Indicator of arteriosclerosis in patients with COPD

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1 ORIGINAL ARTICLES Indicator of arteriosclerosis in patients with COPD Akinori Ebihara 1 Akifumi Watanabe 2 Asuka Nagai 1 Rurika Hamanaka 3 Naoko Imamura 3 Chizumi Yamada 4 Tokuzen Iwamoto 1 Ichiro Kuwahira 1 1 Pulmonary Medicine, Tokai University Tokyo Hospital 2 Erimo Town Clinic 3 General Thoracic Surgery, Tokai University Tokyo Hospital 4 Internal Medicine, Tokai University Tokyo Hospital ABSTRACT Background Cardiovascular events are important comorbidities and complications of chronic obstructive pulmonary disease (COPD). We analyzed data on the maximum intima media thickness (max-imt), the ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA), and the Ankle Brachial Pressure Index (ABI) to determine whether there are any correlations among these parameters. Methods A total of 149 subjects (84 men, 65 women) were enrolled in the study between May, 2007 and January, 2014 at the Erimo town clinic in Hokkaido after providing their informed consent. Potential subjects were divided into two groups: Group 1 (G1) had a history of COPD and moderate to severe exposure to tobacco smoke, and a Brinkman Index>400; Group 2 (G2) had a history of other diseases without COPD, such as diabetes, hypertension, and hyperlipidemia. Results G1 included 73 subjects (47 men, 26 women) and G2 included 76 subjects (37 men, 39 women). The max-imt was1.49±0.83 mm for G1 and 1.36±0.68 mm for G2, the ABI values were 0.81±0.48 and 0.91±0.21, and the EPA/AA values 0.41±0.13 and 0.47±0.16, respectively. The Max-IMT of G1 was thus significantly larger than that of G2, and the ABI of G1 was significantly lower than that of G2. There was no significant difference in EPA/AA between G1 and G2. Conclusion In COPD patients with moderate to severe exposure to smoke, a significant increase in max-imt and decrease in ABI were observed. The results of the present study suggest that COPD patients are at increased risk of smoke-related cardiovascular diseases such as acute myocardial infarction and stroke. However, the EPA/AA ratio might not be a good biomarker for assessing cardiovascular risks in COPD. (HEP. 2014; 41: ) Key words Intima Media Thickness (IMT), Eicosapentaenoic Acid (EPA), Arachidonic Acid(AA), EPA/AA, Ankle Brachial Pressure Index(ABI), Tobacco Smoke, COPD. Introduction Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity worldwide 1, 2). Although COPD has been regarded as a respiratory disease for many years, the multisystemic nature of the disease, which presents with comorbidities such as diabetes mellitus and cardiovascular diseases, is currently an area of interest. Whether these comorbidities are related to risk factors such as smoking, aging, and genetic predisposition has yet to be elucidated 3). Patients with COPD are at increased risk of cardiovascular morbidity and mortality 1). Accumulated evidence has shown a close association between COPD and cardiovascular diseases, especially coronary artery disease 3). In the literature, tobacco smoking has been identified as a causal connection between COPD and coronary artery disease. However, recent epidemiologic studies have shown that systemic inflammation plays a significant role in both atherogenesis and COPD 4). Received: May 14, 2014, Accepted: June 4, Address; Tokai University Tokyo Hospital Yoyogi, Shibuya-ku Tokyo , Japan TEL: , FAX: akinoriebihara@hotmail.com A reduced ratio of plasma eicosapentaenoic acid to arachidonic acid (EPA/AA) is a newly recognized atherosclerotic risk factor. However, this ratio has not been fully investigated in peripheral artery disease 5). A lower EPA concentration is a significant risk factor for ischemic stroke, as are a lower body mass index, lower high-density lipoprotein cholesterol, and smoking. A lower EPA/ AA ratio and a lower body mass index are also significant risk factors for myocardial infarction 6). Recently, Itakura et al. reported in the Japan EPA Lipid Intervention Study (JELIS) that the risk of major coronary events was significantly decreased in individuals with high plasma