the COPD group; however, both segmental wall motion abnormalities (SWMA) and a dilated right side were observed only in COPD patients (25.8 and 45.2%, respectively), whereas it is not detected in the control group. Th e EF% was signifi cantly lower in the COPD group than in the control group, but it was still within normal range in both studied groups (Table 2). By comparing diff erent stages of COPD, we found no signifi cant diff erences between the diff erent stages regarding CIMT, the presence of plaques, and ABI.
In contrast PASP and a dilated right side increased signifi cantly with progressive staging of COPD (Table 3). Correlations between ABG parameters and cardiovascular parameters revealed signifi cant negative correlations between PaO 2 and each of PASP and CIMT, and signifi cant positive correlations between PaCO 2 and each of PASP and CIMT (Fig. 2).

Discussion
In addition to pulmonary limitations that are frequently exaggerated by COPD exacerbations, comorbidities and systemic manifestations markedly aff ect the clinical course and the prognosis of COPD [10] . CVD is one  amount; meanwhile, they disagreed with our results in that they found that the CIMT was signifi cantly correlated with a decrease in lung function, but Pobeha et al. [16], while studying the caroti d IMT in COPD, reported that the average IMT was 0.85 ± 0.22, with no signifi cant diff erence from stage II to stage IV of the disease; this result supported our fi ndings. Also, Barr et al. [17] reported that the obstructive pattern of spirometry and emphysema was associated with subclinical atherosclerosis in the carotid arteries and peripheral circulation in terms of an increased CIMT and a decreased ABI. In another study, Pecci et al. [18] observed that asymptomatic peripheral arterial diseases (PAD) highly prevalent in COPD and abnormal ABI were associated with severe COPD. In agreement with our study, Matsuoka et al. [19] observed that the prevalence of subclinical PAD in COPD patients was higher than that in healthy control smokers and the ABI in COPD patients was lower than in healthy smokers. Th ey also stated that hypoxia in advanced stages of COPD and the resulting infl ammation may play role in the pathogenesis of subclinical atherosclerosis. Our study revealed that cardiac abnormalities are more common in COPD than in the control group and this is in agreement with Freixa et al. [20] as they found that signifi cant cardiac alterations were present in 64% of the COPD patients. Th e most common were right ventricle enlargement (30%) and pulmonary hypertension (19%). Left ventricle enlargement was present in 6%, left ventricle systolic dysfunction in 13%, left ventricle diastolic impairment in 12%, and left atrial dilatation in 29% of the cases. We observed of these factors, FEV 1 was reported to be correlated with cardiovascular risk in these patients [10]. Other studies demonstrated that oxidative stress and chronic hypoxia in COPD patients may contribute to the development of CVD, but the most obvious factor is thought to be the systemic infl ammation [11]. Airway infl ammation may induce systemic infl ammation, particularly CRP production, which is also associated with the progression of atherosclerosis [12,13]. In this study, COPD patients had signifi cantly increased total cholesterol, total triglyceride, and LDL levels than controls. Th ese factors play an important role in the cardiovascular dysfunction observed in those patients. Moreover, the CRP level in our patients was signifi cantly increased compared with the control group, which acts as a serious novel cardiovascular risk factor and an infl ammatory marker. Gan et al. [14] demonstrated that levels of systemic infl ammatory markers, including the bloo d leukocyte count, CRP , interleukin-6, and fi brinogen, were elevated in patients with COPD compared with healthy controls, which agreed with our fi ndings. In the present study, we tried to assess some subclinical cardiovascular changes in patients with COPD. Regarding vascular changes, we observed a higher CIMT, a lower ABI, and an increased frequency of carotid plaques in the COPD group compared with the control group. Th is was in agreement with the results of Ozgen Alpaydin et al. [10] who reported that the COPD group had a statistically thicker carotid IM compared with controls (P < 0.001). Th ese changes were present in all stages of COPD with no signifi cant diff erences observed between them. Kim et al. [15] agreed with our results: they observed that newly diagnosed, untreated patients with COPD had a signifi cant increase in the CIMT compared with healthy individuals matched for age, sex , BMI, the smoking status, and the smoking Gray-scale assessment of CIMT demonstrating the increased thickening of the wall with the presence of a carotid plaque (white arrow). CIMT, carotid intima-media thickness .

