Abstract
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). Little is known about the prevalence and clinical profiles of patients with COPD‐PH. We report the clinical characteristics, hemodynamic profiles, and prognosis in a large population of patients with COPD referred for right heart catheterization (RHC). We extracted data from all patients referred for RHC between 1997 and 2017 in Vanderbilt's deidentified medical record. PH was defined as mean pulmonary artery pressure >20 mmHg. Pre‐ and postcapillary PH were defined according to contemporary guidelines. COPD was identified using a validated rules‐based algorithm requiring international classification of diseases codes relevant to COPD. We identified 6065 patients referred for RHC, of whom 1509 (24.9%) had COPD and 1213 had COPD and PH. Patients with COPD‐PH had a higher prevalence of diabetes, atrial fibrillation, and heart failure compared with COPD without PH. Approximately 55% of patients with COPD‐PH had elevated left ventricle (LV) filling pressure. Pulmonary function testing data from individuals with COPD‐PH revealed subtype differences, with precapillary COPD‐PH having lower diffusion capacity of the lungs for carbon monoxide (DLCO) values than the other COPD‐PH subtypes. Patients with COPD‐PH had significantly increased mortality compared with COPD alone (hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.28–2.26) with the highest mortality among the combined pre‐ and postcapillary COPD‐PH subgroup (HR: 2.39; 95% CI: 1.64–3.47). PH is common among patients with COPD referred for RHC. The etiology of PH in patients with COPD is often mixed due to multimorbidity and is associated with high mortality, which may have implications for risk factor management.
Keywords: COPD, hemodynamic phenotyping, survival outcomes
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible airway inflammation that leads to persistent airflow obstruction. Pulmonary hypertension (PH) is a known complication of COPD and is associated with a worse prognosis. 1 , 2 However, the clinical characteristics and disease‐related factors that increase the risk for COPD‐PH are unclear. Moreover, the prevalence of PH and the hemodynamic profiles among patients with COPD‐PH referred for right heart catheterization (RHC) are not well described, particularly considering the recent redefinition of PH at the Sixth World Symposium on PH. 3
The prevalence of COPD‐PH is not well established and the severity of PH is not clearly related to the severity of disease in prior reports. The prevalence of PH varies widely based on the definition used and the diagnostic modality (RHC vs. echocardiography). 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 PH in COPD is variable but is usually mild to moderate. Previously reported survival rates of individuals with COPD are significantly different after 3 years when mean pulmonary arterial pressure (mPAP) is >20 mmHg. 4 There are some reported exceptions with approximately 5%–10% of patients having “disproportionate” PH, defined previously and a priori as mPAP >40 mmHg with little to no airflow obstruction. 2 , 13 , 14 With the severity of PH not clearly linked to the severity of COPD, other comorbidities that are common in the COPD‐PH population may play a role in pathogenesis as well as clinical outcomes. Drivers of COPD‐PH risk are important to identify to inform clinical management.
In this study, we describe a cohort of patients with COPD referred for RHC with a focus on PH prevalence, hemodynamic profile, and clinical characteristics. We also related PH severity to the severity of airflow obstruction in patients with pulmonary function testing (PFT). This study builds on prior work in this area by examining a large referral cohort that also includes COPD patients who do not have PH on invasive testing, an important distinction from prior reports. 2 , 15 , 16 , 17 We hypothesized that PH, and specifically mixed hemodynamic profiles, would be common among patients with COPD referred for RHC.
METHODS
Availability of data and materials
For additional information, see the Methods section in the Supporting Information. All data generated or analyzed during this study are included in this published article and its supplementary information files.
Study population
The Vanderbilt University Institutional Review Board (IRB #140544) approved this study. Data for this study were extracted from Vanderbilt's Synthetic Derivative database, a deidentified version of Vanderbilt's electronic medical record. The design and implementation of the Synthetic Derivative were previously described. 18 , 19
Patient selection and COPD classification
The Synthetic Derivative database was queried for all patients who underwent RHC between 1998 (when RHC reports were digitalized) and 2017. As previously described, a unique algorithm using regular expressions and pattern matching was created to extract structured, quantitative data from all RHC reports. 20 Individuals with COPD were identified using an internally validated algorithmic approach based on the presence/absence of international classification of diseases (ICD) codes relevant to COPD, as previously described. 21 An age cutoff of 45 was used to increase specificity for COPD disease, which is rare among younger adults. Exclusion criteria included indeterminate status (i.e., inadequate coding to assign a COPD status), ICD codes for other restive and obstructive lung diseases (Table S1). Additional detail on COPD classification and PFT extraction is provided in an online data supplement.
