ORIGINAL ARTICLE
METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2015 Mary Ann Liebert, Inc. Pp. 1–8 DOI: 10.1089/met.2014.0117
The Complex Association of Metabolic Syndrome and Its Components with Computed Tomography–Determined Emphysema Index Hye Yun Park, MD, PhD,1,* Byung Woo Jhun, MD,1,* Ho Jung Jeong, MD,1 Hae Ri Chon, MD,1 Won-Jung Koh, MD, PhD,1 Gee Young Suh, MD, PhD,1 Hojoong Kim, MD, PhD,1 Myung Jin Chung, MD, PhD,2 Hee Jung Jun, MD,3 Yoon-Ho Choi, MD, PhD,3 and Seong Yong Lim, MD, PhD 4
Abstract
Background: Recent reports have suggested the association between emphysema and cardiovascular disease (CVD); however, there are few reports regarding association of emphysema severity with metabolic syndrome and its components representing CVD risk factors. Methods: A retrospective cross-sectional study was performed in 2814 adult male subjects over age 40 who visited the Health Promotion Center in Samsung Medical Center for a health checkup program. Results: We classified patients according to the quintiles of forced expiratory volume in 1 sec (FEV1) and emphysema index (EI). FEV1 percentage predicted values (% pred) was inversely associated with prevalence of metabolic syndrome and most of its components, such as abdominal obesity, hypertension, fasting hyperglycemia, and low high-density lipoprotein cholesterol. Although there was no association between prevalence of metabolic syndrome and EI, hypertension was positively associated with EI (P < 0.001) and high triglycerides (TGs) were inversely associated with EI (P = 0.021). These associations persisted after adjustment of other variables (P < 0.001 in hypertension and P = 0.039 in high TGs). Conclusion: The computed tomography–determined EI has a complex association with components of metabolic syndrome that is associated with increased prevalence of hypertension but decreased prevalence of high TGs, whereas FEV1 (% pred) has an inverse association with metabolic syndrome and most of its components with consistent direction. uation below the set threshold.6 A large population-based study reported that quantitative CT emphysema is linearly associated with the impaired left ventricular filling and a reduction in cardiac output,7 Moreover, CT emphysema is an independent predictor of endothelial dysfunction and atherosclerotic disease as evidenced by its association with arterial stiffness and thoracic aortic calcification.8–10 A recent report also showed that consistent and positive association with heart failure was seen for self-reported diagnosis of emphysema in the long-term Atherosclerosis Risk in Communities cohort study.11 On the basis of these results, the effects of emphysema on cardiovascular structure and function can also be considered as important a factor as those of traditional risk factors such as smoking and diabetes.12
Introduction
C
ardiovascular disease (CVD) is the leading cause of morbidity and mortality in mild-to-moderate chronic obstructive pulmonary disease (COPD), accounting for nearly half of all hospital admission and a quarter of all deaths.1 In addition, airflow limitation doubles the risk of cardiovascular mortality independent of smoking.2–4 Emphysema, one of the components of COPD, is characterized by an abnormal permanent enlargement of the airspace distal to the terminal bronchioles and destruction of alveolar walls without obvious fibrosis.5 Emphysema severity has been quantified in vivo by computed tomography (CT) as the ‘‘low attenuation area’’ in the lung with atten-
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, 2Department of Radiology, and 3Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 4 Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. *These authors contributed equally to this work.
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Metabolic syndrome refers to a cluster of abdominal obesity, dyslipidemia, hypertension, insulin resistance, and prothrombotic states that predisposes to CVD.13 Recent several population-based studies suggest that impaired lung function, as measured by forced vital capacity (FVC) or forced expiratory volume in 1 sec (FEV1), are associated with the components of metabolic syndrome,14–17 which is explained by persistent low-grade systemic inflammation.15,18 Despite this significant association, to our knowledge, studies on the association between emphysema and metabolic syndrome, an aggregation of CVD risk factors, are sparse. Therefore, in the present study, we aimed to determine the association of metabolic syndrome and its components with emphysema severity and airflow limitation.
Methods Study participants This study was approved by the Institutional Review Board of Samsung Medical Center, and the patient consent requirement was waived given the retrospective nature of the study. Data from patients who participated in the health checkup program at the Health Promotion Center of Samsung Medical Center (a 1961-bed, university-affiliated, tertiary referral hospital in Seoul, South Korea) between January, 2009, and June, 2009, were included. Final analysis was performed on 2814 male subjects over age 40, in whom data for pulmonary function test, low-dose chest CT, and metabolic syndrome parameters were available. Current or past smokers were classified as smokers.
Assessment of emphysema CT scans were obtained using a 64-channel multidetector CT (MDCT) scanner (LightSpeed VCT, GE Medical Systems, Milwaukee, WI). CT examinations were acquired with 40-mm collimation. The exposure setting was 120 kVp, 60 mA, 0.6 sec rotation time, and 1:1.375 table pitch. Axial images were reconstructed with 1.25-mm slice thickness without an interslice gap from lung base to lung apices. A threshold value of - 950 Hounsfield Units (HU) was used to detect emphysema, as proposed for MDCT scan examinations. Total lung volume, emphysema volume, and their ratio [% of low-attenuation area] were calculated automatically from the CT data using commercially available software (Extended Brilliance Workspace v3.0, Philips Medical Systems, Cleveland, OH), and the ratio was termed the emphysema index (EI).
Measurement of lung function Spirometry was performed as recommended by the American Thoracic Society19 using a Vmax 22 system (SensorMedics, OH). The highest FVC and forced expiratory volume in 1 sec (FEV1) value of the three or more tests with acceptable curves was used. Absolute values of FVC and FEV1 were obtained and percentage predicted values (% pred) for FEV1 and FVC were calculated from the following equations obtained in a representative Korean sample.20 Predicted FVC ¼ 4:8434 [0:00008633 · age2 (years)] þ [0:05292 · height (cm)] þ (0:01095 · weight (kg))
Predicted FEV1 ¼ 3:4132 [0:0002484 · age2 (years)] þ [0:04578 · height (cm)]
Anthropometric measurements and blood tests Height, weight, waist circumference (WC), systolic (SBP), and diastolic blood pressure (DBP) were measured. Blood pressure was measured according to the Hypertension Detection and Follow-Up Program protocol by using a mercury blood pressure device after the subjects had rested for more than 5 min.21 For subjects with a SBP higher than 140 mmHg and a DBP higher than 90 mmHg, blood pressure was measured two more times after resting and the average value was used. Height and weight were measured by automatic scale, and body mass index (BMI) was calculated by weight (kg) divided by the squared value of height (meters) (kg/m2). WC was measured at the part of the trunk located midway between the lower costal margin (bottom of lower rib) and the iliac crest (top of pelvic bone) while the patient was standing. After a 12-hr fast, fasting blood glucose (FBG) with the hexokinase method, C-reactive protein (CRP) with turbid immunoassay, total cholesterol (TC), triglycerides (TGs) with the enzymatic colorimetric method, high-density lipoprotein cholesterol (HDL-C) with the modified enzymatic method, and low-density lipoprotein-cholesterol (LDL-C) with the direct surfactant method were automatically measured using an autoanalyzer (Hitachi, Modular D 2400; Tokyo, Japan).
