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Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease
Clinical Imaging 46 (2017) 85–90
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Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease Shuko Mashimo a, Shotaro Chubachi a,⁎, Akihiro Tsutsumi a, Naofumi Kameyama a, Mamoru Sasaki a, Masahiro Jinzaki b, Hidetoshi Nakamura c, Koichiro Asano d, John J. Reilly Jr. e, Tomoko Betsuyaku a a
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Department of Diagnostic Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan d Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa 259-1193, Japan e School of Medicine, University of Colorado, 13001 E. 17th Place, Aurora, CO 80045, United States b c
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Article history: Received 12 May 2017 Received in revised form 12 July 2017 Accepted 17 July 2017 Available online xxxx Keywords: COPD CT scan cross-sectional area Small pulmonary vessel Emphysema
a b s t r a c t Objectives: To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD). Methods: Forty-nine patients were included. The percentage of cross-sectional area of vessels b 5 mm2 (%CSA b 5) and extent of emphysema were assessed. Results: Less than half of the COPD patients demonstrated an inverse correlation between %CSA b 5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA b 5 was homogeneously distributed. Conclusion: Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA b 5 and LAA% in individual lungs. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD), which is characterized by progressive and partially reversible airflow limitation, is among the leading causes of death worldwide [1]. Emphysema is a central feature of COPD and is often heterogeneously distributed in lungs with COPD [2]. The pathogenesis of heterogeneous development of emphysema in the lungs has been extensively investigated. Long-term cigarette smoking, which is a definite exogenous cause of COPD, contributes to the development and progression of emphysema mainly in the upper portion of the lung [3]. In contrast, emphysema associated with α1antitrypsin deficiency has been described as predominantly basal [4]. The clinical features of emphysema are likewise heterogeneous. Upper lobe-predominant emphysema may present with a more rapid decrease in lung function [5], whereas lower lobe-predominant emphysema is associated with lower exercise capacity and worse prognosis [6, 7]. Therefore, assessment of emphysema distribution contributes clinically relevant information to the evaluation and treatment of patients.
Abbreviations: COPD, chronic obstructive pulmonary disease; CT, computed tomography; %CSA b5, percentage of vessel cross-sectional area b5 mm2; LAA%, percentage of low attenuation area to total lung volume. ⁎ Corresponding author. E-mail address: [email protected] (S. Chubachi).
http://dx.doi.org/10.1016/j.clinimag.2017.07.008 0899-7071/© 2017 Elsevier Inc. All rights reserved.
The potential association between emphysema and the narrowing and diminution of small pulmonary vessels has been shown on conventional angiography [8] and pathologic examination of lung specimens [9,10]. Pulmonary vascular remodeling is known to be present not only in end-stage COPD, but also in patients with mild COPD [10]. However, the currently available tools for pulmonary vasculature assessment, such as histologic examination and right heart catheterization, are invasive and might not be feasible in a large number of subjects. Recently, Matsuoka et al. demonstrated that vascular alteration, which was measured from the cross-sectional area (CSA) of small pulmonary vessels on computed tomography (CT), is inversely correlated with the severity of emphysema [11] and the magnitude of pulmonary hypertension in severe emphysema [12]. Conventionally, most past studies empirically calculated the total CSA of small pulmonary vessels b5 mm2 (CSA b 5) from the percentage of CSA b 5 of the total lung area (%CSA b5) of three axial slices that were selected arbitrarily [11–14]. However, the accuracy of using the three arbitrary slices in estimating the %CSA b5 of small pulmonary vessels that are heterogeneously altered in an entire lung remains unclear [11]. The aim of the present study was to thoroughly quantify the %CSA b 5 and percentage of low attenuation area to total lung volume (LAA%) using all CT axial slices and to assess the association between alteration of small pulmonary vessels and the degree of emphysema in an individual lung with COPD.
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2. Materials and methods
2.3. Computed tomography scan examination
2.1. Study population
Volumetric CT examination at full inspiration in the supine position was performed using three multi-detector CT scanners (General Electric Medical Systems, Milwaukee, WI, USA), including one 16-detector machine (BrightSpeed) in 5 patients and two 64-detector machines (LightSpeed VCT and Discovery CT 750 HD) in 24 and 20 patients, respectively. The scanning parameters were as follows: detector collimation of 0.625 mm, beam pitch of 1.375, reconstruction thickness of 1.25 mm, reconstruction interval of 1.5 mm, rotation time of 0.4–0.5 s, tube voltage of 120 kVp, Auto mAs tube current (SD = 12–15) and chest reconstruction kernel. For calibration among the three CT scanners, a test object (Multipurpose Chest Phantom N1; Kyoto Kagaku, Kyoto, Japan) was scanned at the start of every CT examination [16].
