ORIGINAL ARTICLE
Coronary Artery Calcification on Computed Tomography Correlates With Mortality in Chronic Obstructive Pulmonary Disease Phoebe E. O’Hare, MBBS,* Jonny F. Ayres, FRCR,† Rachael L. O’Rourke, FRANZCR,† Richard E. Slaughter, FRANZCR,† Henry M. Marshall, FRACP,‡ Rayleen V. Bowman, FRACP, PhD,*‡ Kwun M. Fong, FRACP, PhD,*‡ and Ian A. Yang, FRACP, PhD*‡ Objective: This cross-sectional study assessed the prognostic implications of computed tomography (CT) coronary artery calcification (CAC), independent of emphysema, in patients with chronic obstructive pulmonary disease (COPD). Materials and Methods: Coronary artery calcification and emphysema were assessed on noncontrast, ungated chest CT scans of patients with COPD using the validated CAC ordinal visual scale (CAC OVS; range, 0–12) and visual CT emphysema index. Results: A total of 200 CT images were analyzed. All-cause mortality was associated with CAC OVS greater than 4 (hazard ratio, 2.03; 95% confidence interval, 1.08–3.82; P = 0.028) and with moderate to severe CTemphysema index (hazard ratio, 4.34; 95% confidence interval, 1.53–12.33; P = 0.006). Increased emphysema severity, myocardial infarction, hypertension, and male sex independently correlated with CAC OVS greater than 4. Conclusions: Coronary artery calcification severity and emphysema severity on CT images are related and are strongly as well as independently associated with prognosis in patients with moderate to severe COPD. The potential to use CAC OVS on unenhanced nongated CT as a screening tool for coronary artery disease and as a prognostic marker in patients with COPD needs further investigation in prospective studies. Key Words: chronic obstructive pulmonary disease, coronary artery calcification, emphysema, computed tomography (J Comput Assist Tomogr 2014;38: 753–759)
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hronic obstructive pulmonary disease (COPD) is characterized by air flow limitation that is not fully reversible. The extrapulmonary effects associated with COPD are being increasingly recognized. Cardiovascular morbidity and mortality are highly prevalent in patients with COPD, who have a 5-fold increased risk for cardiovascular disease compared with those without COPD.1 There is now considerable evidence of an association between COPD and cardiovascular disease, even after adjusting for shared causal factors, the most well-recognized being cigarette smoking.2,3 From the *School of Medicine, The University of Queensland; Departments of †Medical Imaging, and ‡Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland, Australia. Received for publication January 30, 2014; accepted April 29, 2014. Reprints: Phoebe E. O’Hare, MBBS, Thoracic Department, Level 2, Administration Building, The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, Queensland 4032, Australia (e‐mail: [email protected]). Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jcat.org). Supported by an National Health and Medical Research Council Career Development Fellowship 1026215 (I.Y.), National Health and Medical Research Council Practitioner Fellowship 1019891 (K.F.), and a Health and Medical Research project grant. The authors declare no conflict of interest. Copyright © 2014 by Lippincott Williams & Wilkins
In support of the increased cardiovascular risk in COPD, various clinical and radiological markers of COPD severity have been associated with cardiovascular disease. Air flow obstruction, measured as reduced forced expiratory volume in 1 second (FEV1), and rate of FEV1 decline have been reported to be independent markers of cardiovascular disease and mortality.4–6 Severe emphysema has been associated with a high prevalence of coronary artery disease (CAD) and subclinical atherosclerosis in the carotid arteries and peripheral circulation.7,8 Despite knowledge of these relationships and the increased risk for cardiac events in patients with COPD, the importance of systematic screening for CAD and structured prevention of cardiac complications has not been emphasized in clinical guidelines for COPD. Coronary artery calcification (CAC) is a pathognomonic marker of CAD, and its extent is directly associated with the total burden of coronary atherosclerosis.9 It is an independent predictor of cardiovascular morbidity and mortality.10,11 In support of its prognostic value, inclusion of CAC improves the prognostic value of Framingham risk categories and CAC alone outperforms the Framingham risk score for predicting future cardiovascular events.10,11 Furthermore, an assessment of CAC using an ordinal visual scale (CAC OVS) on ungated computed tomographic (CT) images in a lung cancer screening cohort was shown to predict cardiovascular death.12 The extent of systemic calcified atherosclerosis has recently been associated with emphysema and air flow limitation.13 We aimed to further these investigations via determining whether quantification of CAC using CAC OVS is related to clinical and radiological markers of COPD. In addition, we aimed to assess the prognostic potential of a visual index of CT emphysema severity and prognostic significance of CAC in a population of patients with COPD.
