Background

Emphysema is a chronic inflammatory response due to cigarette smoke and other noxious particles with subsequent progressive airflow limitation ending in gas trapping [1]. On one side, COPD in most patients is associated with chronic diseases that share with the COPD the same risk factors like smoking, aging, and inactivity; these chronic diseases affect the morbidity and mortality of COPD [2]. COPD as a chronic inflammatory disease and through inflammatory mediators in the circulation may lead to the development or deterioration of other comorbidities like ischemic heart disease, metabolic syndrome, etc. [1].

The pathogenesis of the pulmonary emphysema had been suggested to be due to the increased elastolytic activity of neutrophil proteinases [3], oxidative stress that increases with cell senescence [4], the cellular and molecular factors, alveolar cell apoptosis, autoimmune, and genetic factors [5]. In addition, matrix metalloproteinases unbalance with their tissue inhibitors was suggested to contribute to the cerebrovascular damage in COPD [6]. Also, the systemic inflammation and endothelial dysfunction, according to several studies, are incriminated in the development of the pulmonary and extrapulmonary vascular changes in COPD [7,8,9,10,11,12,13,14,15].

This systemic inflammation with endothelial dysfunction, also, promote the systemic vascular alteration in atherosclerosis [15,16,17,18,19], elevating the suggestion of the relation between atherosclerosis and COPD as regards to the same pathogenesis, particularly after the conclusion of many studies that atherosclerosis is predominantly an inflammatory reaction of the vessel wall [20].

The risk stratification of cardiovascular morbidity and mortality in COPD lacks established biomarkers, besides the normal lipid profile in most patients [21]. Hence, using common carotid artery ultrasonography being able to measure intima-media thickness (IMT) and to detect early atherosclerotic lesions, is a useful tool for risk-stratification [22, 23]. The carotid intima-media thickness (CIMT) measurement by ultrasonography is not only an indicator of atherosclerosis but also an indicator of cardiovascular (CV) events and mortality [24,25,26,27]. Besides that, there is a correlation between CIMT increase and airflow obstruction severity in COPD [28,29,30]. Explanation of the increase of CIMT in COPD is claimed to be due to systemic inflammation, endothelial dysfunction, hypoxia [30], a sedentary lifestyle, high smoking prevalence [31], hypercoagulability, platelet activation, and oxidative stress [32,33,34] rather than lipid-driven atherosclerosis [35]. Moreover, elastin degradation in the extracellular matrix of the arterial wall results in emphysema in the lungs and atherosclerosis in the vasculature [34, 36].

So, if both conditions (emphysema and atherosclerosis) have the same pathogenesis, the different stages of both could coincide. If this is proved, the relationship between them may be considered inherent more than just association.

Purpose

To study the relationship between carotid atherosclerosis and pulmonary emphysema extent and airflow obstruction.

Methods

3.1. Study design

This study was conducted on 80 patients with emphysema and 40 controls, conducted at the Chest Department, in the period from November 2016 to November 2017. The diagnosis of COPD was based on GOLD criteria [1]. All included subjects were submitted to the following: (1) full history taking: with special attention to the main complaint, age, sex, smoking status, duration of disease, risk factors (occupation, pollution, resident area, diabetes mellitus, dyslipidemia, etc.); (2) clinical examination; (3) HRCT of the chest reported by two observers; (4) ABG: PH, partial arterial oxygen tension (PaO2), partial arterial carbon dioxide tension (PaCO2), and arterial oxygen saturation (SaO2) were measured in the arterial blood sample at room air after 20 min from performing the HRCT; (5) spirometric tests: all subjects underwent spirometry with special measurement of; forced vital capacity (FVC), forced expiratory volume in 1 second% predicted (FEV1%), and FEV1/FVC ratio; (6) carotid duplex; control group consisted of age and sex-matched volunteers with no history of chronic chest diseases; in addition, lipid profile, fasting and postprandial BS, liver, kidney functions were done.

3.2. Exclusion criteria

The presence of systemic hypertension, diabetes mellitus, known cardio/cerebrovascular diseases, dyslipidemia, or history of lipid-lowering drug intake excluded the subject from the study.