The patients for this study were selected from the cohort of the Keio COPD Comorbidity Research, the overall design of which has been previously published [15,16]. In brief, it was a 3-year, prospective observational study. A total of 572 subjects were enrolled between April 2010 and December 2012, including patients diagnosed as having COPD and those referred for investigation of possible COPD. Inclusion criteria were: (i) age ≥ 40 years; (ii) FEV 1/forced vital capacity (FVC) b 0.7; (iii) presence of emphysematous changes on chest CT; and (iv) chronic respiratory symptoms with significant smoking history (≥ 30 packyears). The COPD group fulfilled criteria (i) and (ii), while the nonCOPD group met the criteria (i) and either (iii) or (iv) without airflow limitation (FEV1/FVC ≥ 0.7). For the purposes of this present study, only COPD patients with LAA% N 10% and non-COPD subjects with LAA% b 10 were selected. Patients who had obvious interstitial abnormalities, nodules, or other bronchial lesions were excluded (Fig. 1). The ethics committee of Keio University approved the study protocol. All patients provided written, informed consent to analyze and present their data. All aspects of the study conformed with the principles of the Declaration of Helsinki, which was adopted by the 59th World Medical Association General Assembly, Seoul, Republic of Korea, October 2008.
2.2. Assessment of clinical parameters All patients were clinically stable and did not have exacerbations for at least 1 month prior to recruitment. At enrollment, full medical and smoking histories were obtained. All patients who were in stable condition were assessed by electronic spirometry, in accordance with the guidelines of the American Thoracic Society [17]. The predicted values of spirometric measurements were derived from the pulmonary function test guidelines by the Japanese Respiratory Society [18]. The Japanese versions of the COPD assessment test [19] and the St. George Respiratory Questionnaire [20,21] were used for evaluation of COPDspecific health status.
2.4. Analyses of computed tomography scan data The extent of pulmonary emphysema and vascular segmentation were extracted semi-automatically from the CT images using custommade software (Lexus 64, AZE Ltd., Tokyo, Japan). The low attenuation area (LAA) was obtained using a threshold value of −950 HU [16]. Images of vascular segments were converted into binary images at a window level of 720 HU. Data of the lungs and vessels were imported into ImageJ software (ImageJ version 1.51 k; freeware available at https:// imagej.nih.gov/ij/index.html) for calculation of LAA and CSA b5 [11– 14]. The LAA% and %CSA b5 on each CT image were calculated as the percentage of LAA and CSA b5, respectively, per total lung area using threshold values between − 500 HU and − 1024 HU. Each subject's lung was divided into ten equal parts from the apex to the base; the most apical and basal portions were excluded to eliminate partial volume artifacts [22]. The thickness of all CT images was 1.25 mm, and N150 cross-sectional slices per subject were analyzed for %CSA b 5 and LAA%. 2.5. Statistical analysis Data are presented as means ± standard deviation (SD) or as medians ± interquartile range (IQR). Data were compared between two groups using the Mann–Whitney U test. Correlations between %CSA b5 and %LAA% were evaluated by Pearson's correlation coefficient. Two-sided p values of b 0.05 were considered significant for all tests. Data were analyzed using JMP 10 software (SAS Institute, Cary, NC, USA). 3. Results 3.1. Characteristics of the study population The clinical characteristics of the study population are shown in Table 1. There were 36 COPD patients and 13 non-COPD patients, with Table 1 Baseline characteristics of the study population (N = 49)
N Women, n (%) Age, years Smoking index, pack-years Current smokers, n (%) BMI, kg/m2 FEV1/FVC %FEV1 Fig. 1. Process of patient selection in this study. COPD, chronic obstructive pulmonary disease; CT, computed tomography; LAA%, percentage of low attenuation area to total lung volume.
Non-COPD
COPD
13 1 (7.7) 58.5 ± 5.9 47.1 ± 26.7 2 (15.4) 23.9 ± 3.3 76.6 ± 4.5 98.7 ± 9.6
36 4 (11.1) 71.8 ± 7.5 62.7 ± 23.0 2 (5.5) 22.6 ± 2.5 44.3 ± 10.9 56.5 ± 20.3
Data are presented as mean ± standard deviation, unless otherwise specified. BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; %FEV1, percent predicted forced expiratory volume in 1 s; COPD, chronic obstructive pulmonary disease.