Diagnosis of metabolic syndrome Metabolic syndrome was defined based on the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or International Diabetes Federation (IDF) guidelines. WC was defined by the World Health Organization (WHO) Western Pacific Region criteria for obesity criteria.22 The diagnosis of metabolic syndrome according to AHA/NHLBI was made when the subjects satisfied more than three of the five components described below.13 1. 2. 3. 4. 5.
Abdominal obesity: WC ‡ 90 cm; High TGs: ‡ 150 mg/dL (1.7 mmol/L); Low HDL-C: < 40 mg/dL (1.0 mmol/L); Hypertension: ‡ 130/85 mmHg; and Fasting hyperglycemia: ‡ 100 mg/dL (5.6 mmol/L).
According to the IDF definition, metabolic syndrome is diagnosed when the subjects have abdominal obesity plus any two of the factors described above: High TGs, low HDL-C, hypertension, and fasting hyperglycemia.23 Because obesity is defined as a BMI ‡ 25 kg/m2 in Asian populations, BMI in our study was categorized using a 25kg/m2 cutoff point for obesity.
Statistical analysis Data are presented as mean – standard deviation (SD) or median (interquartile range) for continuous variables and as numbers (percentages) for categorical variables. Tests of trend across categories of emphysema and airflow obstruction were performed with analysis of variance (ANOVA) and Cochran– Armitage tests, as appropriate. For continuous measurements (EI, TGs, and LDL-C), we used a linear regression to assess the association of EI with TGs and LDL-C. Statistical adjustments were age, smoking status, BMI, and FEV1/FVC. Two-sided
METABOLIC SYNDROME AND EMPHYSEMA
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P values less than 0.05 were considered statistically significant. All statistical tests were performed with Predictive Analytics Software 21.0 (by SPSS, Inc., Chicago, IL).
Results Clinical characteristics of the study population The clinical characteristics of the participants are shown in Table 1. Among 2814 study participants, the mean age was 55 years, and 83.5% were current or ex-smokers. The prevalence of metabolic syndrome was 30.5% by AHA/NHLBI criteria and 21.6% by IDF criteria. The median value for CRP and mean values for FBG and TC were 0.6 mg/L, 100 mg/dL, and 195 mg/dL, respectively. The mean – SD quantitative CT EI was 14 – 6%.
Prevalence of metabolic syndrome or its components by quintiles of FEV1 (% pred) We classified patients according to the quintiles of FEV1 (% pred), and the subjects in the lowest FEV1 (1st quintile)
Table 1.
Demographic and Clinical Characteristics of the Study Population (N = 2814)
Variables Clinical risk factors Age, years Smoking status None, % Past, % Current,% BMI ‡ 25 (kg/m2), % Laboratory test WBC ( · 103/mL) CRP (mg/L) FBG (mg/dL) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL) Metabolic syndrome (AHA/NHLBI), % Metabolic syndrome (IDF), % Waist circumference ‡ 90cm Low HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150 mg/dL or specific treatment, % SBP ‡ 130/DBP ‡ 85 mmHg or antihypertensive treatment, % Fasting glucose ‡ 100 mg/dL or diabetes treatment, % Pulmonary function test FEV1/FVC ratio, % FVC, % pred FEV1, % pred Emphysema index (%)
55 – 8 16.5 42.8 40.7 44.3 6.0 – 1.6 0.6 (0.4–1.3) 100 – 20 195 – 34 121 – 30 49 – 12 149 – 84 30.5 21.6 35.3 23.4
were slightly older and more likely to be smokers. Inflammatory markers such as white blood cell (WBC) and CRP, homeostasis model assessment of insulin resistance (HOMA-IR), and the prevalence of metabolic syndrome were significantly elevated in the lowest FEV1 group (Table 2). Among the individual metabolic syndrome components, the prevalence of abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C ( < 40 mg/dL) was inversely associated with FEV1 (% pred), whereas high TGs ( ‡ 150 mg/dL) had no significant association with FEV1 (% pred). However, EI was not significantly different between the FEV1 groups. The inverse association between FEV1 (% pred) and the prevalence of metabolic syndrome (P < 0.001), abdominal obesity (P < 0.001), fasting hyperglycemia (P < 0.001), and low HDL-C (P = 0.002) was persistent, even after adjusting for confounding factors, including age, smoking status, BMI, and CRP.
Prevalence of metabolic syndrome or its components by quintiles of quantitative CT EI When we analyzed the severity of emphysema according to the quintiles of CT EI, as shown in Table 3, subjects in the highest EI (5th quartile) were slightly older and more likely to have higher FVC (% pred) and lower FEV1/FVC (%) values. Although there was no association between prevalence of metabolic syndrome and EI, among the individual metabolic syndrome components, the prevalence of hypertension was positively associated with EI (P < 0.001) and the prevalence of high TG ( ‡ 150 mg/dL) was inversely associated with EI (P = 0.021) (Fig. 1). The prevalence of high LDL-C ( ‡ 160 mg/dL) also had an inverse association with EI (P = 0.020). These associations persisted after adjustment of age, smoking status, BMI, and FEV1/FVC (%) (P < 0.001 in hypertension, P = 0.039 in high TGs, and P = 0.046 in high LDL-C).
Association of EI as a continuous variable with a lipid profile As a continuous variable of EI, EI had a significant inverse association of TG (P = 0.001), LDL-C (P = 0.023), and TC (P = 0.002) (Fig. 2). After adjustment of age, smoking status, BMI, and FEV1/FVC, the inverse association of TG (P = 0.004) and TC (P = 0.010) with EI persisted.
40.0
Discussion 45.7 37.6 77.6 – 6.7 86.2 – 11.3 86.7 – 12.5 14 – 6
Values are expressed as percentages, mean – standard deviation or median (interquartile range). BMI, body mass index; WBC, white blood cell; CRP, C-reactive protein; FBG, fasting blood glucose; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; SBP, systolic blood pressure; DBP, diastolic blood pressure; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.
To our knowledge, this is the first large cross-sectional study to evaluate the association between emphysema severity and the presence of metabolic syndrome or its components. In our study, CT-determined EI was not significantly associated with the presence of metabolic syndrome itself, but was positively associated with the prevalence of hypertension and inversely associated with high TGs. Additionally, CT-determined EI had an inverse association with other lipids such as LDL-C and TC. In terms of lung function, low FEV1 (% pred) showed a definite association with metabolic syndrome and most of its components, such as abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C, with a consistent same direction. These results suggest that the effect of emphysema on the cardiovascular system might be less definite than one from airway obstruction because of the complex association of emphysema with cardiovascular risk factors.