MATERIALS AND METHODS The participants were patients with COPD under the care of the Department of Thoracic Medicine, The Prince Charles Hospital. Clinical databases were interrogated to identify patients with COPD. Adult patients (>18 years of age) with COPD were included if they had undergone an ungated noncontrast highresolution CT lung scan for routine clinical purposes at The Prince Charles Hospital consecutively between 1999 and 2012. A final sample of 200 patients was studied. Chronic obstructive pulmonary disease was defined by a previously recorded thoracic physician diagnosis or according to the Global Obstructive Lung Disease international guidelines.14 Because of potential confounding effects on lung function test results, patients were excluded if other major respiratory comorbidities were present. Patients were also excluded if they had previously undergone coronary artery stent placement, coronary artery bypass grafting, or heart transplant due to interference with
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CAC assessment. Patient demographics and medical history were extracted from the hospital medical records. Lung function and exercise capacity were measured according to the American Thoracic Society/European Respiratory Society standards during routine clinic visits at The Prince Charles Hospital.15–17 Tests performed within 12 months before or 12 months after the date of CT were considered, and results of the test performed as close as possible to the date of CT were used. The survival status and date of last contact with each participant were recorded from the medical record. Time to status was recorded as the period of time that had passed from the date of the CT to the date of last known recorded contact or the date of death.
CT Imaging Computed tomographic imaging was performed using a 64slice multidetector scanner (Phillips Brilliance) with scan parameters at 120 kV and 250 mAs, with pitch of 0.891 and collimation of 0.625. The images were acquired from the lung apices to bases during a single inspiratory breath hold. Intravenous contrast medium and cardiac gating were not used. The high-resolution CT lung images that were used for scoring the visual emphysema index had section thickness ranging from 0.63 to 1.25 mm, with an increment of 10.0 to 15.0 mm. For CAC OVS scoring, the mediastinal volumetric images were reconstructed with a 3.0- to 6.5-mm section thickness range and increment of 2.5 to 5.0 mm. If a patient had more than 1 chest CT during the study period, only the first was included for the purpose of this study. The CT images were assessed by 2 radiologists (J.A. and R.O.) trained in the visual scoring of CAC and emphysema on CT. The CT images were de-identified and randomly assigned to one or the other reader. Scoring for emphysema index and CAC was performed at different times and in random order to minimize potential reader bias. To assess interreader variability, both radiologists independently scored an initial subset of 4% of the images.
Visual CAC Score and Emphysema Index Coronary artery calcification was scored from the mediastinal CT images, with the use of a validated ordinal visual score (CAC OVS).12 The score was calculated by categorizing calcification in each of the left main, left anterior descending, circumflex, and right coronary arteries as absent (0), mild (1), moderate (2), or severe (3).12 Mild calcification indicated that less than one third of the length of the entire artery showed calcification; moderate one third to two thirds and severe indicated that more than two thirds of the length showed calcification.12 The total CAC OVS severity score ranged from 0 to a maximum of 12. Emphysema severity was scored with the use of the modified National Emphysema Treatment Trial Research Group scoring system.18,19 This involved a division of the right and left lungs craniocaudally into 3 zones and assigning a severity score for each zone (Appendix A, http://links.lww.com/RCT/A29).18,19 Areas of low radioattenuation were used to define emphysema. The score assigned to each of the 6 lung regions was totaled, allowing a maximum score of 24. Three categories of severity were assigned according to the total score: mild, less than 8; moderate, 8 to 16; and severe, greater than 16.20 In addition, the distribution of emphysema was classified as homogeneous or heterogeneous (Appendix B, http://links.lww.com/RCT/A29)18 and its craniocaudal distribution was described (Appendix C, http://links.lww.com/RCT/A29).21
into 4 categories of severity (0, 1–3, 4–6, and 7–12).12 Intraclass correlation coefficients (ICC, average measures) were calculated for the paired CAC OVS and CT emphysema scores performed by the 2 radiologists. Correlations between total CAC OVS score and known cardiovascular risk factors were analyzed using the Spearman ρ correlation coefficient. The w2 test was used to assess the association between CAC OVS scores (dichotomized at the median score of 4), CT emphysema severity, and distribution with other variables. Odds ratios (ORs) with 95% confidence intervals were calculated. Multiple logistic regression analysis was performed with variables significant on the w2 analyses. KaplanMeier curves were plotted with univariate log rank, and multivariate Cox regression analyses were performed. A P value less than 0.05 (2-tailed) was considered statistically significant. We estimated that this study of 200 participants had 80% power, at a significance (α) level of 0.05, to detect hazard ratio for death of 1.88 for higher CAC OVS, assuming an accrual interval of 156 months, additional follow-up after the accrual interval of 36 months, and median survival time of 105 months for a lower CAC OVS (PS Power Calculation Program).