EPA concentrations compared with those with low concentrations 7). There is a trend toward utilization of the plasma EPA/AA ratio as a new risk marker for cardiovascular disease 8, 9). Carotid artery intima media thickness (IMT) is associated with cardiovascular risk factors and prevalent cardiovascular disease, and is predictive of cardiovascular events 9-11). We have previously reported that early exposure to tobacco smoke significantly increases the prevalence of COPD 12). As a follow up, we hypothesized that COPD resulting from early exposure to tobacco smoke may cause an increase in IMT that correlates with the increase in the prevalence of smoke-related vascular comorbidities such as cardiovascular and cerebrovascular diseases. Peripheral artery disease can be diagnosed and quantified by 16 (528)

2 Ebihara et al.: Indicator of arteriosclerosis in COPD means of the Ankle Brachial Pressure Index (ABI), which compares the systolic pressure at the ankle with the systolic pressure in the arm 10). In the present study, we analyzed the max-imt, EPA/AA ratio, and ABI to determine whether there were any correlations among them. 1. Materials and Methods A total of 149 subjects (84 men, 65 women) were enrolled in the study between May, 2007 and January, 2014 at the Erimo town clinic in Hokkaido. All provided their informed consent (Table 1). The patients underwent spirometry (GRAPH junior HI-101: Chest, Inc. Japan) and completed a self-report questionnaire on their clinical history and COPD risk factors including exposure to tobacco smoke and age of smoking initiation. COPD was diagnosed using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 13). Because we were unable to perform airway reversibility testing, we used the following four questions on the questionnaire in the same order as in the NICE study 14) : (1) During the past 12 months have you had more than one episode of waking at night or early in the morning as a result of spasmodic breathlessness even when you did not have a cold? (2) During the past 12 months have you had more than one episode of waking at night or early in the morning as a result of wheezing or whistling in the chest even when you did not have a cold? (3) Have you ever been told by a doctor that you had bronchial asthma? (4) Were you ever diagnosed as having asthma during your childhood? An affirmative response to any combination of these questions defined the patient as having possible asthma. The remainder of the patients with airflow limitation were considered to have COPD 14). Stage category was classified according to airflow limitation (%FEV 1 ) in accordance with the GOLD classification. Stage I included mild airflow limitation (%FEV 1 80%), Stage II moderate flow limitation (50% %FEV 1 <80%), Stage III severe flow limitation (30% %FEV 1 <50%), and Stage IV very severe flow limitation (%FEV 1 <30%) 13). We defined moderate and severe smoking as a value>400 on the Brinkman Index (B.I.). The B.I is based on the number of cigarettes smoked per day as well as the number of years of smoking. For example, a B.I of 400 indicates a person who smoked 20 cigarettes per day for 20 years. We divided the potential subjects into two groups: G1) Group 1 had a history of COPD with complications, severe and moderate exposure to tobacco smoke, and a B.I>400. G2) Group 2 had a history of diseases such as diabetes, hypertension, and hyperlipidemia without COPD, severe and moderate exposure to tobacco smoke, and a B.I>400. AA and EPA were measured from a fasting venous blood sample collected in the morning. After plasma separation, AA and EPA were determined in the SRL in Sapporo. ABI was determined as follows: ABI was defined as the highest of two measurements of ankle systolic pressure divided by brachial pressure in the arms 15). An ABI of 0.9 was considered diagnostic. Statistical analyses were performed using SPSS v19.0 (SPSS, Inc.). Analyses were performed using an unpaired t test for continuous variables and the χ 2 test for categorical variables. The standard P<0.05 significance level was used for these tests. All values in the text and tables