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a mean age of 68.3 ± 9.3 years. The Global Initiative for Chronic Obstructive Lung (GOLD) severity of airflow limitation [1] varied among the COPD patients and was categorized as I in 7 patients, II in 12 patients, III in 13 patients, and IV in 4 patients. 3.2. Distribution of %CSA b5 in non-COPD subjects Fig. 2 shows a representative distribution of LAA% and %CSA b5 in the entire lung of a non-COPD subject. In the absence of recognizable emphysema, %CSA b 5 was almost evenly distributed. Of note, %CSA b 5 was slightly higher in the basal parts of the lungs even if the CT scan was performed in the supine position. The methodologic limitations of previous studies limited to analyzing three slices distributed in the lung precluded the detection of this pattern that is clearly demonstrated in the present data [11–14]. 3.3. %CSA b 5 in the entire lungs of non-COPD subjects and COPD patients %CSA b5 in the entire lungs was significantly lower in COPD patients than in non-COPD subjects (1.58% vs. 2.05%, p = 0.0012) (Fig. 3). The present results demonstrate that, compared with non-COPD patients, COPD patients with radiographically demonstrable emphysema have loss of small pulmonary vessels (lower %CSA b5).
Fig. 2. Relationship of LAA% with %CSA b5 in non-COPD subjects. (a) The number of CT slices is 145. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in the entire lungs is 2.7% and 1.8%, respectively. (b) Correlation between LAA% and %CSA b5 (r = 0.73, p b 0.00001) %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
Fig. 3. Comparison of %CSA b5 in the entire lungs between non-COPD subjects and COPD subjects. Median and 25th and 75th percentile values are presented. %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; COPD, chronic obstructive pulmonary disease.
Fig. 4. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a reverse distribution of %CSA b5. (a) The number of CT slices is 150. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 29.5% and 1.7%, respectively. (b) Correlation between LAA% and %CSA b5 (r = − 0.88, p b 0.00001) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
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the upper and lower lobes, but %CSA b 5 was homogenously distributed. The pattern demonstrated in this case implied that, despite the extent of emphysema, preservation of small pulmonary vessels was possible. For this case that had 161 CT slices analyzed, there was only a weak correlation between %CSA b5 and LAA% in each slice (r = 0.24, p = 0.0026). Another pattern observed was a homogenously low %CSA b5 despite a heterogeneous distribution of emphysema (Fig. 7). For this patient in whom 182 CT slices were analyzed, there was no correlation between %CSA b5 and LAA% in each slice (r = −0.026, p = 0.73). 3.6. Comparison of baseline characteristics of subjects according to the distribution of %CSA Table 2 shows that forced expiratory volume in 1 s, LAA%, %CSA b5, and health status in COPD subjects did not differ significantly between heterogeneous and homogenous distributions of %CSA. 4. Discussion To the best of our knowledge, this is the first study showing the association of small pulmonary vessel alterations with the distribution of emphysema in individual lungs with COPD. We would like to emphasize that these results were made possible by extensive and meticulous
Fig. 5. Relationship of LAA% with %CSA b5 in COPD subjects who had lower lungpredominant emphysema and a reverse distribution of %CSA b5. (a) The number of CT slices is 180. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 26.8% and 1.6%, respectively. (b) Correlation between LAA% and %CSA b5 (r = −0.91, p b 0.00001) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
3.4. Heterogeneous distribution of %CSA b 5 in COPD patients with emphysema Fig. 4 shows a representative distribution of LAA% and %CSA b5 in the entire lungs of a COPD subject. Emphysema was predominant and %CSA b5 was decreased in the upper lobes; in contrast, the lower lobes had less emphysematous changes and higher %CSA b5. On 150 CT slices, a negative correlation between %CSA b5 and LAA% (r = −0.88, p b 0.00001) was demonstrated in this subject. In a COPD patient with lower lobe-predominant emphysema (Fig. 5), there was reverse distribution of %CSA b 5. On 180 CT slices, a negative correlation between %CSA b 5 and LAA% (r = −0.91, p b 0.00001) was demonstrated in this subject. Of the 36 COPD patients, 17 showed a significant negative correlation between %CSA b5 and LAA% within the individual lungs.