RESULTS The characteristics of the study population are in Table 1. Interobserver reliability for CAC and emphysema scores was excellent, with ICC of 0.99 for the total CAC OVS scores and ICC of 0.98 for the CT emphysema scores (n = 8 patients, P < 0.001). Coronary artery calcification of any severity was detected in 175 (87%) of the participants (Table 1). Coronary artery calcification significantly correlated with age, smoking duration and inversely with estimated glomerular filtration rate (eGFR) (Table 2). In addition, more severe CAC OVS were associated with the physician-diagnosed cardiovascular risk factors hypertension and hyperlipidaemia as well as cardiac disease including myocardial infarction, angina, and heart failure. There was no significant association when comparing severe CAC OVS against emphysema distribution or reduced lung function (Table 3). There was radiological evidence of emphysema (≥1 for the visual CT emphysema index) in 199 (99.5%) participants (Table 1). Total emphysema was significantly associated with lung function (including percentage predicted FEV1, FEV1/vital capacity (VC), and carbon monoxide diffusing capacity (KCO), lower body mass index (BMI), and pack-years smoked (Supplementary Tables 1 and 2, http://links.lww.com/RCT/A28). Multiple logistic regression analysis showed that increased CT emphysema severity (moderate to severe), together with a history of myocardial infarction, hypertension, and male sex, was significant independent predictors of CAC OVS scores greater than 4, after adjusting for other covariates listed in Table 4. The median follow-up time was 36 months (range, 0– 140 months). During this period, there were 46 deaths. Higher CAC OVS (>4 vs ≤4) were significantly associated with all-cause mortality (P = 0.001) (Fig. 1). All-cause mortality was significantly related to moderate to severe CT emphysema severity (P = 0.02) (Fig. 2). Cox regression showed that CAC OVS, emphysema, and peripheral vascular disease remained significant predictors of mortality (Table 5), even after adjusting for other factors significant on the univariate log rank analyses. Inclusion in the Cox regression model of an interaction term between median CAC OVS (>4 vs ≤4) and CTemphysema score (moderate to severe vs mild) showed no statistically significant interaction (P = 0.60 for the interaction term).
Statistical Analysis Statistical analyses were performed using Statistical Package for the Social Sciences software (IBM SPSS Statistics version 20). Coronary artery calcification ordinal visual scale was stratified
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DISCUSSION This cross-sectional study found a high prevalence of CAC and emphysema in patients with moderate to severe COPD. © 2014 Lippincott Williams & Wilkins
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CAC on CT Correlates With Mortality in COPD
TABLE 1. Summary of Demographic and Clinical Features Parameter (No. Continuous Values are Given as Mean ± SD or Median (IQR) Demographics Age, y Sex, n (%) Male Female BMI, kg/m2 Smoking status, n (%) Current smoker Ex-smoker Lifelong nonsmoker Duration smoked, y Pack-years smoked, pack-years Alpha-1 antitrypsin phenotype, n = 92 (42%) MM, n (%) Phenotype other than MM, n (%) Echocardiography Left ventricular ejection fraction, n = 127 (%) Right ventricular systolic pressure, n = 79 (mm Hg) eGFR (mL/min per 1.73 m2) Lung function FEV1 percentage predicted FEV1/VC percentage predicted KCO percentage predicted Six-minute walk test distance (m), n = 63 (31.5%) Cardiovascular risk factors, n (%) Hypertension Hyperlipidaemia Chronic kidney disease Diabetes Family history of premature cardiac death Cardiovascular comorbidity, n (%) Angina Myocardial infarction Heart failure Peripheral vascular disease Coronary artery calcification visual score, n (%) 0 1–3 4–6 7–12 Emphysema Total emphysema severity score Mild, 16, n (%) Heterogeneity, n (%) Homogenous Heterogeneous Craniocaudal distribution, n (%) Diffuse Upper lobe predominant Lower lobe predominant
All Patients (n = 200)
Range
68.6 ± 9.8
28.7–90.4
112 (56%) 88 (44%) 25.5 ± 5.5
14.6–44.8
39 (19%) 153 (77%) 8 (4%) 42.4 ± 13.8 50.0 (31.5–71.6)
0–70 0–234.5
78 (85%) 14 (15%) 61.0 ± 11.2 45.6 ± 13.7 70.0 ± 22.9
22–81 18–96 14–141
46.5 ± 19.2 42.8 (31.0–54.6) 51.8 (37.7–68.0) 350 (255–425)
15.8–103.1 19.9–70.0 14.9–138.4 100–525
96 (48%) 65 (32%) 29 (14%) 18 (9%) 18 (9%) 35 (17%) 25 (12%) 19 (9%) 13 (6%) 25 (13%) 70 (35%) 54 (27%) 51 (25%) 14 (7–22) 50 (25%) 60 (35%) 89 (44.5%)
0–24
144 (72%) 55 (28%) 93 (46%) 85 (43%) 21 (11%)
IQR, interquartile range; MM, normal M gene.
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associated with higher levels of CAC, after adjusting for known predictors of increased CAC. The findings highlight the interrelationship between CAC and emphysema and suggest that scoring of their severity on CT chest scans could be of prognostic value in patients with COPD.
