respiratory investigation 53 (2015) 111–116
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Low arterial blood oxygenation is associated with calcification of the coronary arteries in patients with chronic obstructive pulmonary disease Sumito Inouen, Yoko Shibata, Hiroyuki Kishi, Hiromasa Hasegawa, Joji Nitobe, Tadateru Iwayama, Yoshinori Yashiro, Takako Nemoto, Kento Sato, Hiroshi Nakano, Masamichi Sato, Keiko Nunomiya, Yasuko Aida, Keiko Yamauchi, Akira Igarashi, Shuichi Abe, Isao Kubota Yamagata University School of Medicine, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Cigarette smoking is a well-known major cause of both chronic obstructive
Received 2 September 2014
pulmonary disease (COPD) and atherosclerosis. However, few studies have investigated the
Received in revised form
correlation between COPD and coronary atherosclerosis.
26 December 2014
Methods: We recruited 54 patients with stable COPD (51 men, 3 women) but without angina
Accepted 7 January 2015
symptoms. Arterial blood gas analyses were performed, pulmonary function was assessed,
Available online 21 February 2015
and calcification of the coronary arteries was evaluated by computed tomography (CT).
Keywords:
Results: Calcification of the coronary arteries was noted in 25 patients. There were no
Chronic obstructive pulmonary
significant differences in age, body mass index, respiratory function, and levels of low-
disease
density lipoprotein cholesterol, hemoglobin A1c, glucose, or C-reactive protein between
Coronary artery
patients with or without calcification of the coronary arteries. Arterial blood oxygenation
Calcification
was significantly lower in patients with calcification of the coronary arteries. On both
Low arterial blood oxygenation
univariate and multivariate analyses, low arterial blood oxygenation was an independent
Cardiac multi-detector computed
risk factor for calcification of the coronary arteries.
tomography
Conclusions: In patients with COPD, low arterial blood oxygenation was strongly associated with calcification of the coronary arteries and may be a significant predictor of cardiovascular disease. & 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
n
Corresponding author. Tel.: þ81 23 628 5302; fax: þ81 23 628 5305. E-mail addresses: [email protected] (S. Inoue), [email protected] (Y. Shibata), [email protected] (H. Kishi), [email protected] (H. Hasegawa), [email protected] (J. Nitobe), [email protected] (T. Iwayama), [email protected] (Y. Yashiro), [email protected] (T. Nemoto), [email protected] (K. Sato), [email protected] (H. Nakano), [email protected] (M. Sato), [email protected] (K. Nunomiya), [email protected] (Y. Aida), [email protected] (K. Yamauchi), [email protected] (A. Igarashi), [email protected] (S. Abe), [email protected] (I. Kubota). http://dx.doi.org/10.1016/j.resinv.2015.01.002 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
112
1.
respiratory investigation 53 (2015) 111 –116
Introduction
Cigarette smoking causes a variety of respiratory disorders, including chronic obstructive pulmonary disease (COPD) [1]. COPD, a common disease characterized by varying airflow limitation levels, is globally the leading cause of death and a major medical problem in both Japan and worldwide [2]. A previous study showed that the prevalence of airflow limitation in Japanese people agedZ40 years wasZ10% [3,4]. COPD was recently shown to be both a respiratory and systemic disease. Higher serum levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α have been observed in patients with COPD [5– 7]. Comorbidities such as lower body mass index (BMI), cardiovascular disease, osteoporosis, diabetes mellitus, and renal dysfunction are recognizes to occur more frequently in patients with COPD [2,8–10]. As we previously demonstrated, differences in genetic backgrounds among patients with COPD are involved in this exaggerated inflammatory response [11–13]. COPD and atherosclerosis are both strongly associated with cigarette smoking [14], and large numbers of patients with COPD die of cardiovascular disease [2]. Smokers with airflow limitations have increased subclinical atherosclerosis. Iwamoto et al. measured carotid intima-media thickness and focal atheromatous plaques as indicators of subclinical atherosclerosis [14]. It is important to evaluate atherosclerosis in patients with COPD to estimate the prevalence of cardiovascular disease. However, detecting ischemic heart disease in patients with COPD is difficult because their ventilation limitations during exercise constrain the cardiac demands [15]. Little is known about the burden of subclinical coronary artery disease in patients with COPD, and there have been few studies investigating the correlation between COPD and coronary atherosclerosis. Despite being an invasive procedure, coronary angiography is commonly used to evaluate atherosclerosis of the coronary arteries. Multi-detector computed tomography (MDCT) is a non-invasive and reliable examination method that is useful for evaluating coronary artery stenosis or calcification [16]. Coronary artery calcification is associated with atherosclerosis [17] and predictive of cardiovascular events [18]. In this study, we evaluated coronary artery calcification in patients with COPD using 64-slice MDCT and analyzed the correlations between coronary artery calcification and clinical parameters in patients with stable COPD. The aim of this study was to identify predictive clinical factors for coronary artery calcification in patients with stable COPD who had neither history nor symptoms of angina pectoris such as chest pain.
