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Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease
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Respiratory Medicine (2014) xx, 1e7
Available online at www.sciencedirect.com
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Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease Stephanie Shin a, Christopher S. King b, A. Whitney Brown b, Maria C. Albano c, Melany Atkins c, Michael J. Sheridan b, Shahzad Ahmad b, Kelly M. Newton d, Nargues Weir b, Oksana A. Shlobin b, Steven D. Nathan b,* a
Pulmonary & Critical Care Medicine, University of California San Diego, San Diego, CA, USA Advanced Lung Disease and Lung Transplant Program, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA c Fairfax Radiological Consultants, Falls Church, VA, USA d Department of Medicine, Division of Critical Care and Hospital Medicine, National Jewish Health, Denver, CO, USA b
Received 9 June 2014; accepted 25 August 2014
KEYWORDS Chronic obstructive pulmonary disease; Pulmonary to aortic artery diameter ratio; Pulmonary hypertension; Pulmonary artery diameter
Summary Rationale: The relationship between pulmonary artery size with underlying pulmonary hypertension and mortality remains to be determined in COPD. We sought to evaluate the relationships in a cohort of patients with advanced COPD. Methods: A retrospective study of advanced COPD patients evaluated between 1998 and 2012 was conducted at a tertiary care center. Patients with chest computed tomography images and right heart catheterizations formed the study cohort. The diameters of the pulmonary artery and ascending aorta were measured by independent observers and compared to pulmonary artery pressures. Intermediate-term mortality was evaluated for the 24-month period subsequent to the respective studies. Cox proportional hazards model was used to determine independent effects of variables on survival.
Abbreviations: COPD, chronic obstructive pulmonary disease; PA:A, pulmonary to aortic artery diameter ratio; PH, pulmonary hypertension; FEV1, forced expiratory volume in 1 second; DLco, diffusing capacity for carbon monoxide; CT, computed tomography; mPAP, mean pulmonary artery pressure; RHC, right heart catheterization; sPAP, systolic pulmonary artery pressure; dPAP, diastolic pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; HR, hazard ratio; PAD, pulmonary artery diameter; AUC, area under the ROC curve. * Corresponding author. Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, VA 22042, USA. Tel.: þ1 703 776 3610; fax: þ1 703 776 3515. E-mail address: [email protected] (S.D. Nathan). http://dx.doi.org/10.1016/j.rmed.2014.08.009 0954-6111/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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S. Shin et al. Results: There were 65 subjects identified, of whom 38 (58%) had pulmonary hypertension. Patients with and without pulmonary hypertension had mean pulmonary artery diameters of 34.4 mm and 29.1 mm, respectively (p Z 0.0003). The mean PA:A ratio for those with and without pulmonary hypertension was 1.05 and 0.87, respectively (p Z 0.0003). The PA:A ratio was an independent predictor of mortality with a reduced survival in those with a PA:A >1 (p Z 0.008). Conclusions: The PA:A ratio is associated with underlying pulmonary hypertension in patients with COPD and is an independent predictor of mortality. This readily available measurement may be a valuable non-invasive screening tool for underlying pulmonary hypertension in COPD patients and appears to impart important independent prognostic information. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States [1]. Known risk factors for mortality include the forced expiratory volume in 1 second (FEV1), arterial blood gas values and age [2]. Recent studies have also demonstrated that smoking status, anemia, and reductions in lean body mass may be associated with reduced survival in this population [2e4]. Despite the ready availability of these parameters, the outcomes of COPD patients are still notoriously difficult to predict. Pulmonary hypertension (PH) frequently complicates the course of patients with advanced COPD [5]. The presence of PH may be important to identify, as these patients tend to have greater oxygen needs, reduced functional ability, an apparent increased risk of acute exacerbations and an increased risk of mortality [5e7]. Indeed, areas on the composite BODE index performs well as a prognostic indicator could be attributable to its latter two components which may be affected by the presence of underlying PH. It is difficult to predict the presence of underlying PH based on lung function alone given the lack of a clear relationship between the severity of PH and spirometric indices. Screening tools that have been touted include serologic markers (brain natriuretic peptide/N-terminal pro b-type natriuretic peptide), the six-minute walk test and a reduced single-breath diffusing capacity for carbon monoxide (DLco) [8e11]. The most commonly used screening tool for PH is echocardiography. However, this is inherently inaccurate, especially in patients with COPD, where severe hyperinflation often hinders the attainment of an adequate window [12]. Prior studies suggest a relationship between the pulmonary arterial (PA) diameter and PH in patients with various underlying disorders [13,14]. There is data to suggest a relationship between PA size and acute exacerbations of COPD [13,15]. A recent smaller retrospective study presented data that suggests a correlation between pulmonary artery size on computed tomography (CT) images and pulmonary artery pressures on right heart catheterization (RHC) [16]. However, the prognostic value of PA size remains unclear and uninvestigated in patients with COPD. We therefore sought to validate the relationship between PA:A ratio and PA diameter size on CT imaging with the mean pulmonary artery pressure (mPAP) measured
by RHC in a cohort of COPD patients. In addition, we also sought to evaluate the prognostic ability of these readily available CT measurements in comparison to other more commonly established COPD prognostic indicators, including the FEV1 and mPAP.
Methods Patients with a primary diagnosis of COPD evaluated in an Advanced Lung Disease clinic for potential lung transplantation or volume reduction surgery between January 1998 and December 2012 were identified. Only those with available chest CT scans and contemporaneous RHC data were eligible to be included in this study. For those with PH, a comprehensive evaluation was undertaken to exclude other potential contributors to their PH. The PA:A ratio was calculated from the diameters of the PA and ascending aorta measured by five of the authors who independently and in a blinded fashion read the CT scans of all the patients. The PA segment was measured at the bifurcation with the greatest diameter of the aorta measured at the same level [15]. These were compared to the mPAP, systolic pulmonary artery pressure (sPAP), and the diastolic pulmonary artery pressure (dPAP), as measured on RHC. A subgroup analysis, excluding those with ascending thoracic aorta dilation/aneurysm and pulmonary capillary wedge pressures (PCWP) > 15 mmHg on RHC [World Health Organization (WHO) Group II PH], was performed [17]. The definition of ascending thoracic aorta aneurysm/dilation accounted for the effects of age and gender [18]. Transplant-free survival based on the PA segment size, the PA:A ratio, the mPAP and the FEV1 were evaluated over the 2-year period subsequent to the respective studies. Time zero for each patient from which survival was calculated was the date of the CT scan, the date of the RHC and date of the pulmonary function tests (PFTs), respectively. Patients were censored at the time of death or lung transplantation. The study was approved by the Inova institutional review board (IRB00002273).