TABLE 2. Correlations Between CAC and Known Cardiac Risk Factors Correlation With Total CAC Score Age, y BMI, kg/m2 Pack-years smoked (pack-years) Cigarettes per day Smoking duration, y Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg eGFR, mL/min per 1.73 m2 LVEF, % RVSP, mm Hg
Spearmanρ Correlation Coefficient*
P
0.38 0.03 0.09
4)
95% CI Parameter Age (>69.9 vs ≤69.9 y) Sex (male vs female) Smoking Pack years smoked (>50 vs ≤50 pack-years) Duration smoked (>42 vs ≤42 y) Lung function FEV1 percentage predicted (69.9 y vs ≤69.9 y) Sex (female vs male) CAC (5–12 vs 0–4) CT emphysema severity (moderate to severe vs mild) Angina Heart failure Peripheral vascular disease
clinical teams treating patients with chronic lung disease. We show here that CAC severity scoring (as opposed to ascertainment of presence or absence) has the potential to provide clinically important, prognostic information for patients with COPD, without the use of electrocardiographically gated acquisition or specialized cardiac software. Visual CT emphysema index was predictive of all-cause mortality in our population of patients with COPD. This result supports the work by others who have demonstrated that emphysema, either visually or quantitatively assessed on CT, is predictive of respiratory mortality in patients with various stages of COPD.29,30 Similarly to CAC, our findings and those of others advocate the importance of detecting and quantifying emphysema in those patients with COPD who have had CT imaging, in light of its prognostic significance. It remains to be tested whether it would be useful to perform CT imaging in all moderate to severe patients with COPD, either for COPD diagnostic/prognostic purposes or for lung cancer screening, or whether CAC score could enhance established prognostic indices such as the body-mass index, airflow obstruction, dyspnoea, and exercise capacity index (BODE).31
Methodological Considerations and Limitations We used published visual scores for CAC12 and emphysema.18,19 Although we used a visual score, we found an excellent interobserver reproducibility between the 2 readers. We could not prospectively assess postbronchodilator spirometry and were therefore unable to stratify the population according to the Global Obstructive Lung Disease stages of COPD. Although we could not calculate the Framingham risk score for cardiovascular disease, important cardiac diseases and risk factors were captured and, as expected, found to be associated with CAC.25,26,32 In addition, patients with coronary artery stents or those who had undergone coronary artery bypass graft surgery were excluded, potentially underestimating the value of CAC scoring in the COPD population. Because ungated CT images with varying slice thickness were used, there is the potential to miss subtle calcification reducing the precision of the CAC OVS. However, because prognosis is determined by CAC score categories, the clinical significance should not be affected. The effects of slice thickness, movement artifact, and volume averaging are further accounted for by the organization of CAC into categories of severity. The exact cause of death was unable to be ascertained; therefore, allcause mortality was used as the main mortality outcome.
CONCLUSIONS In conclusion, CAC and emphysema are both highly prevalent on CT imaging of patients with moderate to severe COPD. We have shown that visual CAC severity and visual CT emphysema index are related and are both independent predictors of
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all-cause mortality in patients with COPD. The potential of using visual CAC severity to noninvasively screen for CAD in patients with COPD should be prospectively investigated.
REFERENCES 1. Feary JR, Rodrigues LC, Smith CJ, et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65:956–962. 2. Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms. Chest. 2013;143:798–807. 3. Boschetto P, Beghe B, Fabbri LM, et al. Link between chronic obstructive pulmonary disease and coronary artery disease: implication for clinical practice. Respirology. 2012;17:422–431. 4. Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest. 2005;127:1952–1959. 5. Tockman MS, Pearson JD, Fleg JL, et al. Rapid decline in FEV1. A new risk factor for coronary heart disease mortality. Am J Respir Crit Care Med. 1995;151:390–398. 6. Engstrom G, Hedblad B, Janzon L, et al. Respiratory decline in smokers and ex-smokers: an independent risk factor for cardiovascular disease and death. J Cardiovasc Risk. 2000;7:267–272. 7. 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. 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. Rumberger JA, Simons DB, Fitzpatrick LA, et al. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995;92: 2157–2162. 10. Greenland P, LaBree L, Azen SP, et al. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210–215. 11. Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. 2005;46: 158–165. 12. Shemesh J, Henschke CI, Shaham D, et al. Ordinal scoring of coronary artery calcifications on low-dose CT scans of the chest is predictive of death from cardiovascular disease. Radiology. 2010;257:541–548. 13. Chae EJ, Seo JB, Oh YM, et al. Severity of systemic calcified atherosclerosis is associated with airflow limitation and emphysema. J Comput Assist Tomogr. 2013;37:743–749.
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14. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: http://www.goldcopd.org/. Accessed 24 January 2014.
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systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003;107:1514–1519.
15. Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720–735.
24. Barr RG, Mesia-Vela S, Austin JH, et al. Impaired flow-mediated 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.
16. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338.