are given as the mean±sd. 2. Results Table 1 shows the characteristics of the patients in the present Table 1 Patients Characteristics G1 (n=73) G2 (n=76) COPD with complications Disease without COPD Gender (male) Age 76±4 72±8 B.I 657±163* 472±263* DM 7* 13* HTN HL 9 6 DM+HTN 7* 12* DM+HL 5 5 HTN+HL 5 5 DM+HTN+HL (*P<0.05) Group 1 had a history of COPD with complications. Group 2 had a history of other diseases, such as diabetes, hypertension, and hyperlipidemia without COPD. Data are the number of patients or mean±sd. B.I; Brinkman Index, DM; Diabetes mellitus, HTN; Hypertension, HL; Hyperlipidemia. There were significant differences in the complication rate of diabetes and smoking status (Brinkman Index) between G1 and G2. Brinkman Index is significantly higher in G1 than in G2. Diabetes is significantly lower in G1 than in G2. (529) 17

3 Fig. 1 Rate of complications in each group Fig. 1 shows the rate of complications in each group. Hypertension is the most common complications in each group. Rate of diabetes in the G2 is higher than G1. Fig. 2 The GOLD Stage in Group 1 Fig. 2 shows the GOLD stage in Group 1. GOLD stage II is the highest among all stages. Fig. 3 Max-IMT in each group G1 had significantly higher max-imt than G2. study. G1 included 73 subjects (47 men, 26 women, mean age 76±4 years) and G2 included 76 subjects (37 men, 39 women, mean age 72±8 years). The number and percentage of complications in each group are shown in Table 1 and Fig. 1: G1 (diabetes: 7 subjects, 9.6%; hypertension: 23 subjects, 31.5%; hyperlipidemia: 9 subjects, 12.4%; other complications: 30 subjects, 41.1%); G2 (diabetes: 32 subjects, 42.1%; hypertension: 48 subjects, 63.2%; hyperlipidemia: 29 subjects, 38.2%; other complications: 33 subjects, 43.4%). The most common complication was hypertension (G1: 23 subjects, 31.5% vs. G2: 48 subjects, 63.2%). G1 had a much higher B.I than G2 (G1: 657±163, G2: 472±263) (Table 1). There were significant differences in the complication rate of diabetes and smoking status (Brinkman Index) between G1 and G2. Brinkman Index is significantly higher in G1 than in G2. Diabetes is significantly lower in G1 than in G2. Because max- IMT and ABI which are the marker of arteriosclerosis, are significantly different between the two groups, the results suggest COPD rather than diabetes would promote arteriosclerosis further. Figure 2 shows the GOLD stage in each group. G1 had 14 subjects in stage I, 35 subjects in stage II, 15 subjects in stage III, and 9 subjects in stage IV. GOLD stage II was the most common category. There was no significant difference in the EPA/AA, max-imt and ABI in the GOLD Stage I/II and the GOLD Stage III/IV. The present results suggest that smoking may promote arteriosclerosis in all stages of COPD, resulting in an increase in the cardiovascular events. The max-imt values in G1 and G2 were 1.49±0.83 mm and 1.36±0.68 mm, respectively. G1 had a significantly higher max- IMT than G2 (Fig. 3). The ABI (0.9<ABI<1.3) was 0.81±0.48 in G1 and 0.91± 0.21 in G2. The mean EPA concentration was 74.5±23.5 μg/ml in G1 and 56.3±22.4 in G2. The mean AA concentration was 132.9±24.9 μg/ml in G1 and 118.2±38.5 μg/ml in G2. The EPA/ AA ratio was 0.56±0.13 in G1 and 0.48±0.16 in G2 (Table 2). There was no significant difference in EPA/AA between G1 and G2. However, G1 had lower ABI ratio values than G2 (Fig. 4). There was a significant correlation between max-imt and ABI. However, there was no correlation between max-imt and EPA/AA, and ABI and EPA/AA (Fig. 5). Table 2 EPA/AA ratio, ABI, Max-IMT, EPA, and AA in each group G1 EPA/AA 0.56± ±0.16 Max-IMT(mm) 1.49±0.83* 1.36±0.68* EPA (μg/ml) 74.5± ±22.4 AA (μg/ml) 132.9± ±38.5 (*P<0.05) EPA (Eicosapentaenoic Acid):11.6~107.2, ABI (ankle brachial index): 0.9<ABI<1.3, EPA/ AA ratio: 0.11~0.50, AA (Arachidonic Acid): 85.1~207.8 G2 18 (530)