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33.0 23.6 37.0 45.7 38.5 23.4 41.2 42.5 11.6
36.7 27.4 43.1 50.1 44.9 28.0 40.0 40.6 11.4
47.7 12.9
43.4
35.4 47.4 39.9 24.4
32.5 23.5
6.0 – 1.6 0.6 (0.3–1.3) 2.3 – 1.3 (n = 455) 14 – 6
54 – 8 83.8 25 – 3 43.8
3rd (85–90%) n = 587
FEV1 % predicted Quintiles
41.4 10.7
37.4
31.5 42.0 32.0 21.4
25.0 17.1
5.8 – 1.6 0.6 (0.3–1.0) 2.1 – 1.4 (n = 420) 13 – 6
53 – 7 82.3 25 – 2 43.1
4th (91–97%) n = 543
42.5 11.7
37.5
28.3 42.5 31.7 19.1
24.0 15.7
5.7 – 1.6 0.5 (0.3–0.9) 2.0 – 1.0 (n = 423) 15 – 6
54 – 8 78.7 25 – 2 43.4
5th ( ‡ 98%) n = 530
0.644 0.934
0.206
< 0.001* 0.004 < 0.001* < 0.001*
< 0.001* < 0.001*
< 0.001 < 0.001 < 0.001 0.157
< 0.001 < 0.001 0.074 0.273
P value for trend
Values are expressed as percentages, mean – standard deviation or median (interquartile range). *P value < 0.05 after adjustment of age, smoking status, BMI, and CRP in metabolic syndrome, components of metabolic syndrome. and other dyslipidemia. HOMA-IR, homeostasis model assessment-insulin resistance; CRP, C-reactive protein; FEV1, forced expiratory volume in 1 sec; BMI, body mass index; WBC, white blood cell; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol.
6.1 – 1.7 0.7 (0.4–1.5) 2.2 – 1.1 (n = 422) 13 – 6
6.1 – 1.6 0.8 (0.4–1.5) 2.2 – 1.2 (n = 435) 14 – 7
(78–-84%) n = 551 54 – 7 84.9 25 – 2 44.8
2
nd
58 – 8 87.2 25 – 3 46.1
1 ( £ 77%) n = 603
st
HOMA-IR, CRP Values, and Prevalence of the Metabolic Syndrome According to the Quintiles of FEV1 % Predicted (N = 2814)
Age, year Smoker, % BMI, kg/m2 BMI ‡ 25 kg/m2, % Laboratory test WBC ( · 103/mL) CRP (mg/L) HOMA-IR (n = 2155) Emphysema index Metabolic syndrome AHA/NHLBI IDF Components of metabolic syndrome Waist circumference ‡ 90 cm, % Elevated blood pressure, % Impaired glucose metabolism, % HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150 mg/dL or specific treatment, % Other dyslipidemia Total cholesterol ‡ 200 mg/dL LDL-C ‡ 160 mg/dL
Table 2.
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86 – 11 87 – 12 78 – 6 30.8 20.7 33.9 38.8 35.2 19.8 42.1 48.5 13.2
85 – 11 86 – 12 79 – 6 32.1 24.8 36.1 39.5 39.0 24.8 44.5 43.4 14.0
40.6 11.3
36.4
33.3 43.6 37.8 25.1
26.8 18.3
87 – 11 87 – 12 78 – 6
6.1 – 1.7 0.7 (0.4–1.3) 2.1 – 1.1 (n = 423)
53 – 8 85.2 25 – 2 40.8
3rd (12–15%) n = 574
Emphysema Index Quintiles
42.2 9.9
39.3
32.6 49.6 35.3 23.9
29.1 19.7
86 – 11 86 – 12 78 – 6
5.8 – 1.5 0.7 (0.4–1.3) 2.2 – 1.5 (n = 520)
55 – 8 83.4 25 – 2 45.4
4th (16–19%) n = 669
41.4 10.7
38.2
40.9 54.8 40.9 22.5
33.8 25.0
88 – 12 87 – 14 75 – 8
5.7 – 1.4 0.6 (0.3–1.2) 2.1 – 1.0 (n = 439)
56 – 9 83.0 25 – 3 46.1
5th ( ‡ 20%) n = 560
0.152 0.020*
0.021*
0.239 < 0.001* 0.642 0.857
0.823 0.850
< 0.001 0.383 < 0.001
< 0.001 0.516 0.576
< 0.001 0.984 0.358 0.847
P value for trend
Values are expressed as percentages, mean – standard deviation or median (interquartile range). *P value < 0.05 after adjustment of age, smoking status, BMI, and FEV1/FVC (%) in metabolic syndrome, components of metabolic syndrome, and other dyslipidemia. HOMA-IR, homeostasis model assessment-insulin resistance; CRP, C-reactive protein; BMI, body mass index; WBC, white blood cell; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 sec; % pred, percentage predicted value; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol.
6.1 – 1.8 0.6 (0.3–1.3) 2.1 – 1.1 (n = 345)
6.3 – 1.8 0.6 (0.4–1.3) 2.2 – 1.1 (n = 428)
(8–11%) n = 454 54 – 8 81.9 25 – 3 40.7
2
nd
54 – 7 83.7 25 – 2 47.6
1 ( < 8%) n = 557
st
HOMA-IR, CRP Values, and Prevalence of the Metabolic Syndrome According to the Quintiles of Emphysema Index (N = 2814)
Age, year Smoker,% BMI, kg/m2 BMI ‡ 25 kg/m2, % Laboratory test WBC ( · 103/mL) CRP (mg/L) HOMA-IR (n = 2155) Lung function test FVC % pred FEV1 % pred FEV1/FVC (%) Metabolic syndrome AHA/NHLBI IDF Components of metabolic syndrome Waist circumference ‡ 90 cm,% Elevated blood pressure, % Impaired glucose metabolism, % HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150mg/dL or specific treatment, % Other dyslipidemia Total cholesterol ‡ 200 mg/dL LDL-C ‡ 160 mg/dL
Table 3.
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PARK ET AL.
FIG. 1. Association of hypertension and hypertriglyceridemia with emphysema index (*) adjusted with age, smoking status, body mass index, and forced expiratory volume in 1 sec/forced vital capacity (%).
FIG. 2. Inverse association between lipid profiles and emphysema index (*) adjusted with age, smoking status, body mass index, and forced expiratory volume in one second/forced vital capacity (%). LDL-cholesterol, low-density lipoprotein cholesterol.