was approved by the Institutional Ethics Committee of Yamagata University School of Medicine (Approval date: October 21, 2009; Approved #: 21), and all participants provided written informed consent. COPD was diagnosed by using spirometry when the post-bronchodilator ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) waso0.7 [19]. The Japanese Respiratory Society reference values were used [20]. Smoking habits were selfreported. The patients’ profiles are summarized in Table 1. Six subjects were receiving long-term oxygen therapy (LTOT).
2.2.
Laboratory data
Clinical information was obtained from the patients’ medical records. Peripheral blood counts, liver and renal functions, and levels of glucose, glycated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured using routine laboratory techniques. Hypertension was diagnosed as a systolic blood pressure Z140 mmHg and/or diastolic pressure Z90 mmHg or the current use of anti-hypertensive drugs. Diabetes mellitus was diagnosed as a fasting plasma glucose concentration Z126 mg/dL, HbA1c levelZ 6.1% (Japan Diabetes Society), or current use of insulin or hypoglycemic agents. Dyslipidemia was diagnosed as concentrations of LDL-CZ140 mg/dL, TG Z150 mg/dL or HDL-Co40 mg/dL, or current use of anti-hyperlipidemic drugs. Blood samples were obtained from the femoral artery of the subjects without LTOT on room air and from subjects with LTOT inhaling their usual flow of oxygen. Blood gas levels were measured after rest in the supine position for over 10 min.
2.3.
Evaluation of coronary artery calcification
2.
Materials and methods
Cardiac multi-detector computed tomography (MDCT) was performed using a 64-slice MDCT scanner (Aquilion 64; Toshiba, Tokyo, Japan). A total of 51–100 mL of contrast media (Iopamidol; Bayer Co. Ltd., Leverkusen, Germany) was injected at a flow rate of 3.0–4.6 mL/s depending on the patient's body weight. The region of interest (ROI) was placed within the ascending or descending aorta, and scanning was commenced when the CT density reached 250 Hounsfield units (HU) at the ascending aorta or 180 HU at the descending aorta. Scans were performed between the diaphragm and the tracheal bifurcation (collimation width, 0.5 mm; rotation speed, 0.4 s/rotation; tube voltage, 120 kV; and effective tube current, 400–450 mA). Cardiac images were evaluated at the most motionless phase of the cardiac cycle, which was most frequently the mid-diastolic phase, with retrospective cardiac gating at 75% of the R-R interval. Calcification of the coronary arteries was evaluated as lesions composed exclusively of structures with a CT density greater than that of the enhanced coronary lesions [16,21].
2.1.
Subjects
2.4.
We recruited 54 patients with stable COPD (51 men, 3 women) who had no angina symptoms and who had not had a disease exacerbation within the 3 months before the study. The study
Statistical analyses
All data are expressed as means7SD except for C-reactive protein (CRP) level (expressed as median [95% confidence interval]). The Mann–Whitney U-test or chi-square test was
113
respiratory investigation 53 (2015) 111 –116
Table 1 – Patients’ demographic, coronary risk factors, laboratory findings, and pumonary function. All patients n ¼54
Without calcification n ¼ 29
With calcification n ¼ 25
P-value
Age (yr) Sex (male/female) BMI Long term oxygen therapy GOLD classification (I/II/III/IV) Brinkman index
7178 51/3 21.673.3 6 (11.1%) 8/18/21/7 12117615
7179 28/1 21.773.1 4 (13.8%) 4/7/14/4 11877602
7177 23/2 21.573.6 2 (8.0%) 4/11/7/3 12397642
0.958 0.467 0.664 0.499 0.379 0.931
Coronary risk factors Hypertension Dyslipidemia Diabetes mellitus
22 (40.7%) 23 (42.6%) 9 (16.7%)
9 (31.0%) 10 (34.5%) 3 (10.3%)
13 (52.0%) 13 (52.0%) 6 (24.0%)
0.118 0.194 0.179
Laboratory findings LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Hemoglobin A1c (%) Glucose (mg/dL) CRP (mg/dL)
101728 62720 119773 5.570.5 112720 0.070 (0.099–0.422)
100726 63722 103747 5.470.5 112721 0.060 (0.046–0.424)
102730 61717 138792 5.670.5 112719 0.111 (0.002–0.578)
0.633 0.849 0.274 0.091 0.775 0.263
Pulmonary function pH PaCO2 (torr) PaO2 (torr) FVC %predicted (%) FEV1/FVC (%) FEV1 %predicted (%)
7.41070.028 4075 82714 99.4727.6 46.3710.4 52.2721.4
7.40470.031 4175 85715 93.3728.4 47.479.7 51.0723.4
7.41670.024 4074 78712 106.5725.3 45.1711.3 53.7719.2
0.140 0.302 0.026n 0.103 0.390 0.420
BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s. P-values of patients with versus without calcification. All data except for CRP are expressed as mean7standard deviation. CRP was expressed as median (95% confidence interval).