Study protocol

  1. A.

    Spirometry studies: were performed via ZAN MEBGERAEE GMBH D-97223 Oberthulba, Schlimpfhoferstr, Messgeraete GmbH Germany, Spirometry, according to the American Thoracic Society/European Respiratory Society standards [37]. According to GOLD, spirometry was required to diagnose emphysema and FEV1/FVC ratio < 0.70 confirmed persistent airflow limitation presence. Then, the severity of airflow limitation was classified on basis of a post-bronchodilator FEV 1[1].

  2. B.

    Carotid Doppler U/S: was performed with a 7.5 MHZ superficial linear array transducer of (TOSHIBA, Xario 200, TOSHIBA Medical System, Japan) in axial and longitudinal section in B mode, by a single experienced operator. The images obtained during the ultrasonographic imaging were recorded electronically and then evaluated. The patient was lying in a supine position, lifting his neck at an angle of approximately 20° to the front. The far walls of the right and left common carotid arteries were evaluated. The intima-media thickness was defined as the distance between the leading edge of the lumen intima echo and the leading edge of the media-adventitia echo. The averages of the CIMT values obtained from the far walls of the right and left common carotid arteries were calculated. Measurements were taken at least 10 mm proximal to the carotid bifurcation, in the near and far wall of the left and right common carotid arteries. Repeated measurements were performed along with a minimum of 10 mm length. Four measurements were taken from both the left and right common carotid arteries (two in the near and two in the far wall). The maximal measurement from these eight measurements was used for analysis, according to the ‘Mannheim Carotid Intima-Media Thickness Consensus’ [38]. A thickening ≥1.5 mm was categorized as an atheromatous plaque [39].

  1. C.

    HRCT: examination was carried out with (TOSHIBA, Aquilion prime, 80 dual MDCT system, Japan) Examination was performed with the subject in the supine position at the end-inspiratory state. A total of 0.5-mm thick slices at 10-mm intervals (120 kVp, 250 mA, 1-s scanning time) were obtained from the diaphragm to the lung apex. A high-frequency reconstruction algorithm was used. Images format with window setting 1200/ª500 Hounsfield units.

  2. D.

    Visual analysis: radiologist and pulmonologist blindly and independently evaluated CT slices of subjects using the extent of emphysema. The evaluation was performed slice-by-slice, both lung fields together, and results were later combined as the total scores of each subject [40]. Emphysema was defined as hypovascular areas of pulmonary parenchyma not associated with a fissure, usually lacking a well-defined wall. Changes were decreased attenuation, few or no vessels, and bullae with a well- or ill-defined wall. The scale used was: 0 = normal; 1 = emphysema in 25% of the slice; 2 = emphysema in 25–50% of the slice; 3 = emphysema in 50–75% of the slice; and 4 = emphysema in >75% of the slice; as the maximum score in each slice was 4 and 10 slices were imaged per patient, the maximum possible score was 40 [41].

Statistical methodology

Data entry and analysis were done using SPSS version 17, data were presented as mean, SD, Median, No., and percentage, Cochran Armitage chi-square test was used to compare qualitative data between the two groups of patients, independent samples T test was used to compare means of both groups, paired samples T test was used to compare means before and after the procedure (CA or PCI) in the same group. P value is considered significant when it is <0.05; Regression analysis was done and or was calculated for independent risk factors, all results were presented in the form of tables and figures.

Results

In the present study, there was no significant difference between studied groups as regards to patient age and sex. However, there was a statistically significant difference between studied groups as regards to cigarette smoking index (Table 1).

Table 1 Patient characteristics of studied populations
Full size table

Patients were classified into GOLD 1 (mild): FEV1 ≥ 80% predicted (n. = 6 [7.5%])/GOLD 2 (moderate): 50% ≤ FEV1 < 80% predicted (n. = 48 [60%])/GOLD 3 (severe): 30% ≤ FEV1 < 50% predicted (n. = 14 [17.5%]) /GOLD 4 (very severe): FEV1 < 30% predicted (n. = 12 [15%]). There was a statistically significant difference between studied groups as regards to SaO2, PH, PaO2, and PaCO2 (Fig. 1) (Table 2).

Fig. 1
figure 1

GOLD classification

Full size image
Table 2 Correlation between emphysema score and carotid duplex
Full size table

There was a statistically significant difference between studied groups as regard to FEV1%, FEV1/FVC, SaO2, PH, PaO2, and PaCO2 (Table 3). However, there was no significant difference between studied groups as regard to cholesterol, TG, fasting, and postprandial BS (Table 4).