METABOLIC SYNDROME AND EMPHYSEMA
We observed that the presence of hypertension was the main factor linked with high EI. Mounting evidence has identified links between COPD and high blood pressure. In the pooled analysis of two large population-based cohorts data from 20,296 subjects by Mannino et al., the prevalence of hypertension was 34% in normal subjects and increased to 51% in severe COPD patients.23 However, there has been no population-based study investigating the association between emphysema severity and hypertension. Consistent with study results by Mannino et al., in the present study, prevalence of hypertension was 39.5% in lowest emphysema ( < 8%) group, increasing to 54.8% in the highest emphysema ( > 20%) group. The mechanism to explain this association may be the vascular insults that affect both the coronary and pulmonary vasculature. It has been shown that there are apoptotic endothelial cells in the lungs of patients with COPD24 and that emphysema of the lung and vascular calcification leading to arteriosclerosis occur simultaneously in a transgenic mouse model.25 Clinically, McAllister et al. showed that pulse wave velocity–measured arterial stiffness is linearly associated with CT-assessed emphysema severity and mean arterial pressure after multiple linear regression modeling in COPD patients.8 In addition, Barr et al. demonstrated that the percentage of patients with CT emphysema had a strong and linear association with endothelial dysfunction as measured by flow-measured dilation of the bronchial artery across the spectrum of disease from normal lung function to moderately severe COPD.26 Another finding in the present study was the independent association between emphysema severity and dyslipidemia, including TC and TGs. A higher serum TG or TC level was associated with attenuated severity of emphysema. As there is little factual data to explain the link between emphysema and dyslipidemia in the general population and COPD, it is not possible to draw a definitive conclusion on the basis of this study alone. Nevertheless, there have been several studies supporting our finding. Interestingly, Mineo et al. observed that serum TC, HDL-C, and TGs levels were significantly increased together with respiratory function after lung volume reduction surgery in patients with moderate to severe emphysema,27 indicating that less emphysema is associated with a higher serum lipid level. These findings suggest that emphysema severity itself might be associated with lipid profile regulation. Several studies have described that pulmonary emphysema in severe stages of COPD causes respiratory cachexia with persistent inflammation, which leads to increased resting energy expenditure, protein wasting, and preferential lipid substrate utilization with an altered lipid profile (i.e., low cholesterol and TGs levels).28–31 Especially, it is well recognized that lean mass depletion and low BMI were observed more in emphysema patients compared with chronic bronchitis patients in severe COPD.30 However, we did not find an association between EI and BMI. The most plausible explanation for this insignificant result is that because this study was conducted with subjects visiting the Health Promotion Center for the health checkup program, the severity of the emphysema might be low to reflect a change of BMI. As such, we speculate that an altered lipid profile might occur ahead of a BMI change as emphysema progresses in the lung. In contrast to emphysema severity, the prevalence of metabolic syndrome increased significantly according to the decrement of quintile of FEV1 (% pred) irrespective of
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criteria of metabolic syndrome. Inflammatory markers, including WBC and CRP and the prevalence of components of metabolic syndrome, such as abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C ( < 40 mg/dL), were also significantly higher in the lower FEV1 (% pred), which is consistent with previous studies.14,15 These inverse associations of lung function with metabolic syndrome, with metabolic syndrome components, and with inflammatory markers lead to increased cardiovascular morbidity or mortality. The positive association of emphysema severity with hypertension and negative association of emphysema severity with dyslipidemia cancel each other out, thus leading to showing that there is no visible association of emphysema severity with metabolic syndrome. Further research is needed to determine how this phenomenon could affect cardiovascular events in patients with an emphysemadominant phenotype. This study had several limitations. It was a retrospective study performed on individuals who voluntarily visited our center for health examinations, particularly for lung examination. Therefore, a large portion (83%) of the subjects were smokers (current or past), which resulted in no difference in smoker proportion according to quintile of EI. Second, this study was conducted with only males. Because emphysema severity differs according to gender32 and the number of females presenting for health examinations was relatively low, we analyzed only the data of males to reduce selection bias. Third, we calculated the EI using volumetric CT and set - 950 HU as the threshold for detecting emphysema, because previous CT pathological correlations with macroscopic/ microscopic measurements are well established using this criterion.33 However, we could not obtain an EI according to segment area, such as upper lobe and lower lobe areas. Finally, the present study was conducted at a single center, which might influence generalization of the findings. In conclusion, we have shown for the first time that a CTdetermined EI has a complex association with components of metabolic syndrome, whereas FEV1 (% pred) has an inverse association with metabolic syndrome and most of its components with consistent direction.
Acknowledgment This study was supported by Samsung Medical Center Foundation for Medical Research (SMO1140211).
Author Disclosure Statement No competing financial interests exist.
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4. Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: A populationbased study and a systematic review of the literature. Chest 2005;127:1952–1959. 5. The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop. Am Rev Respir Dis 1985;132:182–185. 6. Gevenois PA, de Maertelaer V, De Vuyst P, et al. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1995;152:653–657. 7. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med 2010;362:217–227. 8. McAllister DA, Maclay JD, Mills NL, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:1208– 1214. 9. Dransfield MT, Huang F, Nath H, et al. CT emphysema predicts thoracic aortic calcification in smokers with and without COPD. COPD 2010;7:404–410. 10. Barr RG, Ahmed FS, Carr JJ, et al. Subclinical atherosclerosis, airflow obstruction and emphysema: The MESA Lung Study. Eur Respir J 2012;39:846–854. 11. Agarwal SK, Heiss G, Barr RG, et al. Airflow obstruction, lung function, and risk of incident heart failure: The Atherosclerosis Risk in Communities (ARIC) study. Eur J Heart Fail 2012;14:414–422. 12. Heckbert SR, Post W, Pearson GD, et al. Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: The Multiethnic Study of Atherosclerosis. J Am Coll Cardiol 2006;48:2285–2292. 13. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752. 14. Leone N, Courbon D, Thomas F, et al. Lung function impairment and metabolic syndrome: The critical role of abdominal obesity. Am J Respir Crit Care Med 2009;179: 509–516. 15. Park HY, Lim SY, Hwang JH, et al. Lung function, coronary artery calcification, and metabolic syndrome in 4905 Korean males. Respir Med 2010;104:1326–1335. 16. Lin WY, Yao CA, Wang HC, et al. Impaired lung function is associated with obesity and metabolic syndrome in adults. Obesity (Silver Spring) 2006;14:1654–1661. 17. Nakajima K, Kubouchi Y, Muneyuki T, et al. A possible association between suspected restrictive pattern as assessed by ordinary pulmonary function test and the metabolic syndrome. Chest 2008;134:712–718. 18. Lee HM, Le TV, Lopez VA, et al. Association of C-reactive protein with reduced forced vital capacity in a nonsmoking U.S. population with metabolic syndrome and diabetes. Diabetes Care 2008;31:2000–2002. 19. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26: 948–968.