used to evaluate differences in mean values between the two groups. Univariate and multivariate analyses were used to identify risk factors for calcification of the coronary arteries. All statistical analyses were performed by using JMP version 11.0.0 software (SAS Institute Inc., Cary, NC, USA). Values of Po0.05 were defined as statistically significant.
3.
Results
According to the coronary CT angiography results, the patients were divided into two groups: those with calcification of coronary arteries (n¼ 25) and those without (n¼ 29). The respiratory function test results and laboratory data are summarized in Table 1. There were no significant differences in age, BMI, Brinkman index (daily consumption of cigarettes years of smoking), frequencies of hypertension, dyslipidemia, or diabetes mellitus, or levels of LDL cholesterol, HDL cholesterol, triglycerides, HbA1c, glucose, or CRP between the two groups. All hypertensive subjects were taking antihypertensive medicines. There was no difference in the ratio of subjects receiving medicines for hypertension, dyslipidemia, and diabetes mellitus between the two groups. Respiratory function parameters such as FVC% predicted and FEV1% predicted did not differ between the two groups. The partial pressure of oxygen (PaO2) of the arterial blood was significantly
Table 2 – Univariate analysis to detect the risk factors of coronary artery calcification.
Age (increasing 1 SD) Male gender PaO2 (increasing 1 SD)
Odds ratio
95% CI
P-value
1.06 0.411 0.55
0.613–1.839 0.018–4.549 0.278–0.974
0.8413 0.4648 0.0401n
CI, confidence interval. n Po0.05.
lower in patients with calcified coronary arteries than in those without. On univariate analysis, the PaO2 of the arterial blood was a significant risk factor for calcification of the coronary arteries (Table 2). Multivariate analysis showed that the PaO2 of the arterial blood was significantly predictive for calcification of the coronary arteries independent of age and gender (Table 3).
4.
Discussion
This study showed that low oxygenation of the arterial blood is an independent risk factor for calcification of the coronary arteries in patients with stable COPD. The natural history of COPD involves frequent respiratory tract infections, which
114
respiratory investigation 53 (2015) 111 –116
Table 3 – Multivariate analysis to detect the risk factors of coronary artery calcification.
Age (increasing 1 SD) Male gender PaO2 (increasing 1 SD)
Odds ratio
95% CI
P-value
1.00 0.50 0.55
0.560–1.784 0.021–6.322 0.279–0.996
0.9996 0.5956 0.0484n
PaO2, partial pressure of oxygen. n Po0.05.
result in disease exacerbations, severe respiratory failure, and even death [22–24]. However, patients with COPD die of either pulmonary or cardiovascular disease. In the TORCH (TOwards a Revolution in COPD Health) study, deaths due to cardiovascular disease accounted for 27% of all-cause deaths in patients with COPD [2]. In the present study, approximately half of the patients with COPD showed coronary artery calcification, which is thought to be associated with atherosclerosis [17,18], even though these patients did not have any angina symptoms. Coronary artery calcification was reported to be more frequent in patients with COPD (67%) than in nonsmokers (28%) or smokers without COPD (47%) in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study [25]). It is important to evaluate the prevalence of atherosclerosis and reduce the incidence of cardiovascular disease in patients with COPD because cardiovascular disease is a major cause of death in patients with COPD [26,27]. However, since most patients with COPD have respiratory symptoms during exercise in addition to a reduced exercise capacity, it is difficult to determine from their clinical symptoms alone whether these patients have ischemic heart disease. Although coronary artery calcification may not always indicate the presence of coronary artery stenosis, one study reported a strong association between coronary artery calcification and cardiovascular events [18]. In the current study, we evaluated calcification of the coronary arteries on coronary CT angiography. Compared with angiography or exercise testing, CT is a non-invasive technique for evaluating the condition of the coronary arteries. We believe that cardiac CT is a very useful, safe, and reliable method for evaluating atherosclerosis of the coronary arteries to predict the likelihood of cardiovascular events in patients with COPD. As a consequence of our results, two patients underwent cardiac scintigraphy and two patients underwent cardiac catheterization following a diagnosis of coronary stenosis. Coronary CT angiography is thought to be useful for the screening of coronary stenosis, even in patients without angina symptoms. In previous studies, low oxygenation levels have been shown to be associated with blood vessel calcification. Sluimer et al. reviewed the precise mechanisms of atherosclerosis and demonstrated that hypoxia is strongly correlated with the progression of atherosclerosis [28]. Fimognari et al. suggested that chronic hypoxia induced platelet activation and blood clotting but decreased endothelial thrombomodulin levels [29]. These may be potential risk factors for atherosclerosis in patients with COPD. These data support the results presented here, which showed that patients with