Table 3 Lipid profile and blood sugar among studied groups
Full size table
Table 4 Intraclass absolute agreement between two observers for emphysema score
Full size table

In our work, the Intraclass Correlation Coefficient (ICC) for absolute agreement between two observers showed a high statistically significant absolute agreement between two observers in the reading of the emphysema score. Our estimated ICC was 0.999, with a 95% confidence interval (CI) (0.998, 0.999), and this was considered excellent.

In the present work, there was a highly positive correlation between emphysema score from one side and each of thrombus size (r = .839 on the right side and r = .861 on the left), plaque size (r = .870 right and r = .305 left) and stenosis percent (r = .878 right and r = .938 left) on both sides (Table 2).

In the studied groups, there was a statistically significant difference between COPD patients and controls as regards to atherosclerotic changes in the right and left carotid U/S findings. The incidence of carotid atherosclerotic plaques reached 68.8% on the right side and 71.3% on the left side, over that, the rest of patients without plaques showed an increase in IMT. The plaques were with smooth surface in 20%, irregular surface in 38.8%, ulcer in 10%, and homogeneous in 28.8%, heterogeneous in 40%, soft in 16.3% and calcific in 52.5% on the right side, and with smooth surface in 22.5%, irregular surface in 38.8%, ulcer in 10%, and homogeneous in 20%, heterogeneous in 51.3%, soft in 18.8%, and calcific in 52.5% on the left side (Table 5), (Fig. 2).

Table 5 Atherosclerotic plaques in studied groups
Full size table
Fig. 2
figure 2

Atherosclerotic plaques in studied groups

Full size image

There were positive correlations between GOLD staging from one side and each of right thrombus size (r = .423), right plaque size (r = .451), right stenosis percent (r = .516), and left thrombus size (r = .440).

Discussion

In our work, the ICC for absolute agreement between two observers in reading emphysema score in chest HRCT showed high statistical significance (0.999, p < 0.001).

The use of B-mode ultrasound and carotid duplex can identify and quantify atherosclerosis and predict the risk for cardiovascular disease (CVD) and stroke in COPD patients [42].

Our study revealed a high incidence of carotid atherosclerotic plaques among about 70% of emphysema patients (68.8% on the right and 71.3% on the left side), while the rest of patients showed an increase in the IMT as an indicator of subclinical atherosclerosis. In addition, carotid atherosclerosis correlated well with emphysema CT score and more than its correlation with GOLD staging. This denotes the intimate association between atherosclerosis and emphysema with the slight prevalence of atherosclerotic changes in the left side. Of note that, cholesterol and TG levels in these patients were in the normal range.

In agreement with our study, Hafez et al. [34] found atherosclerosis prevalence in COPD patients reaching about 64% (approximately two-thirds of COPD patients had atherosclerosis). Also, in agreement with the present study, the emphysema extent and airflow obstruction had been reported to correlate with atherosclerosis [7,8,9,10,11, 43].

FEV1 is considered a clinical indicator commonly used to evaluate the COPD severity [44], and GOLD classification of COPD depends mainly on FEV1. Our study showed a positive correlation between GOLD staging and carotid atherosclerosis.

Barr et al. [35] reported the decrease in FEV1 to be an independent risk factor for carotid atherosclerosis and emphysema. Similarly, Alpaydin et al. [45], after adjusting their study for smoking, TG and cholesterol levels, hypertension, and fasting plasma glucose, had found IMT to be higher in COPD versus controls, and they suggested other mechanisms than smoking to be responsible for the association between COPD and IMT. So, airflow limitation and hypoxia are suggested to be responsible for the association between emphysema and carotid atherosclerosis. In a study by van Gestel et al., [23] they found moderate to severe COPD, independently and irrespective of associating comorbidities and smoking status, to be associated with increased IMT of the common carotid artery. In addition, Kim et al. [46] noticed IMT to be significantly correlated with FEV1, FEV1/FVC, and FVC, and suggested a bi-directional effect of COPD on CVS and vice versa. In a study by Köseoğlu et al.,[47] CIMT >1.25 mm was found to carry a 12-fold increased risk in COPD to have CAD (Figs. 3, 4, 5, and 6).