3.5. Homogeneous distribution of %CSA b5 in COPD patients with emphysema Notably, more than half of the COPD population showed a homogeneous distribution of %CSA b5, regardless of the heterogeneity of the emphysema. Fig. 6 shows the distribution of LAA% and %CSA b 5 in the entire lung of a COPD subject. Emphysema was predominant in both
Fig. 6. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a homogenous high distribution of %CSA b5. (a) The number of CT slices is 161. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 35.0% and 1.5%, respectively. (b) Correlation between LAA% and %CSA b5 (r = 0.24, p = 0.0026) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
S. Mashimo et al. / Clinical Imaging 46 (2017) 85–90
Fig. 7. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a homogenous low distribution of %CSA b5. (a) The number of CT slices is 182. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 22.3% and 0.8%, respectively. (b) Correlation between LAA% and %CSA b5 (r = −0.026, p = 0.73) %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
Table 2 Comparison of COPD subjects according to distribution of %CSA (N = 36)
N Women, n (%) Age, years Smoking index, pack-years Current smokers, n (%) FEV1, L %FEV1 LAA% %CSA b5 CAT SGRQ total score SGRQ symptom score SGRQ activity score SGRQ impact score
Heterogeneous distribution of %CSA
Homogenous distribution of %CSA
p value
17 2 (11.8) 72.4 ± 7.5 61.8 ± 21.2
19 2 (10.5) 71.2 ± 7.9 63.5 ± 25.7
0.906 0.727 0.918
2 (11.8)
0 (0)
0.134
1.5 ± 0.8 59.6 ± 23.0 28.3 ± 10.1 1.7 ± 0.3 11.4 ± 9.3 28.8 ± 22.7 29.7 ± 28.7
1.5 ± 0.6 53.8 ± 18.5 29.3 ± 10.1 1.5 ± 0.4 12.2 ± 5.5 24.1 ± 12.1 25.0 ± 20.3
1.000 0.537 0.516 0.189 0.437 0.635 0.801
43.3 ± 27.2 19.5 ± 19.0
39.6 ± 17.1 13.8 ± 11.5
0.593 0.405
Data are presented as mean ± standard deviation, unless otherwise specified. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; %FEV1, percent predicted forced expiratory volume in 1 s; LAA%, percentage of low attenuation area; %CSA b5, percentage of cross-sectional area of vessels b5 mm2; CAT, COPD assessment test; SGRQ, St. George Respiratory Questionnaire.
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analysis of N 150 cross-sectional CT slices for each subject. As shown in the analyses, calculation of %CSA b 5 from three selected axial slices [11–14] does not fully capture the geographic variation distribution of small pulmonary vessels throughout the lungs of COPD patients. Using representative values from 191 COPD patients, Matsuoka et al. showed a negative relationship between %CSA b 5 and the extent of emphysema [11]. The same negative correlation was observed in individual lungs in b 50% of the present population of COPD patients. The mechanisms underlying this negative correlation between %CSA b5 and the extent of emphysema could be attributed to the decrease in size of the small pulmonary vessels secondary to parenchymal destruction and to passive vascular compression due to the progression of emphysema, hypoxic vasoconstriction, and endothelial dysfunction [12,23]. The fact that the present data show that a substantial proportion of COPD patients do not exhibit this correlation is consistent with the heterogeneity seen in other clinical and radiographic aspects of the syndrome. Similar to the present findings, a recent report by Saruya et al. showed that, in COPD patients with emphysema progression on serial CT scans within N1 year, there was no decrease in %CSA b 5 [14]. Another novel finding of the present study was a pattern of homogeneously low %CSA b5 that was unrelated to the distribution of emphysema in some patients. This homogeneously low %CSA b5 could imply either a beginning process of progression to CT-detectable emphysema or a normal variant. On the other hand, there were some patients in whom %CSA b5 was homogeneously high regardless of the extent of emphysema. Although the mechanism of preservation of small pulmonary vessels in a region with damaged alveolar structures is unknown, an excessive blood supply in the area of alveolar destruction is a possibility. If %CSA b 5 is representative of the surface area of the capillaries in these patients, regional ventilation/perfusion mismatch might be present; this implies the existence of nonfunctional gas exchange that could lead to exercise-induced hypoxia. The clinical characteristics of such patients warrant further investigation. A limitation of this study was that the CT scan images were obtained in patients at full inspiration in a supine position, not in a standing position. Therefore, the dynamic changes in the volume of small pulmonary vessels during tidal breathing in a standing position were not accounted for, although it is essential for understanding respiratory physiology in daily life. It should be noted that pulmonary vascular remodeling is not exclusive to severe emphysema, but it has also been shown in some patients with mild COPD and in smokers with normal pulmonary function [12]. Recently, a variety of COPD phenotypes has been examined. The results of this study may provide another phenotype based on the volume and distribution of small pulmonary vessels in COPD lungs. 5. Conclusion In a substantial portion of COPD patients in this study, the distributions of %CSA b5 and LAA% within an entire lung were inversely correlated, supporting a pathophysiologic association between a decrease of small pulmonary vessels and the development of emphysema. On the other hand, a distribution of small pulmonary vessels independent of emphysema heterogeneity was found in some COPD patients. Acknowledgments The authors acknowledge Ishikawa Naomi and Tsuyoshi Sakamoto of AZE for helping in the analysis of chest CT imaging findings. Role of the funding source This study was supported by Japan Society for the Promotion of Science KAKENHI Grant (Number 25670401).