COPD and low oxygenation levels have additional atherosclerotic lesions in their coronary arteries. Some studies have shown the evaluation of calcification in the coronary artery with CT in the absence of contrast media [30,31]. Clinicians are commonly hesitant to use contrast media due to its possible adverse events, such as anaphylaxis and renal dysfunction. However, it is difficult to evaluate the degree of stenosis in the coronary arteries on chest CT without contrast media, and calcification in the coronary arteries suggests the existence of atherosclerosis. In this study, we observed four cases with possible coronary artery stenosis that required further examination; without the use of CT angiography, we could not diagnose coronary artery disease in these patients. An additional advantage of the use of contrast media is that indicators of cardiac function, such as ejection fraction, cardiac output, and cardiac diameters, can be measured simultaneously on cardiac CT. This information is very informative and valuable because an echocardiogram is sometimes unavailable for patients with COPD due to their hyperinflated lungs. We aim to conduct future studies in which we will further explore this relationship between cardiac function and exercise capacity in patients with COPD. This study has some limitations. First, it was performed at a single center, so the number of subjects enrolled was not large. Second, systemic inflammation was evaluated using CRP levels alone and no other biomarkers such as proinflammatory cytokines. In the present study, CRP levels did not differ between patients with or without coronary artery calcification. However, some studies have shown that enhanced inflammatory responses such as elevated proinflammatory cytokine and/or chemokine levels are due to hypoxia [6,32]. Macrophages play an important role in the pathogenesis of atherosclerosis, including the progression and stability of atherosclerotic lesions. Macrophages release pro-inflammatory cytokines including TNF-α and IL-6 and induce smooth muscle and endothelial cell death. These responses augment the inflammatory response and growth of atherosclerotic lesions [29]. Other inflammatory biomarkers may be associated with coronary artery calcification in patients with COPD. In patients receiving LTOT, the inhaled oxygen concentration may be variable under inhalation through a nasal cannula. Upon the exclusion of patients using LTOT from the analysis, the arterial oxygen concentration tended to be lower in patients with calcification of the coronary artery than in patients without it, although the difference between the two groups did not reach statistical significance (P ¼0.0618). We speculate that the number of analyzed patients was not sufficient to demonstrate a significant difference in PaO2 levels between the two groups after the elimination of LTOT users. Moreover, all patients including the LTOT users were measured for blood gas data after resting for at least 10 min. Hence, for all patients, we believe that PaO2 levels reflect oxygenation during rest, even during oxygen inhalation. To assess the effects of including LTOT users in our analysis, we re-performed the multivariate analysis using age, gender, PaO2 of the arterial blood, and LTOT use as covariates. In this multiple logistic regression model, the
respiratory investigation 53 (2015) 111 –116
arterial blood PaO2 level was still significantly predictive of calcification of the coronary arteries independent of age, gender, and LTOT use (P¼ 0.0318). Thus, we conclude that low oxygenation is a significant independent risk factor for calcification of the coronary artery in patients with COPD. In conclusion, we showed here that low arterial blood oxygenation is strongly associated with coronary artery calcification. To our knowledge, this is the first study to show the connection between low-grade oxygenation in the arterial blood and calcification of the coronary arteries in patients with COPD. Low-grade oxygenation may be a potential risk factor for cardiovascular disease in patients with COPD, even in the absence of angina symptoms. In addition, more rigorous monitoring of oxygenation in patients with COPD is important to identify those suffering from hypoxia during exercise or sleep.
Funding This research received no specific grant from any funding agency.
Conflict of interest Isao Kubota receives subsidies or donations from the following: Teijin Pharma Limited, Takeda Pharmaceutical Company Limited, FUJIFILM RI Pharma Co., Ltd., Astellas Pharma Inc., Mochida Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Daiichi Sankyo Company, Limited, Otsuka Pharmaceutical Co., Ltd., Shionogi & Company, Limited, Novartis Pharma K.K., and Pfizer Japan Inc. Yoko Shibata receives lecture fees from Novartis Pharmaceuticals Japan and Boehringer Ingelheim Japan.
r e f e r e n c e s
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[25] Williams MC, Murchison JT, Edwards LD, et al. Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax 2014;69:718–23. [26] Anthonisen NR, Connett JE, Enright PL, et al. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med 2002;166:333–9. [27] Shibata Y, Inoue S, Igarashi A, et al. A lower level of forced expiratory volume in 1s is a risk factor for all-cause and cardiovascular mortality in a Japanese population: the Takahata study. PLoS One 2013;8: e83725. [28] Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 2009;218:7–29.