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20. Choi JK, Paek D, Lee JO. Normal predictive values of spirometry in Korean population. Tuberc Respir Dis 2005;58:230–242. 21. The hypertension detection and follow-up program: Hypertension detection and follow-up program cooperative group. Prev Med 1976;5:207–215. 22. International Diabetes Institute, World Health Organization. Regional Office for the Western Pacific, International Association for the Study of Obesity, et al. The Asia-Pacific Perspective: Redefining Obesity and Its Treatment. Australia: Health Communications Australia, 2000. 23. Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–969. 24. Demedts IK, Demoor T, Bracke KR, et al. Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 2006;7:53. 25. Kuroo M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45–51. 26. Barr RG, Mesia-Vela S, Austin JH, et al. Impaired flowmediated dilation is associated with low pulmonary function and emphysema in ex-smokers: The Emphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med 2007;176:1200–1207. 27. Mineo D, Ambrogi V, Frasca L, et al. Effects of lung volume reduction surgery for emphysema on glycolipidic hormones. Chest 2008;134:30–37. 28. Jakobsson P, Jorfeldt L, von Schenck H. Fat metabolism and its response to infusion of insulin and glucose in patients with advanced chronic obstructive pulmonary disease. Clin Physiol 1995;15:319–329. 29. Congleton J. The pulmonary cachexia syndrome: Aspects of energy balance. Proc Nutr Soc 1999;58:321–328. 30. Engelen MP, Schols AM, Lamers RJ, et al. Different patterns of chronic tissue wasting among patients with chronic obstructive pulmonary disease. Clin Nutr 1999;18:275–280. 31. Vestbo J, Prescott E, Almdal T, et al. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am J Respir Crit Care Med 2006;173:79–83. 32. Dransfield MT, Washko GR, Foreman MG, et al. Gender differences in the severity of CT emphysema in COPD. Chest 2007;132:464–470. 33. Gevenois PA, De Vuyst P, de Maertelaer V, et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1996;154:187–192.
Address correspondence to: Dr. Seong Yong Lim Department of Medicine Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine Seoul 110-746 Korea E-mail: [email protected]
METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2015 Mary Ann Liebert, Inc. Pp. 1–8 DOI: 10.1089/met.2014.0117
The Complex Association of Metabolic Syndrome and Its Components with Computed Tomography–Determined Emphysema Index Hye Yun Park, MD, PhD,1,* Byung Woo Jhun, MD,1,* Ho Jung Jeong, MD,1 Hae Ri Chon, MD,1 Won-Jung Koh, MD, PhD,1 Gee Young Suh, MD, PhD,1 Hojoong Kim, MD, PhD,1 Myung Jin Chung, MD, PhD,2 Hee Jung Jun, MD,3 Yoon-Ho Choi, MD, PhD,3 and Seong Yong Lim, MD, PhD 4
Abstract
Background: Recent reports have suggested the association between emphysema and cardiovascular disease (CVD); however, there are few reports regarding association of emphysema severity with metabolic syndrome and its components representing CVD risk factors. Methods: A retrospective cross-sectional study was performed in 2814 adult male subjects over age 40 who visited the Health Promotion Center in Samsung Medical Center for a health checkup program. Results: We classified patients according to the quintiles of forced expiratory volume in 1 sec (FEV1) and emphysema index (EI). FEV1 percentage predicted values (% pred) was inversely associated with prevalence of metabolic syndrome and most of its components, such as abdominal obesity, hypertension, fasting hyperglycemia, and low high-density lipoprotein cholesterol. Although there was no association between prevalence of metabolic syndrome and EI, hypertension was positively associated with EI (P < 0.001) and high triglycerides (TGs) were inversely associated with EI (P = 0.021). These associations persisted after adjustment of other variables (P < 0.001 in hypertension and P = 0.039 in high TGs). Conclusion: The computed tomography–determined EI has a complex association with components of metabolic syndrome that is associated with increased prevalence of hypertension but decreased prevalence of high TGs, whereas FEV1 (% pred) has an inverse association with metabolic syndrome and most of its components with consistent direction. uation below the set threshold.6 A large population-based study reported that quantitative CT emphysema is linearly associated with the impaired left ventricular filling and a reduction in cardiac output,7 Moreover, CT emphysema is an independent predictor of endothelial dysfunction and atherosclerotic disease as evidenced by its association with arterial stiffness and thoracic aortic calcification.8–10 A recent report also showed that consistent and positive association with heart failure was seen for self-reported diagnosis of emphysema in the long-term Atherosclerosis Risk in Communities cohort study.11 On the basis of these results, the effects of emphysema on cardiovascular structure and function can also be considered as important a factor as those of traditional risk factors such as smoking and diabetes.12
Introduction
C
ardiovascular disease (CVD) is the leading cause of morbidity and mortality in mild-to-moderate chronic obstructive pulmonary disease (COPD), accounting for nearly half of all hospital admission and a quarter of all deaths.1 In addition, airflow limitation doubles the risk of cardiovascular mortality independent of smoking.2–4 Emphysema, one of the components of COPD, is characterized by an abnormal permanent enlargement of the airspace distal to the terminal bronchioles and destruction of alveolar walls without obvious fibrosis.5 Emphysema severity has been quantified in vivo by computed tomography (CT) as the ‘‘low attenuation area’’ in the lung with atten-
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, 2Department of Radiology, and 3Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 4 Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. *These authors contributed equally to this work.
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Metabolic syndrome refers to a cluster of abdominal obesity, dyslipidemia, hypertension, insulin resistance, and prothrombotic states that predisposes to CVD.13 Recent several population-based studies suggest that impaired lung function, as measured by forced vital capacity (FVC) or forced expiratory volume in 1 sec (FEV1), are associated with the components of metabolic syndrome,14–17 which is explained by persistent low-grade systemic inflammation.15,18 Despite this significant association, to our knowledge, studies on the association between emphysema and metabolic syndrome, an aggregation of CVD risk factors, are sparse. Therefore, in the present study, we aimed to determine the association of metabolic syndrome and its components with emphysema severity and airflow limitation.
Methods Study participants This study was approved by the Institutional Review Board of Samsung Medical Center, and the patient consent requirement was waived given the retrospective nature of the study. Data from patients who participated in the health checkup program at the Health Promotion Center of Samsung Medical Center (a 1961-bed, university-affiliated, tertiary referral hospital in Seoul, South Korea) between January, 2009, and June, 2009, were included. Final analysis was performed on 2814 male subjects over age 40, in whom data for pulmonary function test, low-dose chest CT, and metabolic syndrome parameters were available. Current or past smokers were classified as smokers.