Statistics All demographic and PFT data are presented as means if continuous, or as frequencies if categorical with standard
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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Pulmonary artery size as a predictor of PH and outcomes in patients with COPD deviations (SD). Parametric statistics were used where the data was confirmed to have a normal distribution. The median values of PA diameter and PA:A ratio measured by five authors were used. The intraclass correlation coefficient was used to assess the level of agreement among readers for the continuous variables of PA diameter and PA:A ratio [19,20]. Pearson’s correlation coefficient was utilized to compare pulmonary diameter and PA:A ratio to the pulmonary pressures. Comparisons of measurements between two groups were performed with unpaired t-tests. A receiver operating characteristic (ROC) analysis was completed to assess the performance characteristics of the PA:A ratio and PA diameter for the detection of PH. Only all-cause mortality was considered in this study. Transplant-free survival analyses were performed with KaplaneMeier curves and log-rank testing. A multivariable Cox proportional hazards analysis was performed to assess the association between PA:A ratio and death or transplantation by controlling for potential confounding factors including patient age, BMI (body mass index) and FEV1%. Hazard ratios (HR) were attained from the Cox model. All calculations were performed using SAS software (v9.2, SAS Institute; Cary, NC) and IBM SPSS software (v20.0, IBM; Armonk, NY).
Results We initially identified 94 COPD patients who were evaluated over the 14-year period in whom PFTs, chest CT images and RHC data were available. There were 65 patients in whom the CT scan to RHC time interval was less than 3 months apart that formed the final study population. The demographics and lung function of the group are shown in Table 1. The patients were divided into two groups based on those with (mPAP 25 mmHg) and without PH Table 1 Patient characteristics stratified by the presence of pulmonary hypertension. Demographic and PFTa variables
mPAP <25 mmHg (N Z 27)
MPAP 25 mmHg (N Z 38)
p Value
Age (years) BMI (kg/m2) Female gender (n) FVC (% predicted) FEV1 (% predicted) FEV1/FVC (%) TLC (% predicted) DLco (% predicted)
57 25 15 56 24 33 126 36
61 28 17 63 37 47 111 30
0.02 0.04 0.40 0.27 0.01 <0.01 0.19 0.05
Data presented as means. Significance tests for comparisons between groups based on 2-sample independent t-test for continuous patient characteristics and Pearson’s chi-square test for categorical patient characteristics. Abbreviations: PFT Z pulmonary function test; mPAP Z mean pulmonary artery pressure; BMI Z body mass index; FVC Z forced vital capacity; FEV1 Z forced expiratory volume in 1 second; TLC Z total lung capacity; DLco Z diffusing capacity of the lung for carbon monoxide. a PFT missing patient data: FEV1 (n Z 4); FVC (n Z 4); TLC (n Z 17); DLco (n Z 11).
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(mPAP < 25 mmHg). For the group with PH, an evaluation for other causes revealed one patient with obstructive sleep apnea, none with systolic heart failure, and 17 patients in whom the PCWP was >15 mmHg on RHC. The baseline characteristics between the two subgroups were not statistically significant with the exception of the age, BMI, FEV1 and DLco. Specifically, the FEV1 was higher in the PH group, while the DLco was lower. The median time interval between the chest CT and RHC was 0.7 months (range: 0.03e2.83 months; mean: 0.89 months). The overall mean PA diameter and PA:A ratio were 34.0 mm (95% CI [32.6e35.5]) and 1.02 (95% CI [0.97e1.06]), respectively. The intraclass correlation coefficient for both PA:A ratio and PA diameter amongst the five readers showed excellent agreement with values of 0.94 (95% CI [0.91e0.96], p < 0.01) and 0.93 (95% CI [0.90e0.96], p < 0.01), respectively. The mean sPAP, dPAP and mPAP of the cohort were 46 mmHg, 20 mmHg and 31 mmHg, respectively. As shown in Table 2, patients with mPAP <25 mmHg (n Z 27) had a mean PA diameter of 29.1 mm compared to 34.4 mm in those with mPAP 25 mmHg (n Z 38), (p Z 0.0003). The mean PA:A ratio for patients with mPAP <25 mmHg was 0.87 versus 1.05 in those with mPAP 25 mmHg (p Z 0.0003). The mean PA:A ratio and PA diameter based on PH severity is shown in Table 3. There was a significant correlation between the pulmonary pressures measured on RHC and PA size on CT scans. In this regard, the mPAP and PA:A ratio showed the best correlation with a coefficient (R) of 0.60 (p < 0.001). The correlation between the sPAP and dPAP with the pulmonary size was weaker with values of 0.53, 0.55 for the PA:A ratio and 0.55, 0.54 for the PA diameter, respectively (both, p < 0.001). Fig. 1 demonstrates the area under the ROC curves (AUC) of PA diameter and PA:A ratio for the detection of PH as 0.78 (CI 0.66e0.90, p < 0.001) and 0.79 (CI 0.68e0.90, p < 0.001), respectively. The sensitivity and specificity for PH detection using a PA:A ratio >1 was 50% and 93%, respectively. The negative predictive value and positive predictive value of this cut point were 57% and 90%, respectively. Transplant-free survival analyses over 24 months stratified by PA:A ratio, PA diameter, mPAP and FEV1 are shown in Fig. 2(A)e(D). Those with PA:A ratio >1 had worse survival compared to those with PA:A 1 (Fig. 2(A), p Z 0.008), while the PA diameter trended towards a survival difference (Fig. 2(B), p Z 0.02). Subjects with mPAP 25 mmHg also had reduced survivals compared to those without PH on RHC (Fig. 2(C), p Z 0.009). The survival analysis based on the median FEV1 demonstrated no statistical significance (Fig. 2(D), p Z 0.32). Furthermore, survival decreased as the mPAP increased (Fig. 3). The subgroup analysis of patients with both a normal aortic size and a PCWP 15 mmHg (N Z 49) showed similar trends in survival as depicted in Fig. 4(A)e(D). The Cox proportional hazards model (Table 4) demonstrated that the PA:A ratio >1 was the only significant predictor of transplant-free survival in both unadjusted and adjusted analyses (HR Z 4.88; 95% CI [1.75e13.6], p Z 0.002) and (HR Z 5.05; 95% CI [1.63e15.6], p Z 0.005), respectively. The other variables included in the model (age, BMI, FEV1) were not statistically significant
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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S. Shin et al. Table 2
Pulmonary artery characteristics stratified by the presence of pulmonary hypertension.