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Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Low arterial blood oxygenation is associated with calcification of the coronary arteries in patients with chronic obstructive pulmonary disease Sumito Inouen, Yoko Shibata, Hiroyuki Kishi, Hiromasa Hasegawa, Joji Nitobe, Tadateru Iwayama, Yoshinori Yashiro, Takako Nemoto, Kento Sato, Hiroshi Nakano, Masamichi Sato, Keiko Nunomiya, Yasuko Aida, Keiko Yamauchi, Akira Igarashi, Shuichi Abe, Isao Kubota Yamagata University School of Medicine, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Cigarette smoking is a well-known major cause of both chronic obstructive
Received 2 September 2014
pulmonary disease (COPD) and atherosclerosis. However, few studies have investigated the
Received in revised form
correlation between COPD and coronary atherosclerosis.
26 December 2014
Methods: We recruited 54 patients with stable COPD (51 men, 3 women) but without angina
Accepted 7 January 2015
symptoms. Arterial blood gas analyses were performed, pulmonary function was assessed,
Available online 21 February 2015
and calcification of the coronary arteries was evaluated by computed tomography (CT).
Keywords:
Results: Calcification of the coronary arteries was noted in 25 patients. There were no
Chronic obstructive pulmonary
significant differences in age, body mass index, respiratory function, and levels of low-
disease
density lipoprotein cholesterol, hemoglobin A1c, glucose, or C-reactive protein between
Coronary artery
patients with or without calcification of the coronary arteries. Arterial blood oxygenation
Calcification
was significantly lower in patients with calcification of the coronary arteries. On both
Low arterial blood oxygenation
univariate and multivariate analyses, low arterial blood oxygenation was an independent
Cardiac multi-detector computed
risk factor for calcification of the coronary arteries.
tomography
Conclusions: In patients with COPD, low arterial blood oxygenation was strongly associated with calcification of the coronary arteries and may be a significant predictor of cardiovascular disease. & 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
n
Corresponding author. Tel.: þ81 23 628 5302; fax: þ81 23 628 5305. E-mail addresses: [email protected] (S. Inoue), [email protected] (Y. Shibata), [email protected] (H. Kishi), [email protected] (H. Hasegawa), [email protected] (J. Nitobe), [email protected] (T. Iwayama), [email protected] (Y. Yashiro), [email protected] (T. Nemoto), [email protected] (K. Sato), [email protected] (H. Nakano), [email protected] (M. Sato), [email protected] (K. Nunomiya), [email protected] (Y. Aida), [email protected] (K. Yamauchi), [email protected] (A. Igarashi), [email protected] (S. Abe), [email protected] (I. Kubota). http://dx.doi.org/10.1016/j.resinv.2015.01.002 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
112
1.
respiratory investigation 53 (2015) 111 –116
Introduction
Cigarette smoking causes a variety of respiratory disorders, including chronic obstructive pulmonary disease (COPD) [1]. COPD, a common disease characterized by varying airflow limitation levels, is globally the leading cause of death and a major medical problem in both Japan and worldwide [2]. A previous study showed that the prevalence of airflow limitation in Japanese people agedZ40 years wasZ10% [3,4]. COPD was recently shown to be both a respiratory and systemic disease. Higher serum levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α have been observed in patients with COPD [5– 7]. Comorbidities such as lower body mass index (BMI), cardiovascular disease, osteoporosis, diabetes mellitus, and renal dysfunction are recognizes to occur more frequently in patients with COPD [2,8–10]. As we previously demonstrated, differences in genetic backgrounds among patients with COPD are involved in this exaggerated inflammatory response [11–13]. COPD and atherosclerosis are both strongly associated with cigarette smoking [14], and large numbers of patients with COPD die of cardiovascular disease [2]. Smokers with airflow limitations have increased subclinical atherosclerosis. Iwamoto et al. measured carotid intima-media thickness and focal atheromatous plaques as indicators of subclinical atherosclerosis [14]. It is important to evaluate atherosclerosis in patients with COPD to estimate the prevalence of cardiovascular disease. However, detecting ischemic heart disease in patients with COPD is difficult because their ventilation limitations during exercise constrain the cardiac demands [15]. Little is known about the burden of subclinical coronary artery disease in patients with COPD, and there have been few studies investigating the correlation between COPD and coronary atherosclerosis. Despite being an invasive procedure, coronary angiography is commonly used to evaluate atherosclerosis of the coronary arteries. Multi-detector computed tomography (MDCT) is a non-invasive and reliable examination method that is useful for evaluating coronary artery stenosis or calcification [16]. Coronary artery calcification is associated with atherosclerosis [17] and predictive of cardiovascular events [18]. In this study, we evaluated coronary artery calcification in patients with COPD using 64-slice MDCT and analyzed the correlations between coronary artery calcification and clinical parameters in patients with stable COPD. The aim of this study was to identify predictive clinical factors for coronary artery calcification in patients with stable COPD who had neither history nor symptoms of angina pectoris such as chest pain.