25. Alhaj EK, Alhaj NE, Bergmann SR, et al. Coronary artery calcification and emphysema. Can J Cardiol. 2008;24:369–372.
17. American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–117.
26. Sverzellati N, Cademartiri F, Bravi F, et al. Relationship and prognostic value of modified coronary artery calcium score, FEV1, and emphysema in lung cancer screening population: the MILD trial. Radiology. 2012;262: 460–467.
18. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med. 2001;345: 1075–1083. 19. Hersh CP, Washko GR, Jacobson FL, et al. Interobserver variability in the determination of upper lobe-predominant emphysema. Chest. 2007;131: 424–431. 20. Omori H, Nakashima R, Otsuka N, et al. Emphysema detected by lung cancer screening with low-dose spiral CT: prevalence, and correlation with smoking habits and pulmonary function in Japanese male subjects. Respirology. 2006;11:205–210. 21. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348:2059–2073. 22. Thurnheer R, Muntwyler J, Stammberger U, et al. Coronary artery disease in patients undergoing lung volume reduction surgery for emphysema. Chest. 1997;112:122–128. 23. Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of
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27. Rasmussen T, Kober L, Pedersen JH, et al. Relationship between chronic obstructive pulmonary disease and subclinical coronary artery disease in long-term smokers. Eur Heart J Cardiovasc Imaging. 2013;14:1159–1166. 28. 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. 29. Haruna A, Muro S, Nakano Y, et al. CT scan findings of emphysema predict mortality in COPD. Chest. 2010;138:635–640. 30. Zulueta JJ, Wisnivesky JP, Henschke CI, et al. Emphysema scores predict death from COPD and lung cancer. Chest. 2012;141:1216–1223. 31. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005–1012. 32. Newman AB, Naydeck BL, Sutton-Tyrrell K, et al. Coronary artery calcification in older adults to age 99: prevalence and risk factors. Circulation. 2001;104:2679–2684.
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Coronary Artery Calcification on Computed Tomography Correlates With Mortality in Chronic Obstructive Pulmonary Disease Phoebe E. O’Hare, MBBS,* Jonny F. Ayres, FRCR,† Rachael L. O’Rourke, FRANZCR,† Richard E. Slaughter, FRANZCR,† Henry M. Marshall, FRACP,‡ Rayleen V. Bowman, FRACP, PhD,*‡ Kwun M. Fong, FRACP, PhD,*‡ and Ian A. Yang, FRACP, PhD*‡ Objective: This cross-sectional study assessed the prognostic implications of computed tomography (CT) coronary artery calcification (CAC), independent of emphysema, in patients with chronic obstructive pulmonary disease (COPD). Materials and Methods: Coronary artery calcification and emphysema were assessed on noncontrast, ungated chest CT scans of patients with COPD using the validated CAC ordinal visual scale (CAC OVS; range, 0–12) and visual CT emphysema index. Results: A total of 200 CT images were analyzed. All-cause mortality was associated with CAC OVS greater than 4 (hazard ratio, 2.03; 95% confidence interval, 1.08–3.82; P = 0.028) and with moderate to severe CTemphysema index (hazard ratio, 4.34; 95% confidence interval, 1.53–12.33; P = 0.006). Increased emphysema severity, myocardial infarction, hypertension, and male sex independently correlated with CAC OVS greater than 4. Conclusions: Coronary artery calcification severity and emphysema severity on CT images are related and are strongly as well as independently associated with prognosis in patients with moderate to severe COPD. The potential to use CAC OVS on unenhanced nongated CT as a screening tool for coronary artery disease and as a prognostic marker in patients with COPD needs further investigation in prospective studies. Key Words: chronic obstructive pulmonary disease, coronary artery calcification, emphysema, computed tomography (J Comput Assist Tomogr 2014;38: 753–759)
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hronic obstructive pulmonary disease (COPD) is characterized by air flow limitation that is not fully reversible. The extrapulmonary effects associated with COPD are being increasingly recognized. Cardiovascular morbidity and mortality are highly prevalent in patients with COPD, who have a 5-fold increased risk for cardiovascular disease compared with those without COPD.1 There is now considerable evidence of an association between COPD and cardiovascular disease, even after adjusting for shared causal factors, the most well-recognized being cigarette smoking.2,3 From the *School of Medicine, The University of Queensland; Departments of †Medical Imaging, and ‡Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland, Australia. Received for publication January 30, 2014; accepted April 29, 2014. Reprints: Phoebe E. O’Hare, MBBS, Thoracic Department, Level 2, Administration Building, The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, Queensland 4032, Australia (e‐mail: [email protected]). Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jcat.org). Supported by an National Health and Medical Research Council Career Development Fellowship 1026215 (I.Y.), National Health and Medical Research Council Practitioner Fellowship 1019891 (K.F.), and a Health and Medical Research project grant. The authors declare no conflict of interest. Copyright © 2014 by Lippincott Williams & Wilkins