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Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease Shuko Mashimo a, Shotaro Chubachi a,⁎, Akihiro Tsutsumi a, Naofumi Kameyama a, Mamoru Sasaki a, Masahiro Jinzaki b, Hidetoshi Nakamura c, Koichiro Asano d, John J. Reilly Jr. e, Tomoko Betsuyaku a a
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Department of Diagnostic Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan d Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa 259-1193, Japan e School of Medicine, University of Colorado, 13001 E. 17th Place, Aurora, CO 80045, United States b c
a r t i c l e
i n f o
Article history: Received 12 May 2017 Received in revised form 12 July 2017 Accepted 17 July 2017 Available online xxxx Keywords: COPD CT scan cross-sectional area Small pulmonary vessel Emphysema
a b s t r a c t Objectives: To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD). Methods: Forty-nine patients were included. The percentage of cross-sectional area of vessels b 5 mm2 (%CSA b 5) and extent of emphysema were assessed. Results: Less than half of the COPD patients demonstrated an inverse correlation between %CSA b 5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA b 5 was homogeneously distributed. Conclusion: Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA b 5 and LAA% in individual lungs. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD), which is characterized by progressive and partially reversible airflow limitation, is among the leading causes of death worldwide [1]. Emphysema is a central feature of COPD and is often heterogeneously distributed in lungs with COPD [2]. The pathogenesis of heterogeneous development of emphysema in the lungs has been extensively investigated. Long-term cigarette smoking, which is a definite exogenous cause of COPD, contributes to the development and progression of emphysema mainly in the upper portion of the lung [3]. In contrast, emphysema associated with α1antitrypsin deficiency has been described as predominantly basal [4]. The clinical features of emphysema are likewise heterogeneous. Upper lobe-predominant emphysema may present with a more rapid decrease in lung function [5], whereas lower lobe-predominant emphysema is associated with lower exercise capacity and worse prognosis [6, 7]. Therefore, assessment of emphysema distribution contributes clinically relevant information to the evaluation and treatment of patients.
Abbreviations: COPD, chronic obstructive pulmonary disease; CT, computed tomography; %CSA b5, percentage of vessel cross-sectional area b5 mm2; LAA%, percentage of low attenuation area to total lung volume. ⁎ Corresponding author. E-mail address: [email protected] (S. Chubachi).
http://dx.doi.org/10.1016/j.clinimag.2017.07.008 0899-7071/© 2017 Elsevier Inc. All rights reserved.
The potential association between emphysema and the narrowing and diminution of small pulmonary vessels has been shown on conventional angiography [8] and pathologic examination of lung specimens [9,10]. Pulmonary vascular remodeling is known to be present not only in end-stage COPD, but also in patients with mild COPD [10]. However, the currently available tools for pulmonary vasculature assessment, such as histologic examination and right heart catheterization, are invasive and might not be feasible in a large number of subjects. Recently, Matsuoka et al. demonstrated that vascular alteration, which was measured from the cross-sectional area (CSA) of small pulmonary vessels on computed tomography (CT), is inversely correlated with the severity of emphysema [11] and the magnitude of pulmonary hypertension in severe emphysema [12]. Conventionally, most past studies empirically calculated the total CSA of small pulmonary vessels b5 mm2 (CSA b 5) from the percentage of CSA b 5 of the total lung area (%CSA b5) of three axial slices that were selected arbitrarily [11–14]. However, the accuracy of using the three arbitrary slices in estimating the %CSA b5 of small pulmonary vessels that are heterogeneously altered in an entire lung remains unclear [11]. The aim of the present study was to thoroughly quantify the %CSA b 5 and percentage of low attenuation area to total lung volume (LAA%) using all CT axial slices and to assess the association between alteration of small pulmonary vessels and the degree of emphysema in an individual lung with COPD.
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2. Materials and methods
2.3. Computed tomography scan examination
2.1. Study population
Volumetric CT examination at full inspiration in the supine position was performed using three multi-detector CT scanners (General Electric Medical Systems, Milwaukee, WI, USA), including one 16-detector machine (BrightSpeed) in 5 patients and two 64-detector machines (LightSpeed VCT and Discovery CT 750 HD) in 24 and 20 patients, respectively. The scanning parameters were as follows: detector collimation of 0.625 mm, beam pitch of 1.375, reconstruction thickness of 1.25 mm, reconstruction interval of 1.5 mm, rotation time of 0.4–0.5 s, tube voltage of 120 kVp, Auto mAs tube current (SD = 12–15) and chest reconstruction kernel. For calibration among the three CT scanners, a test object (Multipurpose Chest Phantom N1; Kyoto Kagaku, Kyoto, Japan) was scanned at the start of every CT examination [16].