4 Ebihara et al.: Indicator of arteriosclerosis in COPD Fig. 4 EPA/AA and ABI in each group There was no significant difference in EPA/AA between G1 and G2. G1 had lower ABI values than G2. Fig. 5 There was a significant correlation between max-imt and ABI 3. Discussion The World Health Organization (WHO) has predicted that COPD will become the fifth largest disease burden and the third greatest cause of death by ). Because COPD is not usually detected until patients seek medical attention for dyspnea or exacerbation 17), COPD is under-diagnosed and available prevalence and mortality data are thus likely to be greatly underestimated by healthcare providers. There is, therefore, a need to improve our diagnostic and therapeutic options for such a devastating disease. In a multiple logistic regression analysis in a previous study, a lower EPA concentration was identified as a significant risk factor for myocardial infarction, as were a lower body mass index, lower high-density lipoprotein cholesterol, and smoking. In the analysis of subtypes, a lower EPA/AA ratio and a lower body mass index were identified as significant risk factors for myocardial infarction 18). However, large-artery atherosclerosis was not related to the EPA concentration or the EPA/AA ratio. The risk of coronary artery disease thus appears to be influenced by variations in plasma fatty acid composition. Traditional cardiovascular risk factors are common in COPD. It has been reported that there is an increased prevalence of diabetes and hypertension in patients with COPD compared with healthy individuals, and this increased prevalence was even more evident in GOLD stages III and IV in the Atherosclerosis Risk in Communities Study population 19). The vascular risk in COPD is less likely to be attributed to an atherogenic lipid pattern 20). In the present study, there was thickening of the IMT and a decrease in ABI that was significant in patients that had both COPD and complications such as diabetes or hypertension. However, there was no significant difference in the EPA/AA ratio. One reason for this could be that the mechanisms mediating arteriosclerosis are different between COPD and dyslipidemia. In particular, chronic inflammation associated with COPD could produce thickening of the vascular endothelium by calcification and fibrosis, which may result in a significant change in ABI and IMT. However, in this instance, and unlike the case with an abnormal metabolism such as diabetes, the EPA/AA ratio might not be affected by the chronic inflammation induced by COPD. These findings suggest that the EPA/AA ratio might not be a good biomarker in COPD. There are several limitations to the present study. First, we studied a relatively small number of patients with COPD. Second, all of the patients in the COPD group were receiving regular treatment with inhaled bronchodilators and/or steroids, and some subjects in both groups were on antihyperlipidemic agents, which may have been a factor that mitigated the impact of EPA/AA and ABI atherosclerosis. We did not investigate whether these agents had any effect on the study variables. Acknowledgements The authors wish to thank staff of Erimo town clinic and Health Division of Erimo Town. This study was funded by grant from the Japan Society of Health Evaluation and Promotion, and Grants-in-Aid for Scientific Research (No ). The authors state that they have no Conflict of Interest (COI). REFERENCES 1) John D, William M: Cardiovascular disease in COPD. Chest: 143: , ) Johonston A, Mannino D, Hagan G, et al.: Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-age cohort. Thorax: 63: , ) Dyerberg J, Bang H, Stoffersen E, et al.: Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet: 2: , ) Mannino D, Doherty D, Sonia Buist A: Global Initiative on obstructive lung disease (GOLD) classification of lung disease and mortality: finding from the atherisclerosis. Risk in communities (ARIC) study. Respir Med: 100: , ) Ikeya Y, Fukuyama N, Kitajima W, et al.: Comparison of eicosapentaenoic acid concentrations in plasma between patients with ischemic stroke and control subjects. Nutrition: 29: , ) Bang H, Dyerberg J, Sinclair H. et al.: The composition of the Eskimo food in north western Greenland. Am J Clin Nutr: 33: , ) Itakura, M. Yokoyama, M. Matsuzaki, et al.: Relationships (531) 19

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