In support of the increased cardiovascular risk in COPD, various clinical and radiological markers of COPD severity have been associated with cardiovascular disease. Air flow obstruction, measured as reduced forced expiratory volume in 1 second (FEV1), and rate of FEV1 decline have been reported to be independent markers of cardiovascular disease and mortality.4–6 Severe emphysema has been associated with a high prevalence of coronary artery disease (CAD) and subclinical atherosclerosis in the carotid arteries and peripheral circulation.7,8 Despite knowledge of these relationships and the increased risk for cardiac events in patients with COPD, the importance of systematic screening for CAD and structured prevention of cardiac complications has not been emphasized in clinical guidelines for COPD. Coronary artery calcification (CAC) is a pathognomonic marker of CAD, and its extent is directly associated with the total burden of coronary atherosclerosis.9 It is an independent predictor of cardiovascular morbidity and mortality.10,11 In support of its prognostic value, inclusion of CAC improves the prognostic value of Framingham risk categories and CAC alone outperforms the Framingham risk score for predicting future cardiovascular events.10,11 Furthermore, an assessment of CAC using an ordinal visual scale (CAC OVS) on ungated computed tomographic (CT) images in a lung cancer screening cohort was shown to predict cardiovascular death.12 The extent of systemic calcified atherosclerosis has recently been associated with emphysema and air flow limitation.13 We aimed to further these investigations via determining whether quantification of CAC using CAC OVS is related to clinical and radiological markers of COPD. In addition, we aimed to assess the prognostic potential of a visual index of CT emphysema severity and prognostic significance of CAC in a population of patients with COPD.
MATERIALS AND METHODS The participants were patients with COPD under the care of the Department of Thoracic Medicine, The Prince Charles Hospital. Clinical databases were interrogated to identify patients with COPD. Adult patients (>18 years of age) with COPD were included if they had undergone an ungated noncontrast highresolution CT lung scan for routine clinical purposes at The Prince Charles Hospital consecutively between 1999 and 2012. A final sample of 200 patients was studied. Chronic obstructive pulmonary disease was defined by a previously recorded thoracic physician diagnosis or according to the Global Obstructive Lung Disease international guidelines.14 Because of potential confounding effects on lung function test results, patients were excluded if other major respiratory comorbidities were present. Patients were also excluded if they had previously undergone coronary artery stent placement, coronary artery bypass grafting, or heart transplant due to interference with
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CAC assessment. Patient demographics and medical history were extracted from the hospital medical records. Lung function and exercise capacity were measured according to the American Thoracic Society/European Respiratory Society standards during routine clinic visits at The Prince Charles Hospital.15–17 Tests performed within 12 months before or 12 months after the date of CT were considered, and results of the test performed as close as possible to the date of CT were used. The survival status and date of last contact with each participant were recorded from the medical record. Time to status was recorded as the period of time that had passed from the date of the CT to the date of last known recorded contact or the date of death.
CT Imaging Computed tomographic imaging was performed using a 64slice multidetector scanner (Phillips Brilliance) with scan parameters at 120 kV and 250 mAs, with pitch of 0.891 and collimation of 0.625. The images were acquired from the lung apices to bases during a single inspiratory breath hold. Intravenous contrast medium and cardiac gating were not used. The high-resolution CT lung images that were used for scoring the visual emphysema index had section thickness ranging from 0.63 to 1.25 mm, with an increment of 10.0 to 15.0 mm. For CAC OVS scoring, the mediastinal volumetric images were reconstructed with a 3.0- to 6.5-mm section thickness range and increment of 2.5 to 5.0 mm. If a patient had more than 1 chest CT during the study period, only the first was included for the purpose of this study. The CT images were assessed by 2 radiologists (J.A. and R.O.) trained in the visual scoring of CAC and emphysema on CT. The CT images were de-identified and randomly assigned to one or the other reader. Scoring for emphysema index and CAC was performed at different times and in random order to minimize potential reader bias. To assess interreader variability, both radiologists independently scored an initial subset of 4% of the images.