Fig. 3
figure 3

A case of severe emphysematous changes and mild carotid arteries atherosclerotic changes. Mild atherosclerotic changes affect the carotid arteries

Full size image
Fig. 4
figure 4

A case of severe emphysematous changes and mild carotid arteries atherosclerotic changes

Full size image
Fig. 5
figure 5

A case of severe emphysematous changes and moderate carotid arteries atherosclerotic changes

Full size image
Fig. 6
figure 6

A case of severe emphysematous changes and advanced carotid arteries atherosclerotic changes. Advanced atherosclerotic changes affect the carotid arteries; a B mode US of RT CCA shows soft atheromatous plaque involve RT carotid bulb with sever lumina stenosis, b B mode US of RT CCA shows diffuse increase intima-media thickness with an irregular outline, and soft atheromatous plaque. c and d: colour doppler US shows luminal colour filling defect by an atheromatous plaque with severe luminal stenosis. e Axial HRCT cuts in the lung window show severe emphysematous changes and multiple emphysematous bullae

Full size image

Hypoxemia and/or hypercapnia were considered relevant factors for atherosclerosis by Hafez et al. [34], on the basis of the significant decrease of PaO2 and significant increase of PaCO2 in COPD patients with increased CIMT versus those showing a normal CIMT. Systemic inflammation, oxidative stress, increased foam cell production, induction of hemodynamic stress, and upregulation of cell adhesion molecules are the possible mechanisms through which hypoxemia could lead to atherosclerosis [48,49,50].

In contrast to our study, Schroeder et al. [51] did not find an association between FEV1% and carotid plaque. In addition, Matsuoka et al. [15] did not find FEV1 to be significantly correlated with the severity of aortic calcification, but they explained that by the difference in the evaluation techniques and the difference in the pathological processes involved in different stages of atherosclerosis. However, Iwamoto et al. [11] reported a significant correlation between FEV1% and IMT. This may mean that airflow limitation initiates the increase in IMT, then the systemic inflammation induces atherosclerosis progression. Furthermore, atherosclerosis may be related to COPD phenotypes [15].

In a study by Pike et al .[52], they found that lung abnormalities may be directly related to carotid atherosclerosis in absence of airflow limitation in never- and ex-smokers. They suggested that subclinical airways disease may be present in never- and ex-smokers with increased IMT mediated by factors other than smoking. The relation of the extent of emphysema to arterial stiffness [8], and to endothelial dysfunction [7], besides the relation of endothelial dysfunction to systemic inflammation, both supported the conclusion of Matsuoka et al. [15] that emphysema and vascular alteration may be related by endothelial dysfunction and systemic inflammation.

Hypercholesterolemia is considered one of the main triggers of atherosclerosis [53]. So, the normal lipid profile in emphysema patients with atherosclerosis indicates the responsibility of other factors for this association. Atherosclerotic plaque in COPD patients has criteria that make them more easy to rupture [52], hence, the evaluation of carotid plaque composition/texture will be beneficial.

Our study results support the idea of complex heterogeneous lung and vascular disease in the context of an explanation of the relationship between emphysema and atherosclerosis, which also, was supported by other studies; Dransfield et al. [54], Chae et al. [55] showed the relationship between emphysema and each of carotid atherosclerosis, scores of calcification in the aorta, coronary arteries. Pike et al. [56] showed the significant relationship between upper-lobe emphysema and internal carotid IMT. In addition, [6] suggested the contribution of the imbalance of matrix metalloproteinases and their tissue inhibitors in the cerebrovascular damage in COPD [34, 36].

Emphysema & Cancer Action Project study [7] incorporated thoracic CT for the evaluation of the brachial artery flow-mediated dilation in the ex-smokers group with early COPD and showed that reduced FEV1 and greater emphysema indices were associated with attenuation of flow-mediated dilatation giving the conclusion that both lung function and structure influence vascular endothelial function [56].

Conclusion

Atherosclerotic plaques were prevalent in about two-thirds (70%) of emphysema patients and the rest of the patient showed subclinical atherosclerosis. The positive correlation between the carotid atherosclerosis and emphysema CT score was more than with GOLD staging. So, this inherence between pulmonary emphysema and atherosclerosis may not be just an association, it may be a syndrome. Thus, the staging of each of them can be guided from the other, and therapies targeted against the same pathogenesis can benefit both conditions. So, we recommend that management plan for emphysema should include the carotid US for early detection and treatment of atherosclerosis.