was approved by the Institutional Ethics Committee of Yamagata University School of Medicine (Approval date: October 21, 2009; Approved #: 21), and all participants provided written informed consent. COPD was diagnosed by using spirometry when the post-bronchodilator ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) waso0.7 [19]. The Japanese Respiratory Society reference values were used [20]. Smoking habits were selfreported. The patients’ profiles are summarized in Table 1. Six subjects were receiving long-term oxygen therapy (LTOT).
2.2.
Laboratory data
Clinical information was obtained from the patients’ medical records. Peripheral blood counts, liver and renal functions, and levels of glucose, glycated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured using routine laboratory techniques. Hypertension was diagnosed as a systolic blood pressure Z140 mmHg and/or diastolic pressure Z90 mmHg or the current use of anti-hypertensive drugs. Diabetes mellitus was diagnosed as a fasting plasma glucose concentration Z126 mg/dL, HbA1c levelZ 6.1% (Japan Diabetes Society), or current use of insulin or hypoglycemic agents. Dyslipidemia was diagnosed as concentrations of LDL-CZ140 mg/dL, TG Z150 mg/dL or HDL-Co40 mg/dL, or current use of anti-hyperlipidemic drugs. Blood samples were obtained from the femoral artery of the subjects without LTOT on room air and from subjects with LTOT inhaling their usual flow of oxygen. Blood gas levels were measured after rest in the supine position for over 10 min.
2.3.
Evaluation of coronary artery calcification
2.
Materials and methods
Cardiac multi-detector computed tomography (MDCT) was performed using a 64-slice MDCT scanner (Aquilion 64; Toshiba, Tokyo, Japan). A total of 51–100 mL of contrast media (Iopamidol; Bayer Co. Ltd., Leverkusen, Germany) was injected at a flow rate of 3.0–4.6 mL/s depending on the patient's body weight. The region of interest (ROI) was placed within the ascending or descending aorta, and scanning was commenced when the CT density reached 250 Hounsfield units (HU) at the ascending aorta or 180 HU at the descending aorta. Scans were performed between the diaphragm and the tracheal bifurcation (collimation width, 0.5 mm; rotation speed, 0.4 s/rotation; tube voltage, 120 kV; and effective tube current, 400–450 mA). Cardiac images were evaluated at the most motionless phase of the cardiac cycle, which was most frequently the mid-diastolic phase, with retrospective cardiac gating at 75% of the R-R interval. Calcification of the coronary arteries was evaluated as lesions composed exclusively of structures with a CT density greater than that of the enhanced coronary lesions [16,21].
2.1.
Subjects
2.4.
We recruited 54 patients with stable COPD (51 men, 3 women) who had no angina symptoms and who had not had a disease exacerbation within the 3 months before the study. The study
Statistical analyses
All data are expressed as means7SD except for C-reactive protein (CRP) level (expressed as median [95% confidence interval]). The Mann–Whitney U-test or chi-square test was
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Table 1 – Patients’ demographic, coronary risk factors, laboratory findings, and pumonary function. All patients n ¼54
Without calcification n ¼ 29
With calcification n ¼ 25
P-value
Age (yr) Sex (male/female) BMI Long term oxygen therapy GOLD classification (I/II/III/IV) Brinkman index
7178 51/3 21.673.3 6 (11.1%) 8/18/21/7 12117615
7179 28/1 21.773.1 4 (13.8%) 4/7/14/4 11877602
7177 23/2 21.573.6 2 (8.0%) 4/11/7/3 12397642
0.958 0.467 0.664 0.499 0.379 0.931
Coronary risk factors Hypertension Dyslipidemia Diabetes mellitus
22 (40.7%) 23 (42.6%) 9 (16.7%)
9 (31.0%) 10 (34.5%) 3 (10.3%)
13 (52.0%) 13 (52.0%) 6 (24.0%)
0.118 0.194 0.179
Laboratory findings LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Hemoglobin A1c (%) Glucose (mg/dL) CRP (mg/dL)
101728 62720 119773 5.570.5 112720 0.070 (0.099–0.422)
100726 63722 103747 5.470.5 112721 0.060 (0.046–0.424)
102730 61717 138792 5.670.5 112719 0.111 (0.002–0.578)
0.633 0.849 0.274 0.091 0.775 0.263
Pulmonary function pH PaCO2 (torr) PaO2 (torr) FVC %predicted (%) FEV1/FVC (%) FEV1 %predicted (%)
7.41070.028 4075 82714 99.4727.6 46.3710.4 52.2721.4
7.40470.031 4175 85715 93.3728.4 47.479.7 51.0723.4
7.41670.024 4074 78712 106.5725.3 45.1711.3 53.7719.2
0.140 0.302 0.026n 0.103 0.390 0.420
BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s. P-values of patients with versus without calcification. All data except for CRP are expressed as mean7standard deviation. CRP was expressed as median (95% confidence interval).