Visual CAC Score and Emphysema Index Coronary artery calcification was scored from the mediastinal CT images, with the use of a validated ordinal visual score (CAC OVS).12 The score was calculated by categorizing calcification in each of the left main, left anterior descending, circumflex, and right coronary arteries as absent (0), mild (1), moderate (2), or severe (3).12 Mild calcification indicated that less than one third of the length of the entire artery showed calcification; moderate one third to two thirds and severe indicated that more than two thirds of the length showed calcification.12 The total CAC OVS severity score ranged from 0 to a maximum of 12. Emphysema severity was scored with the use of the modified National Emphysema Treatment Trial Research Group scoring system.18,19 This involved a division of the right and left lungs craniocaudally into 3 zones and assigning a severity score for each zone (Appendix A, http://links.lww.com/RCT/A29).18,19 Areas of low radioattenuation were used to define emphysema. The score assigned to each of the 6 lung regions was totaled, allowing a maximum score of 24. Three categories of severity were assigned according to the total score: mild, less than 8; moderate, 8 to 16; and severe, greater than 16.20 In addition, the distribution of emphysema was classified as homogeneous or heterogeneous (Appendix B, http://links.lww.com/RCT/A29)18 and its craniocaudal distribution was described (Appendix C, http://links.lww.com/RCT/A29).21
into 4 categories of severity (0, 1–3, 4–6, and 7–12).12 Intraclass correlation coefficients (ICC, average measures) were calculated for the paired CAC OVS and CT emphysema scores performed by the 2 radiologists. Correlations between total CAC OVS score and known cardiovascular risk factors were analyzed using the Spearman ρ correlation coefficient. The w2 test was used to assess the association between CAC OVS scores (dichotomized at the median score of 4), CT emphysema severity, and distribution with other variables. Odds ratios (ORs) with 95% confidence intervals were calculated. Multiple logistic regression analysis was performed with variables significant on the w2 analyses. KaplanMeier curves were plotted with univariate log rank, and multivariate Cox regression analyses were performed. A P value less than 0.05 (2-tailed) was considered statistically significant. We estimated that this study of 200 participants had 80% power, at a significance (α) level of 0.05, to detect hazard ratio for death of 1.88 for higher CAC OVS, assuming an accrual interval of 156 months, additional follow-up after the accrual interval of 36 months, and median survival time of 105 months for a lower CAC OVS (PS Power Calculation Program).
RESULTS The characteristics of the study population are in Table 1. Interobserver reliability for CAC and emphysema scores was excellent, with ICC of 0.99 for the total CAC OVS scores and ICC of 0.98 for the CT emphysema scores (n = 8 patients, P < 0.001). Coronary artery calcification of any severity was detected in 175 (87%) of the participants (Table 1). Coronary artery calcification significantly correlated with age, smoking duration and inversely with estimated glomerular filtration rate (eGFR) (Table 2). In addition, more severe CAC OVS were associated with the physician-diagnosed cardiovascular risk factors hypertension and hyperlipidaemia as well as cardiac disease including myocardial infarction, angina, and heart failure. There was no significant association when comparing severe CAC OVS against emphysema distribution or reduced lung function (Table 3). There was radiological evidence of emphysema (≥1 for the visual CT emphysema index) in 199 (99.5%) participants (Table 1). Total emphysema was significantly associated with lung function (including percentage predicted FEV1, FEV1/vital capacity (VC), and carbon monoxide diffusing capacity (KCO), lower body mass index (BMI), and pack-years smoked (Supplementary Tables 1 and 2, http://links.lww.com/RCT/A28). Multiple logistic regression analysis showed that increased CT emphysema severity (moderate to severe), together with a history of myocardial infarction, hypertension, and male sex, was significant independent predictors of CAC OVS scores greater than 4, after adjusting for other covariates listed in Table 4. The median follow-up time was 36 months (range, 0– 140 months). During this period, there were 46 deaths. Higher CAC OVS (>4 vs ≤4) were significantly associated with all-cause mortality (P = 0.001) (Fig. 1). All-cause mortality was significantly related to moderate to severe CT emphysema severity (P = 0.02) (Fig. 2). Cox regression showed that CAC OVS, emphysema, and peripheral vascular disease remained significant predictors of mortality (Table 5), even after adjusting for other factors significant on the univariate log rank analyses. Inclusion in the Cox regression model of an interaction term between median CAC OVS (>4 vs ≤4) and CTemphysema score (moderate to severe vs mild) showed no statistically significant interaction (P = 0.60 for the interaction term).