Group
Mean mPAP (mmHg)
(95% CI)
Mean ascending aorta (mm)
(95% CI)
Mean PA diameter (mm)
(95% CI)
Mean PA:A ratio
(95% CI)
mPAP < 25 mmHg (N Z 27) mPAP 25 mmHg (N Z 38) p Value
20.6
(19.5e21.5)
33.4
(32.0e34.7)
29.1
(27.5e30.8)
0.87
(0.83e0.91)
37.8
(33.61e41.91)
33.3
(32.0e34.6)
34.4
(32.4e36.3)
1.05
(0.98e1.12)
<0.0001
0.93
0.0003
0.0003
Data presented as means with 95% confidence intervals. Significance tests for comparisons between groups based on 2-sample t-test. Abbreviations: mPAP Z mean pulmonary artery pressure; CI Z confidence interval; PA Z pulmonary artery; PA:A ratio Z pulmonary artery to aorta diameter ratio.
predictors of mortality. The PA diameter and mPAP were not included in the Cox analysis due to their colinearity with the PA:A ratio with correlation coefficients of 0.80 and 0.60, respectively.
Discussion In this study we demonstrate that a PA:A ratio >1 is an independent predictor of intermediate-term transplantfree survival in COPD patients and also confirm the correlation between PA:A ratio and mPAP. Prior studies have demonstrated that the PA:A ratio measured on CT does correlate with PA pressures, but the sample size of COPD patients studied was smaller than in our current study [13,16,21,22]. A link between PA:A ratio >1 and the risk for acute exacerbations of COPD has previously been described [15]. However, to our knowledge, our study is the first to establish an association between the PA:A ratio and mortality in COPD. The accurate estimation of prognosis in COPD is important for many reasons. Not only does it afford clinicians information to appropriately counsel patients and their families regarding healthcare and end-of-life decisions, but it also enables the optimal timing of lung transplantation with implications for both individual patients and optimal lung resource utilization. Unfortunately, prognostication in COPD remains an imperfect science. Traditionally, prognosis was thought to be primarily based on the severity of airflow obstruction as measured by the FEV1. However this physiologic measurement fails to take into consideration the systemic effects of COPD and the variable outcomes associated with discrete phenotypes. Currently, the BODE index, (which incorporates body mass index, the degree of airflow obstruction,
breathlessness as measured by the modified Medical Research Council dyspnea scale and functional status on six-minute walk test), is the most commonly used prognostic tool [23]. Although this has served clinicians well, ongoing efforts to further refine prognostication in COPD remain necessary. In this regard, the PA:A ratio may represent a valuable ancillary prognostic indicator. Given the positive results of the recent National Lung Screening Trial and subsequent endorsement of low dose CT screening for lung cancer in high-risk patients by a number of organizations, it is likely that many more COPD patients will have CT data available [24,25]. The measurements described appear to be practical for clinicians to perform without the use of intravascular contrast material or special software. Our study is also unique in that we have also demonstrated excellent intraclass correlation among readers with a broad range of clinical experience including a medical resident, a pulmonary fellow, two pulmonologists and a radiologist. This further attests to the value and ease
Table 3 Pulmonary artery size stratified by mean pulmonary artery pressure. mPAP PH severity N (%) (mmHg) 24 25e34 35
Normal PH Severe PH
Mean Mean PA PA:A ratio diameter (mm)
27 (42%) 0.87 21 (32%) 0.94 17 (26%) 1.18
29.1 31.5 37.9
Abbreviations: mPAP Z mean pulmonary artery pressure; PH Z pulmonary hypertension; PA:A Z pulmonary artery to aorta diameter ratio; PA Z pulmonary artery.
Figure 1 ROC curves for pulmonary artery diameter and pulmonary artery to aorta diameter ratio for the detection of PH in patients with severe COPD. Abbreviations: PA:A Z pulmonary artery to aorta diameter ratio, AUC Z area under the ROC curve.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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Pulmonary artery size as a predictor of PH and outcomes in patients with COPD
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Figure 2 Transplant-free survival of the COPD cohort based on (A) PA:A ratio > 1 (B) median PA diameter (C) mPAP (<25 mmHg, 25 mmHg) (D) median FEV1 for the 24-month period from the date of each respective study.
of implementing the measurement of this ratio on a routine basis. The PA:A ratio also demonstrated good positive predictive value for the presence of PH and may serve as a screen for patients who might benefit from information derived from a right heart catheterization. There are several possible explanations for the observed increase in mortality with an increasing PA:A ratio. It is possible that an increase in PA:A ratio serves as a surrogate for underlying PH, which may be responsible for the observed increase in mortality. PH is well recognized as being associated with increased mortality in COPD [26]. Indeed, our survival analysis based on PH severity did demonstrate increasing mortality with sequentially higher PA pressures, as has been demonstrated previously [27]. However, the fact that PH was not associated with mortality in our Cox hazards model raises the possibility that other factors may affect the PA diameter. For example, we cannot rule out that the previously demonstrated predilection to acute exacerbations of COPD with an increased
Figure 3 Transplant-free survival of the COPD cohort based on mPAP gradation (<25 mmHg; 25e34 mmHg; 35 mmHg) for the 24-month period from the date of the RHC.