used to evaluate differences in mean values between the two groups. Univariate and multivariate analyses were used to identify risk factors for calcification of the coronary arteries. All statistical analyses were performed by using JMP version 11.0.0 software (SAS Institute Inc., Cary, NC, USA). Values of Po0.05 were defined as statistically significant.
3.
Results
According to the coronary CT angiography results, the patients were divided into two groups: those with calcification of coronary arteries (n¼ 25) and those without (n¼ 29). The respiratory function test results and laboratory data are summarized in Table 1. There were no significant differences in age, BMI, Brinkman index (daily consumption of cigarettes years of smoking), frequencies of hypertension, dyslipidemia, or diabetes mellitus, or levels of LDL cholesterol, HDL cholesterol, triglycerides, HbA1c, glucose, or CRP between the two groups. All hypertensive subjects were taking antihypertensive medicines. There was no difference in the ratio of subjects receiving medicines for hypertension, dyslipidemia, and diabetes mellitus between the two groups. Respiratory function parameters such as FVC% predicted and FEV1% predicted did not differ between the two groups. The partial pressure of oxygen (PaO2) of the arterial blood was significantly
Table 2 – Univariate analysis to detect the risk factors of coronary artery calcification.
Age (increasing 1 SD) Male gender PaO2 (increasing 1 SD)
Odds ratio
95% CI
P-value
1.06 0.411 0.55
0.613–1.839 0.018–4.549 0.278–0.974
0.8413 0.4648 0.0401n
CI, confidence interval. n Po0.05.
lower in patients with calcified coronary arteries than in those without. On univariate analysis, the PaO2 of the arterial blood was a significant risk factor for calcification of the coronary arteries (Table 2). Multivariate analysis showed that the PaO2 of the arterial blood was significantly predictive for calcification of the coronary arteries independent of age and gender (Table 3).
4.
Discussion
This study showed that low oxygenation of the arterial blood is an independent risk factor for calcification of the coronary arteries in patients with stable COPD. The natural history of COPD involves frequent respiratory tract infections, which
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Table 3 – Multivariate analysis to detect the risk factors of coronary artery calcification.
Age (increasing 1 SD) Male gender PaO2 (increasing 1 SD)
Odds ratio
95% CI
P-value
1.00 0.50 0.55
0.560–1.784 0.021–6.322 0.279–0.996
0.9996 0.5956 0.0484n
PaO2, partial pressure of oxygen. n Po0.05.
result in disease exacerbations, severe respiratory failure, and even death [22–24]. However, patients with COPD die of either pulmonary or cardiovascular disease. In the TORCH (TOwards a Revolution in COPD Health) study, deaths due to cardiovascular disease accounted for 27% of all-cause deaths in patients with COPD [2]. In the present study, approximately half of the patients with COPD showed coronary artery calcification, which is thought to be associated with atherosclerosis [17,18], even though these patients did not have any angina symptoms. Coronary artery calcification was reported to be more frequent in patients with COPD (67%) than in nonsmokers (28%) or smokers without COPD (47%) in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study [25]). It is important to evaluate the prevalence of atherosclerosis and reduce the incidence of cardiovascular disease in patients with COPD because cardiovascular disease is a major cause of death in patients with COPD [26,27]. However, since most patients with COPD have respiratory symptoms during exercise in addition to a reduced exercise capacity, it is difficult to determine from their clinical symptoms alone whether these patients have ischemic heart disease. Although coronary artery calcification may not always indicate the presence of coronary artery stenosis, one study reported a strong association between coronary artery calcification and cardiovascular events [18]. In the current study, we evaluated calcification of the coronary arteries on coronary CT angiography. Compared with angiography or exercise testing, CT is a non-invasive technique for evaluating the condition of the coronary arteries. We believe that cardiac CT is a very useful, safe, and reliable method for evaluating atherosclerosis of the coronary arteries to predict the likelihood of cardiovascular events in patients with COPD. As a consequence of our results, two patients underwent cardiac scintigraphy and two patients underwent cardiac catheterization following a diagnosis of coronary stenosis. Coronary CT angiography is thought to be useful for the screening of coronary stenosis, even in patients without angina symptoms. In previous studies, low oxygenation levels have been shown to be associated with blood vessel calcification. Sluimer et al. reviewed the precise mechanisms of atherosclerosis and demonstrated that hypoxia is strongly correlated with the progression of atherosclerosis [28]. Fimognari et al. suggested that chronic hypoxia induced platelet activation and blood clotting but decreased endothelial thrombomodulin levels [29]. These may be potential risk factors for atherosclerosis in patients with COPD. These data support the results presented here, which showed that patients with