Assessment of emphysema CT scans were obtained using a 64-channel multidetector CT (MDCT) scanner (LightSpeed VCT, GE Medical Systems, Milwaukee, WI). CT examinations were acquired with 40-mm collimation. The exposure setting was 120 kVp, 60 mA, 0.6 sec rotation time, and 1:1.375 table pitch. Axial images were reconstructed with 1.25-mm slice thickness without an interslice gap from lung base to lung apices. A threshold value of - 950 Hounsfield Units (HU) was used to detect emphysema, as proposed for MDCT scan examinations. Total lung volume, emphysema volume, and their ratio [% of low-attenuation area] were calculated automatically from the CT data using commercially available software (Extended Brilliance Workspace v3.0, Philips Medical Systems, Cleveland, OH), and the ratio was termed the emphysema index (EI).
Measurement of lung function Spirometry was performed as recommended by the American Thoracic Society19 using a Vmax 22 system (SensorMedics, OH). The highest FVC and forced expiratory volume in 1 sec (FEV1) value of the three or more tests with acceptable curves was used. Absolute values of FVC and FEV1 were obtained and percentage predicted values (% pred) for FEV1 and FVC were calculated from the following equations obtained in a representative Korean sample.20 Predicted FVC ¼ 4:8434 [0:00008633 · age2 (years)] þ [0:05292 · height (cm)] þ (0:01095 · weight (kg))
Predicted FEV1 ¼ 3:4132 [0:0002484 · age2 (years)] þ [0:04578 · height (cm)]
Anthropometric measurements and blood tests Height, weight, waist circumference (WC), systolic (SBP), and diastolic blood pressure (DBP) were measured. Blood pressure was measured according to the Hypertension Detection and Follow-Up Program protocol by using a mercury blood pressure device after the subjects had rested for more than 5 min.21 For subjects with a SBP higher than 140 mmHg and a DBP higher than 90 mmHg, blood pressure was measured two more times after resting and the average value was used. Height and weight were measured by automatic scale, and body mass index (BMI) was calculated by weight (kg) divided by the squared value of height (meters) (kg/m2). WC was measured at the part of the trunk located midway between the lower costal margin (bottom of lower rib) and the iliac crest (top of pelvic bone) while the patient was standing. After a 12-hr fast, fasting blood glucose (FBG) with the hexokinase method, C-reactive protein (CRP) with turbid immunoassay, total cholesterol (TC), triglycerides (TGs) with the enzymatic colorimetric method, high-density lipoprotein cholesterol (HDL-C) with the modified enzymatic method, and low-density lipoprotein-cholesterol (LDL-C) with the direct surfactant method were automatically measured using an autoanalyzer (Hitachi, Modular D 2400; Tokyo, Japan).
Diagnosis of metabolic syndrome Metabolic syndrome was defined based on the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or International Diabetes Federation (IDF) guidelines. WC was defined by the World Health Organization (WHO) Western Pacific Region criteria for obesity criteria.22 The diagnosis of metabolic syndrome according to AHA/NHLBI was made when the subjects satisfied more than three of the five components described below.13 1. 2. 3. 4. 5.
Abdominal obesity: WC ‡ 90 cm; High TGs: ‡ 150 mg/dL (1.7 mmol/L); Low HDL-C: < 40 mg/dL (1.0 mmol/L); Hypertension: ‡ 130/85 mmHg; and Fasting hyperglycemia: ‡ 100 mg/dL (5.6 mmol/L).
According to the IDF definition, metabolic syndrome is diagnosed when the subjects have abdominal obesity plus any two of the factors described above: High TGs, low HDL-C, hypertension, and fasting hyperglycemia.23 Because obesity is defined as a BMI ‡ 25 kg/m2 in Asian populations, BMI in our study was categorized using a 25kg/m2 cutoff point for obesity.
Statistical analysis Data are presented as mean – standard deviation (SD) or median (interquartile range) for continuous variables and as numbers (percentages) for categorical variables. Tests of trend across categories of emphysema and airflow obstruction were performed with analysis of variance (ANOVA) and Cochran– Armitage tests, as appropriate. For continuous measurements (EI, TGs, and LDL-C), we used a linear regression to assess the association of EI with TGs and LDL-C. Statistical adjustments were age, smoking status, BMI, and FEV1/FVC. Two-sided
METABOLIC SYNDROME AND EMPHYSEMA
3
P values less than 0.05 were considered statistically significant. All statistical tests were performed with Predictive Analytics Software 21.0 (by SPSS, Inc., Chicago, IL).
Results Clinical characteristics of the study population The clinical characteristics of the participants are shown in Table 1. Among 2814 study participants, the mean age was 55 years, and 83.5% were current or ex-smokers. The prevalence of metabolic syndrome was 30.5% by AHA/NHLBI criteria and 21.6% by IDF criteria. The median value for CRP and mean values for FBG and TC were 0.6 mg/L, 100 mg/dL, and 195 mg/dL, respectively. The mean – SD quantitative CT EI was 14 – 6%.
Prevalence of metabolic syndrome or its components by quintiles of FEV1 (% pred) We classified patients according to the quintiles of FEV1 (% pred), and the subjects in the lowest FEV1 (1st quintile)
Table 1.
Demographic and Clinical Characteristics of the Study Population (N = 2814)
Variables Clinical risk factors Age, years Smoking status None, % Past, % Current,% BMI ‡ 25 (kg/m2), % Laboratory test WBC ( · 103/mL) CRP (mg/L) FBG (mg/dL) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL) Metabolic syndrome (AHA/NHLBI), % Metabolic syndrome (IDF), % Waist circumference ‡ 90cm Low HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150 mg/dL or specific treatment, % SBP ‡ 130/DBP ‡ 85 mmHg or antihypertensive treatment, % Fasting glucose ‡ 100 mg/dL or diabetes treatment, % Pulmonary function test FEV1/FVC ratio, % FVC, % pred FEV1, % pred Emphysema index (%)
55 – 8 16.5 42.8 40.7 44.3 6.0 – 1.6 0.6 (0.4–1.3) 100 – 20 195 – 34 121 – 30 49 – 12 149 – 84 30.5 21.6 35.3 23.4
were slightly older and more likely to be smokers. Inflammatory markers such as white blood cell (WBC) and CRP, homeostasis model assessment of insulin resistance (HOMA-IR), and the prevalence of metabolic syndrome were significantly elevated in the lowest FEV1 group (Table 2). Among the individual metabolic syndrome components, the prevalence of abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C ( < 40 mg/dL) was inversely associated with FEV1 (% pred), whereas high TGs ( ‡ 150 mg/dL) had no significant association with FEV1 (% pred). However, EI was not significantly different between the FEV1 groups. The inverse association between FEV1 (% pred) and the prevalence of metabolic syndrome (P < 0.001), abdominal obesity (P < 0.001), fasting hyperglycemia (P < 0.001), and low HDL-C (P = 0.002) was persistent, even after adjusting for confounding factors, including age, smoking status, BMI, and CRP.