PA:A ratio may have contributed to our demonstration of worsened outcomes [15]. Another consideration is that some of the PH observed is due to left-sided heart disease [28]. However, our subgroup analysis those without aortic dilation and elevated PCWPs showed similar relationships between the PA:A ratio and PA pressures on survival. Other conditions associated with PH such as obstructive sleep apnea and venous thromboembolism may have also impacted mortality. Also, the parenchymal lung disease itself may play a role influencing the vascular dimensions. However, it is doubtful that mechanical effects of the hyperinflated lungs would result in compression of the aorta. Similarly, it is unlikely that the surrounding emphysematous lung tissue would enable radial expansion of the PA segment. Our study has several limitations. The study population consists of severe COPD patients referred to a single tertiary institution limiting the applicability of our findings to broader groups of COPD patients. We limited our analysis to only those patients with CT and RHCs within 3 months but there was still a slight time interval between the CT and RHC in some of the patients. While this slight time lag might have impacted our analysis of the relationship between PA pressure and CT measurements, it did not impact our survival analyses since these were all calculated from the date of the respective studies. We arbitrarily chose two years of follow-up for our mortality analysis, since we felt that other interceding events might have an undue influence on outcomes over a longer period. We were limited in our ability to adjust for further variables (i.e. mPAP and DLco) due to colinearity and our small sample size; specifically, inclusion of additional variables would have compromised the overall strength of the Cox proportional hazards model. The narrow range of FEV1’s in our patient cohort together with the small sample size may explain this probable type 2 error where FEV1 was not associated with mortality.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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S. Shin et al.
Figure 4 Transplant-free survival analysis of COPD subgroup without aortic dilation/aneurysm or evidence of pulmonary venous hypertension as defined by PCWP >15 mmHg (N Z 49) based on: (A) PA:A ratio > 1; (B) median PA diameter; (C) mPAP gradation (<25 mmHg; 25e34 mmHg; 35 mmHg); (D) median FEV1. KaplaneMeier survival estimates over 24 months.
Table 4
Unadjusted and adjusted hazard ratios for death or transplant (N Z 65). Unadjusted analysis (N Z 65)
Age BMI (kg/m2) FEV1 (% predicted)a PA:A ratio >1
Adjusted analysis (N Z 61)
Hazard ratio
(95% CI)
p Value
Hazard ratio
(95% CI)
p Value
1.05 0.99 1.02 4.88
0.97e1.13 0.91e1.08 0.99e1.05 1.75e13.6
0.25 0.83 0.06 0.002
0.99 0.99 1.02 5.05
0.91e1.09 0.91e1.06 0.98e1.05 1.63e15.6
0.92 0.70 0.40 0.005
Based on Cox proportional hazards regression model adjusted for age, BMI, FEV1 and PA:A ratio >1. Abbreviations: CI Z confidence interval; PA:A Z pulmonary artery to aorta diameter ratio; BMI Z body mass index; mPAP Z mean pulmonary artery pressure; FEV1 Z forced expiratory volume in 1 second; DLco Z diffusing capacity for carbon monoxide. a 4 patients had missing FEV1 data that resulted N Z 61 for the unadjusted FEV1 and overall adjusted analysis.
In conclusion, the PA:A ratio is an easily obtainable measurement that can be performed on routine chest CT scans. The PA:A ratio correlates with the presence of PH and a PA:A ratio >1 is independently associated with increased mortality in COPD patients. Our study provides an important step toward improved prognostication in COPD. Ideally, the association between PA:A ratio and COPD mortality should be confirmed in future larger, multi-center studies including a wider spectrum of disease severity. Another aspect for future research is whether the addition of the PA:A ratio to known prognostic tools such as the BODE index might improve the accuracy of this or other predictive models.
Financial/nonfinancial disclosures No financial/nonfinancial disclosure to report for all authors (SS, CSK, AWB, MCA, MA, MJS, SA, KMN, NW, OAS, SDN).
Role of the sponsors No funding sources to report in the development of the research and manuscript.
Conflict of interest The authors declare that there is no conflict of interest.
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Pulmonary artery size as a predictor of PH and outcomes in patients with COPD [2] Hersh CP, DeMeo DL, AL-Ansari E, et al. Predictors of survival in severe, early onset COPD. Chest 2004;126(5):1443e52. [3] Piccioni P, Carla E, Bignamini E, et al. Predictors of survival in a group of patients with chronic airflow obstruction. J Clin Epidemiol 1998;51(7):547e55. [4] Celli BR, Cote CG, Lareau SC, Meek PM. Predictors of survival in COPD: more than just the FEV1. Respir Med 2008;102(Suppl. 1):S27e35. [5] Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest 1995;107(5):1193e8. [6] Barbera JA. Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. Pulm Circ 2013;3(1):160e4. [7] Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159(1):158e64. [8] Casserly B, Klinger JR. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent. Drug Des Devel Ther 2009;29(3):269e87. [9] Andersen CU, Mellemkjaer S, Nielsen-Kudsk JE, et al. Echocardiographic screening for pulmonary hypertension in stable COPD out-patients and NT-proBNP as a rule out test. COPD 2012;9(5):505e12. [10] Budev MM, Arroliga AC, Jennings CA. Diagnosis and evaluation of pulmonary hypertension. Cleve Clin J Med 2003;70(Suppl. 1):S9e17. [11] Farha S, Laskowski D, George D, et al. Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension. Respir Res 2013;14(1):6. [12] Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003;167(5): 735e40. [13] Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging 1999;14(4):270e8. [14] Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Medical College of Wisconsin Lung Transplant Group. Chest 1998;113(5):1250e6. [15] Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012;367(10):913e21.