COPD and low oxygenation levels have additional atherosclerotic lesions in their coronary arteries. Some studies have shown the evaluation of calcification in the coronary artery with CT in the absence of contrast media [30,31]. Clinicians are commonly hesitant to use contrast media due to its possible adverse events, such as anaphylaxis and renal dysfunction. However, it is difficult to evaluate the degree of stenosis in the coronary arteries on chest CT without contrast media, and calcification in the coronary arteries suggests the existence of atherosclerosis. In this study, we observed four cases with possible coronary artery stenosis that required further examination; without the use of CT angiography, we could not diagnose coronary artery disease in these patients. An additional advantage of the use of contrast media is that indicators of cardiac function, such as ejection fraction, cardiac output, and cardiac diameters, can be measured simultaneously on cardiac CT. This information is very informative and valuable because an echocardiogram is sometimes unavailable for patients with COPD due to their hyperinflated lungs. We aim to conduct future studies in which we will further explore this relationship between cardiac function and exercise capacity in patients with COPD. This study has some limitations. First, it was performed at a single center, so the number of subjects enrolled was not large. Second, systemic inflammation was evaluated using CRP levels alone and no other biomarkers such as proinflammatory cytokines. In the present study, CRP levels did not differ between patients with or without coronary artery calcification. However, some studies have shown that enhanced inflammatory responses such as elevated proinflammatory cytokine and/or chemokine levels are due to hypoxia [6,32]. Macrophages play an important role in the pathogenesis of atherosclerosis, including the progression and stability of atherosclerotic lesions. Macrophages release pro-inflammatory cytokines including TNF-α and IL-6 and induce smooth muscle and endothelial cell death. These responses augment the inflammatory response and growth of atherosclerotic lesions [29]. Other inflammatory biomarkers may be associated with coronary artery calcification in patients with COPD. In patients receiving LTOT, the inhaled oxygen concentration may be variable under inhalation through a nasal cannula. Upon the exclusion of patients using LTOT from the analysis, the arterial oxygen concentration tended to be lower in patients with calcification of the coronary artery than in patients without it, although the difference between the two groups did not reach statistical significance (P ¼0.0618). We speculate that the number of analyzed patients was not sufficient to demonstrate a significant difference in PaO2 levels between the two groups after the elimination of LTOT users. Moreover, all patients including the LTOT users were measured for blood gas data after resting for at least 10 min. Hence, for all patients, we believe that PaO2 levels reflect oxygenation during rest, even during oxygen inhalation. To assess the effects of including LTOT users in our analysis, we re-performed the multivariate analysis using age, gender, PaO2 of the arterial blood, and LTOT use as covariates. In this multiple logistic regression model, the
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arterial blood PaO2 level was still significantly predictive of calcification of the coronary arteries independent of age, gender, and LTOT use (P¼ 0.0318). Thus, we conclude that low oxygenation is a significant independent risk factor for calcification of the coronary artery in patients with COPD. In conclusion, we showed here that low arterial blood oxygenation is strongly associated with coronary artery calcification. To our knowledge, this is the first study to show the connection between low-grade oxygenation in the arterial blood and calcification of the coronary arteries in patients with COPD. Low-grade oxygenation may be a potential risk factor for cardiovascular disease in patients with COPD, even in the absence of angina symptoms. In addition, more rigorous monitoring of oxygenation in patients with COPD is important to identify those suffering from hypoxia during exercise or sleep.
Funding This research received no specific grant from any funding agency.
Conflict of interest Isao Kubota receives subsidies or donations from the following: Teijin Pharma Limited, Takeda Pharmaceutical Company Limited, FUJIFILM RI Pharma Co., Ltd., Astellas Pharma Inc., Mochida Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Daiichi Sankyo Company, Limited, Otsuka Pharmaceutical Co., Ltd., Shionogi & Company, Limited, Novartis Pharma K.K., and Pfizer Japan Inc. Yoko Shibata receives lecture fees from Novartis Pharmaceuticals Japan and Boehringer Ingelheim Japan.
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