The patients for this study were selected from the cohort of the Keio COPD Comorbidity Research, the overall design of which has been previously published [15,16]. In brief, it was a 3-year, prospective observational study. A total of 572 subjects were enrolled between April 2010 and December 2012, including patients diagnosed as having COPD and those referred for investigation of possible COPD. Inclusion criteria were: (i) age ≥ 40 years; (ii) FEV 1/forced vital capacity (FVC) b 0.7; (iii) presence of emphysematous changes on chest CT; and (iv) chronic respiratory symptoms with significant smoking history (≥ 30 packyears). The COPD group fulfilled criteria (i) and (ii), while the nonCOPD group met the criteria (i) and either (iii) or (iv) without airflow limitation (FEV1/FVC ≥ 0.7). For the purposes of this present study, only COPD patients with LAA% N 10% and non-COPD subjects with LAA% b 10 were selected. Patients who had obvious interstitial abnormalities, nodules, or other bronchial lesions were excluded (Fig. 1). The ethics committee of Keio University approved the study protocol. All patients provided written, informed consent to analyze and present their data. All aspects of the study conformed with the principles of the Declaration of Helsinki, which was adopted by the 59th World Medical Association General Assembly, Seoul, Republic of Korea, October 2008.
2.2. Assessment of clinical parameters All patients were clinically stable and did not have exacerbations for at least 1 month prior to recruitment. At enrollment, full medical and smoking histories were obtained. All patients who were in stable condition were assessed by electronic spirometry, in accordance with the guidelines of the American Thoracic Society [17]. The predicted values of spirometric measurements were derived from the pulmonary function test guidelines by the Japanese Respiratory Society [18]. The Japanese versions of the COPD assessment test [19] and the St. George Respiratory Questionnaire [20,21] were used for evaluation of COPDspecific health status.
2.4. Analyses of computed tomography scan data The extent of pulmonary emphysema and vascular segmentation were extracted semi-automatically from the CT images using custommade software (Lexus 64, AZE Ltd., Tokyo, Japan). The low attenuation area (LAA) was obtained using a threshold value of −950 HU [16]. Images of vascular segments were converted into binary images at a window level of 720 HU. Data of the lungs and vessels were imported into ImageJ software (ImageJ version 1.51 k; freeware available at https:// imagej.nih.gov/ij/index.html) for calculation of LAA and CSA b5 [11– 14]. The LAA% and %CSA b5 on each CT image were calculated as the percentage of LAA and CSA b5, respectively, per total lung area using threshold values between − 500 HU and − 1024 HU. Each subject's lung was divided into ten equal parts from the apex to the base; the most apical and basal portions were excluded to eliminate partial volume artifacts [22]. The thickness of all CT images was 1.25 mm, and N150 cross-sectional slices per subject were analyzed for %CSA b 5 and LAA%. 2.5. Statistical analysis Data are presented as means ± standard deviation (SD) or as medians ± interquartile range (IQR). Data were compared between two groups using the Mann–Whitney U test. Correlations between %CSA b5 and %LAA% were evaluated by Pearson's correlation coefficient. Two-sided p values of b 0.05 were considered significant for all tests. Data were analyzed using JMP 10 software (SAS Institute, Cary, NC, USA). 3. Results 3.1. Characteristics of the study population The clinical characteristics of the study population are shown in Table 1. There were 36 COPD patients and 13 non-COPD patients, with Table 1 Baseline characteristics of the study population (N = 49)
N Women, n (%) Age, years Smoking index, pack-years Current smokers, n (%) BMI, kg/m2 FEV1/FVC %FEV1 Fig. 1. Process of patient selection in this study. COPD, chronic obstructive pulmonary disease; CT, computed tomography; LAA%, percentage of low attenuation area to total lung volume.
Non-COPD
COPD
13 1 (7.7) 58.5 ± 5.9 47.1 ± 26.7 2 (15.4) 23.9 ± 3.3 76.6 ± 4.5 98.7 ± 9.6
36 4 (11.1) 71.8 ± 7.5 62.7 ± 23.0 2 (5.5) 22.6 ± 2.5 44.3 ± 10.9 56.5 ± 20.3
Data are presented as mean ± standard deviation, unless otherwise specified. BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; %FEV1, percent predicted forced expiratory volume in 1 s; COPD, chronic obstructive pulmonary disease.
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a mean age of 68.3 ± 9.3 years. The Global Initiative for Chronic Obstructive Lung (GOLD) severity of airflow limitation [1] varied among the COPD patients and was categorized as I in 7 patients, II in 12 patients, III in 13 patients, and IV in 4 patients. 3.2. Distribution of %CSA b5 in non-COPD subjects Fig. 2 shows a representative distribution of LAA% and %CSA b5 in the entire lung of a non-COPD subject. In the absence of recognizable emphysema, %CSA b 5 was almost evenly distributed. Of note, %CSA b 5 was slightly higher in the basal parts of the lungs even if the CT scan was performed in the supine position. The methodologic limitations of previous studies limited to analyzing three slices distributed in the lung precluded the detection of this pattern that is clearly demonstrated in the present data [11–14]. 3.3. %CSA b 5 in the entire lungs of non-COPD subjects and COPD patients %CSA b5 in the entire lungs was significantly lower in COPD patients than in non-COPD subjects (1.58% vs. 2.05%, p = 0.0012) (Fig. 3). The present results demonstrate that, compared with non-COPD patients, COPD patients with radiographically demonstrable emphysema have loss of small pulmonary vessels (lower %CSA b5).