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[16] Iyer AS, Wells JM, Vishin S, et al. CT measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest 2014;145(4): 824e32. [17] Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension Group 2: pulmonary hypertension due to left heart disease in the adult e a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2012;31(9):913e33. [18] Mao SS, Ahmadi N, Shah B, et al. Normal thoracic aorta diameter on cardiac computed tomography in healthy asymptomatic adults: impact of age and gender. Acad Radiol 2008;15(7):827e34. [19] Crewson PE. Reader agreement studies. Am J Roentgenol 2005;184(5):1391e7. [20] Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull 1971;76(5):378e82. [21] Devaraj A, Wells AU, Meister MG, Corte TJ, Wort SJ, Hansell DM. Detection of pulmonary hypertension with multidetector CT and echocardiography alone and in combination. Radiology 2010;254(2):609e16. [22] Perez-Enquix D, Morales P, Tomas JM, Vera F, Lioret RM. Computed tomographic screening of pulmonary arterial hypertension in candidates for lung transplantation screening. Transplant Proc 2007;39(7):2405e8. [23] 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(10):1005e12. [24] The National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with lowdose computed tomographic screening. N Engl J Med 2011; 365(5):395e409. [25] Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for lung cancer: a systematic review. J Am Med Assoc 2012;307(22):2418e29. [26] Cuttica MJ, Kalhan R, Shlobin OA, et al. Categorization and impact of pulmonary hypertension in patients with advanced COPD. Respir Med 2010;104(12):1877e82. [27] Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172(2):189e94. [28] Task force for diagnosis and treatment of pulmonary hypertension of European Society of Cardiology. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30(20):2493e537.
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Respiratory Medicine (2014) xx, 1e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/rmed
Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease Stephanie Shin a, Christopher S. King b, A. Whitney Brown b, Maria C. Albano c, Melany Atkins c, Michael J. Sheridan b, Shahzad Ahmad b, Kelly M. Newton d, Nargues Weir b, Oksana A. Shlobin b, Steven D. Nathan b,* a
Pulmonary & Critical Care Medicine, University of California San Diego, San Diego, CA, USA Advanced Lung Disease and Lung Transplant Program, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA c Fairfax Radiological Consultants, Falls Church, VA, USA d Department of Medicine, Division of Critical Care and Hospital Medicine, National Jewish Health, Denver, CO, USA b
Received 9 June 2014; accepted 25 August 2014
KEYWORDS Chronic obstructive pulmonary disease; Pulmonary to aortic artery diameter ratio; Pulmonary hypertension; Pulmonary artery diameter
Summary Rationale: The relationship between pulmonary artery size with underlying pulmonary hypertension and mortality remains to be determined in COPD. We sought to evaluate the relationships in a cohort of patients with advanced COPD. Methods: A retrospective study of advanced COPD patients evaluated between 1998 and 2012 was conducted at a tertiary care center. Patients with chest computed tomography images and right heart catheterizations formed the study cohort. The diameters of the pulmonary artery and ascending aorta were measured by independent observers and compared to pulmonary artery pressures. Intermediate-term mortality was evaluated for the 24-month period subsequent to the respective studies. Cox proportional hazards model was used to determine independent effects of variables on survival.
Abbreviations: COPD, chronic obstructive pulmonary disease; PA:A, pulmonary to aortic artery diameter ratio; PH, pulmonary hypertension; FEV1, forced expiratory volume in 1 second; DLco, diffusing capacity for carbon monoxide; CT, computed tomography; mPAP, mean pulmonary artery pressure; RHC, right heart catheterization; sPAP, systolic pulmonary artery pressure; dPAP, diastolic pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; HR, hazard ratio; PAD, pulmonary artery diameter; AUC, area under the ROC curve. * Corresponding author. Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, VA 22042, USA. Tel.: þ1 703 776 3610; fax: þ1 703 776 3515. E-mail address: [email protected] (S.D. Nathan). http://dx.doi.org/10.1016/j.rmed.2014.08.009 0954-6111/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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S. Shin et al. Results: There were 65 subjects identified, of whom 38 (58%) had pulmonary hypertension. Patients with and without pulmonary hypertension had mean pulmonary artery diameters of 34.4 mm and 29.1 mm, respectively (p Z 0.0003). The mean PA:A ratio for those with and without pulmonary hypertension was 1.05 and 0.87, respectively (p Z 0.0003). The PA:A ratio was an independent predictor of mortality with a reduced survival in those with a PA:A >1 (p Z 0.008). Conclusions: The PA:A ratio is associated with underlying pulmonary hypertension in patients with COPD and is an independent predictor of mortality. This readily available measurement may be a valuable non-invasive screening tool for underlying pulmonary hypertension in COPD patients and appears to impart important independent prognostic information. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States [1]. Known risk factors for mortality include the forced expiratory volume in 1 second (FEV1), arterial blood gas values and age [2]. Recent studies have also demonstrated that smoking status, anemia, and reductions in lean body mass may be associated with reduced survival in this population [2e4]. Despite the ready availability of these parameters, the outcomes of COPD patients are still notoriously difficult to predict. Pulmonary hypertension (PH) frequently complicates the course of patients with advanced COPD [5]. The presence of PH may be important to identify, as these patients tend to have greater oxygen needs, reduced functional ability, an apparent increased risk of acute exacerbations and an increased risk of mortality [5e7]. Indeed, areas on the composite BODE index performs well as a prognostic indicator could be attributable to its latter two components which may be affected by the presence of underlying PH. It is difficult to predict the presence of underlying PH based on lung function alone given the lack of a clear relationship between the severity of PH and spirometric indices. Screening tools that have been touted include serologic markers (brain natriuretic peptide/N-terminal pro b-type natriuretic peptide), the six-minute walk test and a reduced single-breath diffusing capacity for carbon monoxide (DLco) [8e11]. The most commonly used screening tool for PH is echocardiography. However, this is inherently inaccurate, especially in patients with COPD, where severe hyperinflation often hinders the attainment of an adequate window [12]. Prior studies suggest a relationship between the pulmonary arterial (PA) diameter and PH in patients with various underlying disorders [13,14]. There is data to suggest a relationship between PA size and acute exacerbations of COPD [13,15]. A recent smaller retrospective study presented data that suggests a correlation between pulmonary artery size on computed tomography (CT) images and pulmonary artery pressures on right heart catheterization (RHC) [16]. However, the prognostic value of PA size remains unclear and uninvestigated in patients with COPD. We therefore sought to validate the relationship between PA:A ratio and PA diameter size on CT imaging with the mean pulmonary artery pressure (mPAP) measured
by RHC in a cohort of COPD patients. In addition, we also sought to evaluate the prognostic ability of these readily available CT measurements in comparison to other more commonly established COPD prognostic indicators, including the FEV1 and mPAP.