Fig. 1
Correlations between arterial blood gas parameters and cardiovascular abnormalities in COPD patients. COPD, chronic obstructive pulmonary disease . pulmonary vasoconstrictor in normal individuals and they documented that many studies have shown a negative correlation between oxygen saturation an d pulmonary artery pressure in patients with COPD.
A positive correlation has also been shown between PaCO 2 and the pulmonary artery pressure [22]. In contrast, the presence of vascular changes in COPD patients without hypoxemia (stage II) suggest that factors other than hypoxemia and hypercapnea such as smoking, oxidative stress, and systemic infl ammation may be responsible for the development of vascular changes in these patients.

Conclusion and recommendations
Th is study found that COPD is a risk factor for many subclinical cardiovascular changes, mainly carotid artery atherosclerosis and PAD. Intervention studies attempting to reduce systemic infl ammation and to improve platelet function and endothelial function and large-vessel stiff ness in COPD patients are required. In addition, large prospective intervention studies with antiplatelet agents and statins would be benefi cial .
that PASP and right ventricular dilatation increased signifi cantly with progressive staging of COPD. We considered that these changes may occur as a logical consequence of the disease, wherein increasing severity o f hypoxemia and hypercapnea with disease progression leads to pulmonary vascular remodeling. Inconsistent with this study, Gupta et al. [21] found that the prevalence of pulmonary hypertension has a linear relationship with the grade and the severity of COPD, and echocardiography helps in the early detection of cardiac complications in COPD cases, giving time for early interventions. Sultan et al. [22] also recorded that the incidence of pulmonary hypertension, right ventricular enlargement, tricuspid regurgitation, and right atrial enlargement increased with the duration and the severity of COPD. Th e present study revealed that the LV systolic function was preserved in diff erent grades of the studied COPD patients despite the presence of SWMA in about one third of them. Similar results were obtained by Vonk-Noordegraaf et al. [23] who stated that in the absence of problems primarily leading to left ventricular systolic function impairment such a s ischemic heart disease, systemic arterial hypertension etc., derangement of systolic function in the course of COPD is rarely found. However, some investigators suggest that even with the presence of a normal EF and a normal left ventricular shortening fraction, subclinical systolic dysfunction is frequently present in COPD patients [24]. Th e higher prevalence of SWMA in our patient group (25.8%) may be due to the high prevalence of GOLD III, IV and consequently hypoxemia and hypercapnia. Th is result matched with that of Mapel et al. [25], who stated that the prevalence of coronary artery disease was 33.6%, which was signifi cantly higher than the 27.1% prevalence seen in a matched cohort without COPD. We found a negative correlation between PaO 2 and each of CIMT and PASP, and a positive correlation between them and PaCO 2 . Th ere was an association between the presence of low-grade systemic infl ammation in COPD and atherosclerotic CVD. Th ese systemic infl ammations in COPD play a role in the pathogenesis of ischemic heart disease and atherosclerosis. Moreover, atherosclerotic plaques show low-grade infl ammation, with increased numbers of macrophages and interferon-c-secreting Th 1 lymphocytes [26]. We suggest that hypoxemia and hypercapnea in COPD result in systemic infl ammation, and consequently, in the development of atherosclerosis and increased CIMT. Also, Chhabra [27] stated that hypoxemia not only promotes vasoconstriction, but also contributes to the process of vascular remodeling as hypoxia inhibits the expression of voltage-gated potassium channels, resulting in membran e depolarization and stimulation of smooth muscle cell proliferation. Rodriguez-Roisin an d MacNee [28] reported that hypoxia is a potent