Prevalence of metabolic syndrome or its components by quintiles of quantitative CT EI When we analyzed the severity of emphysema according to the quintiles of CT EI, as shown in Table 3, subjects in the highest EI (5th quartile) were slightly older and more likely to have higher FVC (% pred) and lower FEV1/FVC (%) values. Although there was no association between prevalence of metabolic syndrome and EI, among the individual metabolic syndrome components, the prevalence of hypertension was positively associated with EI (P < 0.001) and the prevalence of high TG ( ‡ 150 mg/dL) was inversely associated with EI (P = 0.021) (Fig. 1). The prevalence of high LDL-C ( ‡ 160 mg/dL) also had an inverse association with EI (P = 0.020). These associations persisted after adjustment of age, smoking status, BMI, and FEV1/FVC (%) (P < 0.001 in hypertension, P = 0.039 in high TGs, and P = 0.046 in high LDL-C).
Association of EI as a continuous variable with a lipid profile As a continuous variable of EI, EI had a significant inverse association of TG (P = 0.001), LDL-C (P = 0.023), and TC (P = 0.002) (Fig. 2). After adjustment of age, smoking status, BMI, and FEV1/FVC, the inverse association of TG (P = 0.004) and TC (P = 0.010) with EI persisted.
40.0
Discussion 45.7 37.6 77.6 – 6.7 86.2 – 11.3 86.7 – 12.5 14 – 6
Values are expressed as percentages, mean – standard deviation or median (interquartile range). BMI, body mass index; WBC, white blood cell; CRP, C-reactive protein; FBG, fasting blood glucose; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; SBP, systolic blood pressure; DBP, diastolic blood pressure; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.
To our knowledge, this is the first large cross-sectional study to evaluate the association between emphysema severity and the presence of metabolic syndrome or its components. In our study, CT-determined EI was not significantly associated with the presence of metabolic syndrome itself, but was positively associated with the prevalence of hypertension and inversely associated with high TGs. Additionally, CT-determined EI had an inverse association with other lipids such as LDL-C and TC. In terms of lung function, low FEV1 (% pred) showed a definite association with metabolic syndrome and most of its components, such as abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C, with a consistent same direction. These results suggest that the effect of emphysema on the cardiovascular system might be less definite than one from airway obstruction because of the complex association of emphysema with cardiovascular risk factors.
4
33.0 23.6 37.0 45.7 38.5 23.4 41.2 42.5 11.6
36.7 27.4 43.1 50.1 44.9 28.0 40.0 40.6 11.4
47.7 12.9
43.4
35.4 47.4 39.9 24.4
32.5 23.5
6.0 – 1.6 0.6 (0.3–1.3) 2.3 – 1.3 (n = 455) 14 – 6
54 – 8 83.8 25 – 3 43.8
3rd (85–90%) n = 587
FEV1 % predicted Quintiles
41.4 10.7
37.4
31.5 42.0 32.0 21.4
25.0 17.1
5.8 – 1.6 0.6 (0.3–1.0) 2.1 – 1.4 (n = 420) 13 – 6
53 – 7 82.3 25 – 2 43.1
4th (91–97%) n = 543
42.5 11.7
37.5
28.3 42.5 31.7 19.1
24.0 15.7
5.7 – 1.6 0.5 (0.3–0.9) 2.0 – 1.0 (n = 423) 15 – 6
54 – 8 78.7 25 – 2 43.4
5th ( ‡ 98%) n = 530
0.644 0.934
0.206
< 0.001* 0.004 < 0.001* < 0.001*
< 0.001* < 0.001*
< 0.001 < 0.001 < 0.001 0.157
< 0.001 < 0.001 0.074 0.273
P value for trend
Values are expressed as percentages, mean – standard deviation or median (interquartile range). *P value < 0.05 after adjustment of age, smoking status, BMI, and CRP in metabolic syndrome, components of metabolic syndrome. and other dyslipidemia. HOMA-IR, homeostasis model assessment-insulin resistance; CRP, C-reactive protein; FEV1, forced expiratory volume in 1 sec; BMI, body mass index; WBC, white blood cell; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol.
6.1 – 1.7 0.7 (0.4–1.5) 2.2 – 1.1 (n = 422) 13 – 6
6.1 – 1.6 0.8 (0.4–1.5) 2.2 – 1.2 (n = 435) 14 – 7
(78–-84%) n = 551 54 – 7 84.9 25 – 2 44.8
2
nd
58 – 8 87.2 25 – 3 46.1
1 ( £ 77%) n = 603
st
HOMA-IR, CRP Values, and Prevalence of the Metabolic Syndrome According to the Quintiles of FEV1 % Predicted (N = 2814)
Age, year Smoker, % BMI, kg/m2 BMI ‡ 25 kg/m2, % Laboratory test WBC ( · 103/mL) CRP (mg/L) HOMA-IR (n = 2155) Emphysema index Metabolic syndrome AHA/NHLBI IDF Components of metabolic syndrome Waist circumference ‡ 90 cm, % Elevated blood pressure, % Impaired glucose metabolism, % HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150 mg/dL or specific treatment, % Other dyslipidemia Total cholesterol ‡ 200 mg/dL LDL-C ‡ 160 mg/dL
Table 2.
5
86 – 11 87 – 12 78 – 6 30.8 20.7 33.9 38.8 35.2 19.8 42.1 48.5 13.2
85 – 11 86 – 12 79 – 6 32.1 24.8 36.1 39.5 39.0 24.8 44.5 43.4 14.0
40.6 11.3
36.4
33.3 43.6 37.8 25.1
26.8 18.3
87 – 11 87 – 12 78 – 6
6.1 – 1.7 0.7 (0.4–1.3) 2.1 – 1.1 (n = 423)
53 – 8 85.2 25 – 2 40.8
3rd (12–15%) n = 574
Emphysema Index Quintiles
42.2 9.9
39.3
32.6 49.6 35.3 23.9
29.1 19.7
86 – 11 86 – 12 78 – 6
5.8 – 1.5 0.7 (0.4–1.3) 2.2 – 1.5 (n = 520)
55 – 8 83.4 25 – 2 45.4
4th (16–19%) n = 669
41.4 10.7
38.2
40.9 54.8 40.9 22.5
33.8 25.0
88 – 12 87 – 14 75 – 8
5.7 – 1.4 0.6 (0.3–1.2) 2.1 – 1.0 (n = 439)
56 – 9 83.0 25 – 3 46.1
5th ( ‡ 20%) n = 560
0.152 0.020*
0.021*
0.239 < 0.001* 0.642 0.857
0.823 0.850
< 0.001 0.383 < 0.001
< 0.001 0.516 0.576
< 0.001 0.984 0.358 0.847
P value for trend
Values are expressed as percentages, mean – standard deviation or median (interquartile range). *P value < 0.05 after adjustment of age, smoking status, BMI, and FEV1/FVC (%) in metabolic syndrome, components of metabolic syndrome, and other dyslipidemia. HOMA-IR, homeostasis model assessment-insulin resistance; CRP, C-reactive protein; BMI, body mass index; WBC, white blood cell; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 sec; % pred, percentage predicted value; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol.