Methods Patients with a primary diagnosis of COPD evaluated in an Advanced Lung Disease clinic for potential lung transplantation or volume reduction surgery between January 1998 and December 2012 were identified. Only those with available chest CT scans and contemporaneous RHC data were eligible to be included in this study. For those with PH, a comprehensive evaluation was undertaken to exclude other potential contributors to their PH. The PA:A ratio was calculated from the diameters of the PA and ascending aorta measured by five of the authors who independently and in a blinded fashion read the CT scans of all the patients. The PA segment was measured at the bifurcation with the greatest diameter of the aorta measured at the same level [15]. These were compared to the mPAP, systolic pulmonary artery pressure (sPAP), and the diastolic pulmonary artery pressure (dPAP), as measured on RHC. A subgroup analysis, excluding those with ascending thoracic aorta dilation/aneurysm and pulmonary capillary wedge pressures (PCWP) > 15 mmHg on RHC [World Health Organization (WHO) Group II PH], was performed [17]. The definition of ascending thoracic aorta aneurysm/dilation accounted for the effects of age and gender [18]. Transplant-free survival based on the PA segment size, the PA:A ratio, the mPAP and the FEV1 were evaluated over the 2-year period subsequent to the respective studies. Time zero for each patient from which survival was calculated was the date of the CT scan, the date of the RHC and date of the pulmonary function tests (PFTs), respectively. Patients were censored at the time of death or lung transplantation. The study was approved by the Inova institutional review board (IRB00002273).
Statistics All demographic and PFT data are presented as means if continuous, or as frequencies if categorical with standard
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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Pulmonary artery size as a predictor of PH and outcomes in patients with COPD deviations (SD). Parametric statistics were used where the data was confirmed to have a normal distribution. The median values of PA diameter and PA:A ratio measured by five authors were used. The intraclass correlation coefficient was used to assess the level of agreement among readers for the continuous variables of PA diameter and PA:A ratio [19,20]. Pearson’s correlation coefficient was utilized to compare pulmonary diameter and PA:A ratio to the pulmonary pressures. Comparisons of measurements between two groups were performed with unpaired t-tests. A receiver operating characteristic (ROC) analysis was completed to assess the performance characteristics of the PA:A ratio and PA diameter for the detection of PH. Only all-cause mortality was considered in this study. Transplant-free survival analyses were performed with KaplaneMeier curves and log-rank testing. A multivariable Cox proportional hazards analysis was performed to assess the association between PA:A ratio and death or transplantation by controlling for potential confounding factors including patient age, BMI (body mass index) and FEV1%. Hazard ratios (HR) were attained from the Cox model. All calculations were performed using SAS software (v9.2, SAS Institute; Cary, NC) and IBM SPSS software (v20.0, IBM; Armonk, NY).
Results We initially identified 94 COPD patients who were evaluated over the 14-year period in whom PFTs, chest CT images and RHC data were available. There were 65 patients in whom the CT scan to RHC time interval was less than 3 months apart that formed the final study population. The demographics and lung function of the group are shown in Table 1. The patients were divided into two groups based on those with (mPAP 25 mmHg) and without PH Table 1 Patient characteristics stratified by the presence of pulmonary hypertension. Demographic and PFTa variables
mPAP <25 mmHg (N Z 27)
MPAP 25 mmHg (N Z 38)
p Value
Age (years) BMI (kg/m2) Female gender (n) FVC (% predicted) FEV1 (% predicted) FEV1/FVC (%) TLC (% predicted) DLco (% predicted)
57 25 15 56 24 33 126 36
61 28 17 63 37 47 111 30
0.02 0.04 0.40 0.27 0.01 <0.01 0.19 0.05
Data presented as means. Significance tests for comparisons between groups based on 2-sample independent t-test for continuous patient characteristics and Pearson’s chi-square test for categorical patient characteristics. Abbreviations: PFT Z pulmonary function test; mPAP Z mean pulmonary artery pressure; BMI Z body mass index; FVC Z forced vital capacity; FEV1 Z forced expiratory volume in 1 second; TLC Z total lung capacity; DLco Z diffusing capacity of the lung for carbon monoxide. a PFT missing patient data: FEV1 (n Z 4); FVC (n Z 4); TLC (n Z 17); DLco (n Z 11).