Statistical Analysis Statistical analyses were performed using Statistical Package for the Social Sciences software (IBM SPSS Statistics version 20). Coronary artery calcification ordinal visual scale was stratified
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DISCUSSION This cross-sectional study found a high prevalence of CAC and emphysema in patients with moderate to severe COPD. © 2014 Lippincott Williams & Wilkins
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CAC on CT Correlates With Mortality in COPD
TABLE 1. Summary of Demographic and Clinical Features Parameter (No. Continuous Values are Given as Mean ± SD or Median (IQR) Demographics Age, y Sex, n (%) Male Female BMI, kg/m2 Smoking status, n (%) Current smoker Ex-smoker Lifelong nonsmoker Duration smoked, y Pack-years smoked, pack-years Alpha-1 antitrypsin phenotype, n = 92 (42%) MM, n (%) Phenotype other than MM, n (%) Echocardiography Left ventricular ejection fraction, n = 127 (%) Right ventricular systolic pressure, n = 79 (mm Hg) eGFR (mL/min per 1.73 m2) Lung function FEV1 percentage predicted FEV1/VC percentage predicted KCO percentage predicted Six-minute walk test distance (m), n = 63 (31.5%) Cardiovascular risk factors, n (%) Hypertension Hyperlipidaemia Chronic kidney disease Diabetes Family history of premature cardiac death Cardiovascular comorbidity, n (%) Angina Myocardial infarction Heart failure Peripheral vascular disease Coronary artery calcification visual score, n (%) 0 1–3 4–6 7–12 Emphysema Total emphysema severity score Mild, 16, n (%) Heterogeneity, n (%) Homogenous Heterogeneous Craniocaudal distribution, n (%) Diffuse Upper lobe predominant Lower lobe predominant
All Patients (n = 200)
Range
68.6 ± 9.8
28.7–90.4
112 (56%) 88 (44%) 25.5 ± 5.5
14.6–44.8
39 (19%) 153 (77%) 8 (4%) 42.4 ± 13.8 50.0 (31.5–71.6)
0–70 0–234.5
78 (85%) 14 (15%) 61.0 ± 11.2 45.6 ± 13.7 70.0 ± 22.9
22–81 18–96 14–141
46.5 ± 19.2 42.8 (31.0–54.6) 51.8 (37.7–68.0) 350 (255–425)
15.8–103.1 19.9–70.0 14.9–138.4 100–525
96 (48%) 65 (32%) 29 (14%) 18 (9%) 18 (9%) 35 (17%) 25 (12%) 19 (9%) 13 (6%) 25 (13%) 70 (35%) 54 (27%) 51 (25%) 14 (7–22) 50 (25%) 60 (35%) 89 (44.5%)
0–24
144 (72%) 55 (28%) 93 (46%) 85 (43%) 21 (11%)
IQR, interquartile range; MM, normal M gene.
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O’Hare et al
associated with higher levels of CAC, after adjusting for known predictors of increased CAC. The findings highlight the interrelationship between CAC and emphysema and suggest that scoring of their severity on CT chest scans could be of prognostic value in patients with COPD.
TABLE 2. Correlations Between CAC and Known Cardiac Risk Factors Correlation With Total CAC Score Age, y BMI, kg/m2 Pack-years smoked (pack-years) Cigarettes per day Smoking duration, y Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg eGFR, mL/min per 1.73 m2 LVEF, % RVSP, mm Hg
Spearmanρ Correlation Coefficient*
P
0.38 0.03 0.09
4)
95% CI Parameter Age (>69.9 vs ≤69.9 y) Sex (male vs female) Smoking Pack years smoked (>50 vs ≤50 pack-years) Duration smoked (>42 vs ≤42 y) Lung function FEV1 percentage predicted (69.9 y vs ≤69.9 y) Sex (female vs male) CAC (5–12 vs 0–4) CT emphysema severity (moderate to severe vs mild) Angina Heart failure Peripheral vascular disease
clinical teams treating patients with chronic lung disease. We show here that CAC severity scoring (as opposed to ascertainment of presence or absence) has the potential to provide clinically important, prognostic information for patients with COPD, without the use of electrocardiographically gated acquisition or specialized cardiac software. Visual CT emphysema index was predictive of all-cause mortality in our population of patients with COPD. This result supports the work by others who have demonstrated that emphysema, either visually or quantitatively assessed on CT, is predictive of respiratory mortality in patients with various stages of COPD.29,30 Similarly to CAC, our findings and those of others advocate the importance of detecting and quantifying emphysema in those patients with COPD who have had CT imaging, in light of its prognostic significance. It remains to be tested whether it would be useful to perform CT imaging in all moderate to severe patients with COPD, either for COPD diagnostic/prognostic purposes or for lung cancer screening, or whether CAC score could enhance established prognostic indices such as the body-mass index, airflow obstruction, dyspnoea, and exercise capacity index (BODE).31
Methodological Considerations and Limitations We used published visual scores for CAC12 and emphysema.18,19 Although we used a visual score, we found an excellent interobserver reproducibility between the 2 readers. We could not prospectively assess postbronchodilator spirometry and were therefore unable to stratify the population according to the Global Obstructive Lung Disease stages of COPD. Although we could not calculate the Framingham risk score for cardiovascular disease, important cardiac diseases and risk factors were captured and, as expected, found to be associated with CAC.25,26,32 In addition, patients with coronary artery stents or those who had undergone coronary artery bypass graft surgery were excluded, potentially underestimating the value of CAC scoring in the COPD population. Because ungated CT images with varying slice thickness were used, there is the potential to miss subtle calcification reducing the precision of the CAC OVS. However, because prognosis is determined by CAC score categories, the clinical significance should not be affected. The effects of slice thickness, movement artifact, and volume averaging are further accounted for by the organization of CAC into categories of severity. The exact cause of death was unable to be ascertained; therefore, allcause mortality was used as the main mortality outcome.
CONCLUSIONS In conclusion, CAC and emphysema are both highly prevalent on CT imaging of patients with moderate to severe COPD. We have shown that visual CAC severity and visual CT emphysema index are related and are both independent predictors of
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all-cause mortality in patients with COPD. The potential of using visual CAC severity to noninvasively screen for CAD in patients with COPD should be prospectively investigated.
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