6.1 – 1.8 0.6 (0.3–1.3) 2.1 – 1.1 (n = 345)
6.3 – 1.8 0.6 (0.4–1.3) 2.2 – 1.1 (n = 428)
(8–11%) n = 454 54 – 8 81.9 25 – 3 40.7
2
nd
54 – 7 83.7 25 – 2 47.6
1 ( < 8%) n = 557
st
HOMA-IR, CRP Values, and Prevalence of the Metabolic Syndrome According to the Quintiles of Emphysema Index (N = 2814)
Age, year Smoker,% BMI, kg/m2 BMI ‡ 25 kg/m2, % Laboratory test WBC ( · 103/mL) CRP (mg/L) HOMA-IR (n = 2155) Lung function test FVC % pred FEV1 % pred FEV1/FVC (%) Metabolic syndrome AHA/NHLBI IDF Components of metabolic syndrome Waist circumference ‡ 90 cm,% Elevated blood pressure, % Impaired glucose metabolism, % HDL-C < 40 mg/dL or specific treatment, % Triglycerides ‡ 150mg/dL or specific treatment, % Other dyslipidemia Total cholesterol ‡ 200 mg/dL LDL-C ‡ 160 mg/dL
Table 3.
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FIG. 1. Association of hypertension and hypertriglyceridemia with emphysema index (*) adjusted with age, smoking status, body mass index, and forced expiratory volume in 1 sec/forced vital capacity (%).
FIG. 2. Inverse association between lipid profiles and emphysema index (*) adjusted with age, smoking status, body mass index, and forced expiratory volume in one second/forced vital capacity (%). LDL-cholesterol, low-density lipoprotein cholesterol.
METABOLIC SYNDROME AND EMPHYSEMA
We observed that the presence of hypertension was the main factor linked with high EI. Mounting evidence has identified links between COPD and high blood pressure. In the pooled analysis of two large population-based cohorts data from 20,296 subjects by Mannino et al., the prevalence of hypertension was 34% in normal subjects and increased to 51% in severe COPD patients.23 However, there has been no population-based study investigating the association between emphysema severity and hypertension. Consistent with study results by Mannino et al., in the present study, prevalence of hypertension was 39.5% in lowest emphysema ( < 8%) group, increasing to 54.8% in the highest emphysema ( > 20%) group. The mechanism to explain this association may be the vascular insults that affect both the coronary and pulmonary vasculature. It has been shown that there are apoptotic endothelial cells in the lungs of patients with COPD24 and that emphysema of the lung and vascular calcification leading to arteriosclerosis occur simultaneously in a transgenic mouse model.25 Clinically, McAllister et al. showed that pulse wave velocity–measured arterial stiffness is linearly associated with CT-assessed emphysema severity and mean arterial pressure after multiple linear regression modeling in COPD patients.8 In addition, Barr et al. demonstrated that the percentage of patients with CT emphysema had a strong and linear association with endothelial dysfunction as measured by flow-measured dilation of the bronchial artery across the spectrum of disease from normal lung function to moderately severe COPD.26 Another finding in the present study was the independent association between emphysema severity and dyslipidemia, including TC and TGs. A higher serum TG or TC level was associated with attenuated severity of emphysema. As there is little factual data to explain the link between emphysema and dyslipidemia in the general population and COPD, it is not possible to draw a definitive conclusion on the basis of this study alone. Nevertheless, there have been several studies supporting our finding. Interestingly, Mineo et al. observed that serum TC, HDL-C, and TGs levels were significantly increased together with respiratory function after lung volume reduction surgery in patients with moderate to severe emphysema,27 indicating that less emphysema is associated with a higher serum lipid level. These findings suggest that emphysema severity itself might be associated with lipid profile regulation. Several studies have described that pulmonary emphysema in severe stages of COPD causes respiratory cachexia with persistent inflammation, which leads to increased resting energy expenditure, protein wasting, and preferential lipid substrate utilization with an altered lipid profile (i.e., low cholesterol and TGs levels).28–31 Especially, it is well recognized that lean mass depletion and low BMI were observed more in emphysema patients compared with chronic bronchitis patients in severe COPD.30 However, we did not find an association between EI and BMI. The most plausible explanation for this insignificant result is that because this study was conducted with subjects visiting the Health Promotion Center for the health checkup program, the severity of the emphysema might be low to reflect a change of BMI. As such, we speculate that an altered lipid profile might occur ahead of a BMI change as emphysema progresses in the lung. In contrast to emphysema severity, the prevalence of metabolic syndrome increased significantly according to the decrement of quintile of FEV1 (% pred) irrespective of
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criteria of metabolic syndrome. Inflammatory markers, including WBC and CRP and the prevalence of components of metabolic syndrome, such as abdominal obesity, hypertension, fasting hyperglycemia, and low HDL-C ( < 40 mg/dL), were also significantly higher in the lower FEV1 (% pred), which is consistent with previous studies.14,15 These inverse associations of lung function with metabolic syndrome, with metabolic syndrome components, and with inflammatory markers lead to increased cardiovascular morbidity or mortality. The positive association of emphysema severity with hypertension and negative association of emphysema severity with dyslipidemia cancel each other out, thus leading to showing that there is no visible association of emphysema severity with metabolic syndrome. Further research is needed to determine how this phenomenon could affect cardiovascular events in patients with an emphysemadominant phenotype. This study had several limitations. It was a retrospective study performed on individuals who voluntarily visited our center for health examinations, particularly for lung examination. Therefore, a large portion (83%) of the subjects were smokers (current or past), which resulted in no difference in smoker proportion according to quintile of EI. Second, this study was conducted with only males. Because emphysema severity differs according to gender32 and the number of females presenting for health examinations was relatively low, we analyzed only the data of males to reduce selection bias. Third, we calculated the EI using volumetric CT and set - 950 HU as the threshold for detecting emphysema, because previous CT pathological correlations with macroscopic/ microscopic measurements are well established using this criterion.33 However, we could not obtain an EI according to segment area, such as upper lobe and lower lobe areas. Finally, the present study was conducted at a single center, which might influence generalization of the findings. In conclusion, we have shown for the first time that a CTdetermined EI has a complex association with components of metabolic syndrome, whereas FEV1 (% pred) has an inverse association with metabolic syndrome and most of its components with consistent direction.
Acknowledgment This study was supported by Samsung Medical Center Foundation for Medical Research (SMO1140211).
Author Disclosure Statement No competing financial interests exist.
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Address correspondence to: Dr. Seong Yong Lim Department of Medicine Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine Seoul 110-746 Korea E-mail: [email protected]