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(mPAP < 25 mmHg). For the group with PH, an evaluation for other causes revealed one patient with obstructive sleep apnea, none with systolic heart failure, and 17 patients in whom the PCWP was >15 mmHg on RHC. The baseline characteristics between the two subgroups were not statistically significant with the exception of the age, BMI, FEV1 and DLco. Specifically, the FEV1 was higher in the PH group, while the DLco was lower. The median time interval between the chest CT and RHC was 0.7 months (range: 0.03e2.83 months; mean: 0.89 months). The overall mean PA diameter and PA:A ratio were 34.0 mm (95% CI [32.6e35.5]) and 1.02 (95% CI [0.97e1.06]), respectively. The intraclass correlation coefficient for both PA:A ratio and PA diameter amongst the five readers showed excellent agreement with values of 0.94 (95% CI [0.91e0.96], p < 0.01) and 0.93 (95% CI [0.90e0.96], p < 0.01), respectively. The mean sPAP, dPAP and mPAP of the cohort were 46 mmHg, 20 mmHg and 31 mmHg, respectively. As shown in Table 2, patients with mPAP <25 mmHg (n Z 27) had a mean PA diameter of 29.1 mm compared to 34.4 mm in those with mPAP 25 mmHg (n Z 38), (p Z 0.0003). The mean PA:A ratio for patients with mPAP <25 mmHg was 0.87 versus 1.05 in those with mPAP 25 mmHg (p Z 0.0003). The mean PA:A ratio and PA diameter based on PH severity is shown in Table 3. There was a significant correlation between the pulmonary pressures measured on RHC and PA size on CT scans. In this regard, the mPAP and PA:A ratio showed the best correlation with a coefficient (R) of 0.60 (p < 0.001). The correlation between the sPAP and dPAP with the pulmonary size was weaker with values of 0.53, 0.55 for the PA:A ratio and 0.55, 0.54 for the PA diameter, respectively (both, p < 0.001). Fig. 1 demonstrates the area under the ROC curves (AUC) of PA diameter and PA:A ratio for the detection of PH as 0.78 (CI 0.66e0.90, p < 0.001) and 0.79 (CI 0.68e0.90, p < 0.001), respectively. The sensitivity and specificity for PH detection using a PA:A ratio >1 was 50% and 93%, respectively. The negative predictive value and positive predictive value of this cut point were 57% and 90%, respectively. Transplant-free survival analyses over 24 months stratified by PA:A ratio, PA diameter, mPAP and FEV1 are shown in Fig. 2(A)e(D). Those with PA:A ratio >1 had worse survival compared to those with PA:A 1 (Fig. 2(A), p Z 0.008), while the PA diameter trended towards a survival difference (Fig. 2(B), p Z 0.02). Subjects with mPAP 25 mmHg also had reduced survivals compared to those without PH on RHC (Fig. 2(C), p Z 0.009). The survival analysis based on the median FEV1 demonstrated no statistical significance (Fig. 2(D), p Z 0.32). Furthermore, survival decreased as the mPAP increased (Fig. 3). The subgroup analysis of patients with both a normal aortic size and a PCWP 15 mmHg (N Z 49) showed similar trends in survival as depicted in Fig. 4(A)e(D). The Cox proportional hazards model (Table 4) demonstrated that the PA:A ratio >1 was the only significant predictor of transplant-free survival in both unadjusted and adjusted analyses (HR Z 4.88; 95% CI [1.75e13.6], p Z 0.002) and (HR Z 5.05; 95% CI [1.63e15.6], p Z 0.005), respectively. The other variables included in the model (age, BMI, FEV1) were not statistically significant
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S. Shin et al. Table 2
Pulmonary artery characteristics stratified by the presence of pulmonary hypertension.
Group
Mean mPAP (mmHg)
(95% CI)
Mean ascending aorta (mm)
(95% CI)
Mean PA diameter (mm)
(95% CI)
Mean PA:A ratio
(95% CI)
mPAP < 25 mmHg (N Z 27) mPAP 25 mmHg (N Z 38) p Value
20.6
(19.5e21.5)
33.4
(32.0e34.7)
29.1
(27.5e30.8)
0.87
(0.83e0.91)
37.8
(33.61e41.91)
33.3
(32.0e34.6)
34.4
(32.4e36.3)
1.05
(0.98e1.12)
<0.0001
0.93
0.0003
0.0003
Data presented as means with 95% confidence intervals. Significance tests for comparisons between groups based on 2-sample t-test. Abbreviations: mPAP Z mean pulmonary artery pressure; CI Z confidence interval; PA Z pulmonary artery; PA:A ratio Z pulmonary artery to aorta diameter ratio.
predictors of mortality. The PA diameter and mPAP were not included in the Cox analysis due to their colinearity with the PA:A ratio with correlation coefficients of 0.80 and 0.60, respectively.
Discussion In this study we demonstrate that a PA:A ratio >1 is an independent predictor of intermediate-term transplantfree survival in COPD patients and also confirm the correlation between PA:A ratio and mPAP. Prior studies have demonstrated that the PA:A ratio measured on CT does correlate with PA pressures, but the sample size of COPD patients studied was smaller than in our current study [13,16,21,22]. A link between PA:A ratio >1 and the risk for acute exacerbations of COPD has previously been described [15]. However, to our knowledge, our study is the first to establish an association between the PA:A ratio and mortality in COPD. The accurate estimation of prognosis in COPD is important for many reasons. Not only does it afford clinicians information to appropriately counsel patients and their families regarding healthcare and end-of-life decisions, but it also enables the optimal timing of lung transplantation with implications for both individual patients and optimal lung resource utilization. Unfortunately, prognostication in COPD remains an imperfect science. Traditionally, prognosis was thought to be primarily based on the severity of airflow obstruction as measured by the FEV1. However this physiologic measurement fails to take into consideration the systemic effects of COPD and the variable outcomes associated with discrete phenotypes. Currently, the BODE index, (which incorporates body mass index, the degree of airflow obstruction,
breathlessness as measured by the modified Medical Research Council dyspnea scale and functional status on six-minute walk test), is the most commonly used prognostic tool [23]. Although this has served clinicians well, ongoing efforts to further refine prognostication in COPD remain necessary. In this regard, the PA:A ratio may represent a valuable ancillary prognostic indicator. Given the positive results of the recent National Lung Screening Trial and subsequent endorsement of low dose CT screening for lung cancer in high-risk patients by a number of organizations, it is likely that many more COPD patients will have CT data available [24,25]. The measurements described appear to be practical for clinicians to perform without the use of intravascular contrast material or special software. Our study is also unique in that we have also demonstrated excellent intraclass correlation among readers with a broad range of clinical experience including a medical resident, a pulmonary fellow, two pulmonologists and a radiologist. This further attests to the value and ease
Table 3 Pulmonary artery size stratified by mean pulmonary artery pressure. mPAP PH severity N (%) (mmHg) 24 25e34 35
Normal PH Severe PH
Mean Mean PA PA:A ratio diameter (mm)
27 (42%) 0.87 21 (32%) 0.94 17 (26%) 1.18
29.1 31.5 37.9
Abbreviations: mPAP Z mean pulmonary artery pressure; PH Z pulmonary hypertension; PA:A Z pulmonary artery to aorta diameter ratio; PA Z pulmonary artery.