Fig. 2. Relationship of LAA% with %CSA b5 in non-COPD subjects. (a) The number of CT slices is 145. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in the entire lungs is 2.7% and 1.8%, respectively. (b) Correlation between LAA% and %CSA b5 (r = 0.73, p b 0.00001) %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
Fig. 3. Comparison of %CSA b5 in the entire lungs between non-COPD subjects and COPD subjects. Median and 25th and 75th percentile values are presented. %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; COPD, chronic obstructive pulmonary disease.
Fig. 4. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a reverse distribution of %CSA b5. (a) The number of CT slices is 150. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 29.5% and 1.7%, respectively. (b) Correlation between LAA% and %CSA b5 (r = − 0.88, p b 0.00001) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
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the upper and lower lobes, but %CSA b 5 was homogenously distributed. The pattern demonstrated in this case implied that, despite the extent of emphysema, preservation of small pulmonary vessels was possible. For this case that had 161 CT slices analyzed, there was only a weak correlation between %CSA b5 and LAA% in each slice (r = 0.24, p = 0.0026). Another pattern observed was a homogenously low %CSA b5 despite a heterogeneous distribution of emphysema (Fig. 7). For this patient in whom 182 CT slices were analyzed, there was no correlation between %CSA b5 and LAA% in each slice (r = −0.026, p = 0.73). 3.6. Comparison of baseline characteristics of subjects according to the distribution of %CSA Table 2 shows that forced expiratory volume in 1 s, LAA%, %CSA b5, and health status in COPD subjects did not differ significantly between heterogeneous and homogenous distributions of %CSA. 4. Discussion To the best of our knowledge, this is the first study showing the association of small pulmonary vessel alterations with the distribution of emphysema in individual lungs with COPD. We would like to emphasize that these results were made possible by extensive and meticulous
Fig. 5. Relationship of LAA% with %CSA b5 in COPD subjects who had lower lungpredominant emphysema and a reverse distribution of %CSA b5. (a) The number of CT slices is 180. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 26.8% and 1.6%, respectively. (b) Correlation between LAA% and %CSA b5 (r = −0.91, p b 0.00001) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
3.4. Heterogeneous distribution of %CSA b 5 in COPD patients with emphysema Fig. 4 shows a representative distribution of LAA% and %CSA b5 in the entire lungs of a COPD subject. Emphysema was predominant and %CSA b5 was decreased in the upper lobes; in contrast, the lower lobes had less emphysematous changes and higher %CSA b5. On 150 CT slices, a negative correlation between %CSA b5 and LAA% (r = −0.88, p b 0.00001) was demonstrated in this subject. In a COPD patient with lower lobe-predominant emphysema (Fig. 5), there was reverse distribution of %CSA b 5. On 180 CT slices, a negative correlation between %CSA b 5 and LAA% (r = −0.91, p b 0.00001) was demonstrated in this subject. Of the 36 COPD patients, 17 showed a significant negative correlation between %CSA b5 and LAA% within the individual lungs.
3.5. Homogeneous distribution of %CSA b5 in COPD patients with emphysema Notably, more than half of the COPD population showed a homogeneous distribution of %CSA b5, regardless of the heterogeneity of the emphysema. Fig. 6 shows the distribution of LAA% and %CSA b 5 in the entire lung of a COPD subject. Emphysema was predominant in both
Fig. 6. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a homogenous high distribution of %CSA b5. (a) The number of CT slices is 161. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 35.0% and 1.5%, respectively. (b) Correlation between LAA% and %CSA b5 (r = 0.24, p = 0.0026) %CSA b5, percentage of total crosssectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
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Fig. 7. Relationship of LAA% with %CSA b5 in COPD subjects who had upper lungpredominant emphysema and a homogenous low distribution of %CSA b5. (a) The number of CT slices is 182. From left to right, the three dashed lines represent the upper cranial slice taken approximately 1 cm above the upper margin of the aortic arch, the middle slice taken approximately 1 cm below the carina, and the lower caudal slice taken approximately 1 cm below the right inferior pulmonary vein. The distribution of LAA% and %CSA b5 in COPD subjects is 22.3% and 0.8%, respectively. (b) Correlation between LAA% and %CSA b5 (r = −0.026, p = 0.73) %CSA b5, percentage of total cross-sectional area of small pulmonary vessels b5 mm2; LAA%, percentage of low attenuation area to total lung volume; COPD, chronic obstructive pulmonary disease; CT, computed tomography.