Figure 1 ROC curves for pulmonary artery diameter and pulmonary artery to aorta diameter ratio for the detection of PH in patients with severe COPD. Abbreviations: PA:A Z pulmonary artery to aorta diameter ratio, AUC Z area under the ROC curve.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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Pulmonary artery size as a predictor of PH and outcomes in patients with COPD
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Figure 2 Transplant-free survival of the COPD cohort based on (A) PA:A ratio > 1 (B) median PA diameter (C) mPAP (<25 mmHg, 25 mmHg) (D) median FEV1 for the 24-month period from the date of each respective study.
of implementing the measurement of this ratio on a routine basis. The PA:A ratio also demonstrated good positive predictive value for the presence of PH and may serve as a screen for patients who might benefit from information derived from a right heart catheterization. There are several possible explanations for the observed increase in mortality with an increasing PA:A ratio. It is possible that an increase in PA:A ratio serves as a surrogate for underlying PH, which may be responsible for the observed increase in mortality. PH is well recognized as being associated with increased mortality in COPD [26]. Indeed, our survival analysis based on PH severity did demonstrate increasing mortality with sequentially higher PA pressures, as has been demonstrated previously [27]. However, the fact that PH was not associated with mortality in our Cox hazards model raises the possibility that other factors may affect the PA diameter. For example, we cannot rule out that the previously demonstrated predilection to acute exacerbations of COPD with an increased
Figure 3 Transplant-free survival of the COPD cohort based on mPAP gradation (<25 mmHg; 25e34 mmHg; 35 mmHg) for the 24-month period from the date of the RHC.
PA:A ratio may have contributed to our demonstration of worsened outcomes [15]. Another consideration is that some of the PH observed is due to left-sided heart disease [28]. However, our subgroup analysis those without aortic dilation and elevated PCWPs showed similar relationships between the PA:A ratio and PA pressures on survival. Other conditions associated with PH such as obstructive sleep apnea and venous thromboembolism may have also impacted mortality. Also, the parenchymal lung disease itself may play a role influencing the vascular dimensions. However, it is doubtful that mechanical effects of the hyperinflated lungs would result in compression of the aorta. Similarly, it is unlikely that the surrounding emphysematous lung tissue would enable radial expansion of the PA segment. Our study has several limitations. The study population consists of severe COPD patients referred to a single tertiary institution limiting the applicability of our findings to broader groups of COPD patients. We limited our analysis to only those patients with CT and RHCs within 3 months but there was still a slight time interval between the CT and RHC in some of the patients. While this slight time lag might have impacted our analysis of the relationship between PA pressure and CT measurements, it did not impact our survival analyses since these were all calculated from the date of the respective studies. We arbitrarily chose two years of follow-up for our mortality analysis, since we felt that other interceding events might have an undue influence on outcomes over a longer period. We were limited in our ability to adjust for further variables (i.e. mPAP and DLco) due to colinearity and our small sample size; specifically, inclusion of additional variables would have compromised the overall strength of the Cox proportional hazards model. The narrow range of FEV1’s in our patient cohort together with the small sample size may explain this probable type 2 error where FEV1 was not associated with mortality.
Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009
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Figure 4 Transplant-free survival analysis of COPD subgroup without aortic dilation/aneurysm or evidence of pulmonary venous hypertension as defined by PCWP >15 mmHg (N Z 49) based on: (A) PA:A ratio > 1; (B) median PA diameter; (C) mPAP gradation (<25 mmHg; 25e34 mmHg; 35 mmHg); (D) median FEV1. KaplaneMeier survival estimates over 24 months.
Table 4
Unadjusted and adjusted hazard ratios for death or transplant (N Z 65). Unadjusted analysis (N Z 65)
Age BMI (kg/m2) FEV1 (% predicted)a PA:A ratio >1
Adjusted analysis (N Z 61)
Hazard ratio
(95% CI)
p Value
Hazard ratio
(95% CI)
p Value
1.05 0.99 1.02 4.88
0.97e1.13 0.91e1.08 0.99e1.05 1.75e13.6
0.25 0.83 0.06 0.002
0.99 0.99 1.02 5.05
0.91e1.09 0.91e1.06 0.98e1.05 1.63e15.6
0.92 0.70 0.40 0.005
Based on Cox proportional hazards regression model adjusted for age, BMI, FEV1 and PA:A ratio >1. Abbreviations: CI Z confidence interval; PA:A Z pulmonary artery to aorta diameter ratio; BMI Z body mass index; mPAP Z mean pulmonary artery pressure; FEV1 Z forced expiratory volume in 1 second; DLco Z diffusing capacity for carbon monoxide. a 4 patients had missing FEV1 data that resulted N Z 61 for the unadjusted FEV1 and overall adjusted analysis.
In conclusion, the PA:A ratio is an easily obtainable measurement that can be performed on routine chest CT scans. The PA:A ratio correlates with the presence of PH and a PA:A ratio >1 is independently associated with increased mortality in COPD patients. Our study provides an important step toward improved prognostication in COPD. Ideally, the association between PA:A ratio and COPD mortality should be confirmed in future larger, multi-center studies including a wider spectrum of disease severity. Another aspect for future research is whether the addition of the PA:A ratio to known prognostic tools such as the BODE index might improve the accuracy of this or other predictive models.
Financial/nonfinancial disclosures No financial/nonfinancial disclosure to report for all authors (SS, CSK, AWB, MCA, MA, MJS, SA, KMN, NW, OAS, SDN).
Role of the sponsors No funding sources to report in the development of the research and manuscript.
Conflict of interest The authors declare that there is no conflict of interest.
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Please cite this article in press as: Shin S, et al., Pulmonary artery size as a predictor of pulmonary hypertension and outcomes in patients with chronic obstructive pulmonary disease, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.08.009