Table 2 Comparison of COPD subjects according to distribution of %CSA (N = 36)
N Women, n (%) Age, years Smoking index, pack-years Current smokers, n (%) FEV1, L %FEV1 LAA% %CSA b5 CAT SGRQ total score SGRQ symptom score SGRQ activity score SGRQ impact score
Heterogeneous distribution of %CSA
Homogenous distribution of %CSA
p value
17 2 (11.8) 72.4 ± 7.5 61.8 ± 21.2
19 2 (10.5) 71.2 ± 7.9 63.5 ± 25.7
0.906 0.727 0.918
2 (11.8)
0 (0)
0.134
1.5 ± 0.8 59.6 ± 23.0 28.3 ± 10.1 1.7 ± 0.3 11.4 ± 9.3 28.8 ± 22.7 29.7 ± 28.7
1.5 ± 0.6 53.8 ± 18.5 29.3 ± 10.1 1.5 ± 0.4 12.2 ± 5.5 24.1 ± 12.1 25.0 ± 20.3
1.000 0.537 0.516 0.189 0.437 0.635 0.801
43.3 ± 27.2 19.5 ± 19.0
39.6 ± 17.1 13.8 ± 11.5
0.593 0.405
Data are presented as mean ± standard deviation, unless otherwise specified. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; %FEV1, percent predicted forced expiratory volume in 1 s; LAA%, percentage of low attenuation area; %CSA b5, percentage of cross-sectional area of vessels b5 mm2; CAT, COPD assessment test; SGRQ, St. George Respiratory Questionnaire.
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analysis of N 150 cross-sectional CT slices for each subject. As shown in the analyses, calculation of %CSA b 5 from three selected axial slices [11–14] does not fully capture the geographic variation distribution of small pulmonary vessels throughout the lungs of COPD patients. Using representative values from 191 COPD patients, Matsuoka et al. showed a negative relationship between %CSA b 5 and the extent of emphysema [11]. The same negative correlation was observed in individual lungs in b 50% of the present population of COPD patients. The mechanisms underlying this negative correlation between %CSA b5 and the extent of emphysema could be attributed to the decrease in size of the small pulmonary vessels secondary to parenchymal destruction and to passive vascular compression due to the progression of emphysema, hypoxic vasoconstriction, and endothelial dysfunction [12,23]. The fact that the present data show that a substantial proportion of COPD patients do not exhibit this correlation is consistent with the heterogeneity seen in other clinical and radiographic aspects of the syndrome. Similar to the present findings, a recent report by Saruya et al. showed that, in COPD patients with emphysema progression on serial CT scans within N1 year, there was no decrease in %CSA b 5 [14]. Another novel finding of the present study was a pattern of homogeneously low %CSA b5 that was unrelated to the distribution of emphysema in some patients. This homogeneously low %CSA b5 could imply either a beginning process of progression to CT-detectable emphysema or a normal variant. On the other hand, there were some patients in whom %CSA b5 was homogeneously high regardless of the extent of emphysema. Although the mechanism of preservation of small pulmonary vessels in a region with damaged alveolar structures is unknown, an excessive blood supply in the area of alveolar destruction is a possibility. If %CSA b 5 is representative of the surface area of the capillaries in these patients, regional ventilation/perfusion mismatch might be present; this implies the existence of nonfunctional gas exchange that could lead to exercise-induced hypoxia. The clinical characteristics of such patients warrant further investigation. A limitation of this study was that the CT scan images were obtained in patients at full inspiration in a supine position, not in a standing position. Therefore, the dynamic changes in the volume of small pulmonary vessels during tidal breathing in a standing position were not accounted for, although it is essential for understanding respiratory physiology in daily life. It should be noted that pulmonary vascular remodeling is not exclusive to severe emphysema, but it has also been shown in some patients with mild COPD and in smokers with normal pulmonary function [12]. Recently, a variety of COPD phenotypes has been examined. The results of this study may provide another phenotype based on the volume and distribution of small pulmonary vessels in COPD lungs. 5. Conclusion In a substantial portion of COPD patients in this study, the distributions of %CSA b5 and LAA% within an entire lung were inversely correlated, supporting a pathophysiologic association between a decrease of small pulmonary vessels and the development of emphysema. On the other hand, a distribution of small pulmonary vessels independent of emphysema heterogeneity was found in some COPD patients. Acknowledgments The authors acknowledge Ishikawa Naomi and Tsuyoshi Sakamoto of AZE for helping in the analysis of chest CT imaging findings. Role of the funding source This study was supported by Japan Society for the Promotion of Science KAKENHI Grant (Number 25670401).
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