PH classification
For our primary analysis, the cohort was further subdivided according to contemporary consensus recommendations (Table 1). 13 Additional detail on PH classification is provided in an online data supplement.
Table 1.
Hemodynamic classification of COPD‐PH
| mPAP | PAWP | PVR | |
|---|---|---|---|
| No PH | ≤20 mmHg | − | − |
| Pc‐PH | >20 mmHg | ≤15 mmHg | ≥3 wood units |
| Ipc‐PH | >20 mmHg | >15 mmHg | <3 wood units |
| Cpc‐PH | >20 mmHg | >15 mmHg | ≥3 wood units |
| U‐PH | >20 mmHg | ≤15 mmHg | <3 wood units |
Abbreviations: Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; Ipc‐PH, isolated postcapillary pulmonary hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; Pc‐PH, precapillary pulmonary hypertension; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; U‐PH, undefined pulmonary hypertension.
Clinical and outcome data
Demographic data were extracted from the date of RHC. Indications for RHC are shown in Table S2. Comorbidity, echocardiographic, and laboratory data were restricted to within 6 months before or after RHC. Comorbidities were defined on the basis of ICD‐9 coding or previously validated algorithms 22 (Table S3). Quantitative and semiquantitative echocardiographic data were extracted as described previously. 23 Spirometry and PFTs were extracted for patients within our RHC cohort who had undergone this testing within a year of RHC.
Statistical analysis
Data are expressed as median and IQR (interquartile range) for continuous variables, and absolute value and percent for categorical variables, unless stated otherwise. Differences between the two2 groups were assessed using the Mann–Whitney U or χ 2 test, as appropriate. All tables report available raw data. Additional detail on statistical analysis including modeling and survival analyses is provided in an online data supplement.
RESULTS
Demographics and clinical characteristics
We identified a total of 8865 patients referred for RHC (Figure 1); 2800 patients met prespecified exclusion criteria including age <45 years at last visit and minimum record length of 180 days. Of the remaining 6065 patients, a total of 1509 (25%) had COPD. The prevalence of PH was 80% (1213/1509) among those with COPD. Among those with COPD‐PH, 153 had Pc‐PH (12.6%), 408 had Ipc‐PH (33.6%), 261 had Cpc‐PH (21.5%), and 188 with U‐PH (15.5%) were included in our subsequent analysis. Similar demographic characteristics were seen in the 203 individuals within our COPD‐PH cohort did not have pulmonary vascular resistance (PVR) and/or pulmonary arterial wedge pressure (PAWP) necessary for subgrouping compared to the larger COPD‐PH population (Table S4). The prevalence of PH among those with COPD decreased from 80% to 66% when applying the historical mean pulmonary artery (PA) pressure cutoff of ≥25 mmHg. The distribution of hemodynamic profiles for each definition is shown in Figure S1.
Figure 1.
Flow diagram for patient categorization. RHC, right heart catheterization; COPD, chronic obstructive pulmonary disease; PH, pulmonary hypertension; Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; Ipc‐PH, isolated postcapillary pulmonary hypertension; mPAP, mean pulmonary arterial pressure; Pc‐PH, precapillary pulmonary hypertension; U‐PH, undefined pulmonary hypertension; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance
Patients with COPD‐PH were significantly younger and had a higher body mass index (BMI) compared to patients with COPD without PH (Table 2). Additionally, COPD‐PH patients were more likely to be black and had a higher prevalence of diabetes mellitus, atrial fibrillation, and heart failure than patients with COPD without PH. Diuretic, anticoagulant, PH‐specific (prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase‐5 inhibitors) and inhaled airway (inhaled corticosteroids [ICSs], long‐acting muscarinic antagonists [LAMA], long‐acting beta agonists [LABA]) medications were prescribed more often in patients with COPD‐PH compared to patients with COPD without PH (p < 0.05 for all comparisons). Bicarbonate and B‐type natriuretic protein (BNP) were higher in the COPD‐PH group compared with COPD without PH.
Table 2.
Demographic and clinical characteristics of the COPD cohort
| COPD‐PH | ||||||
|---|---|---|---|---|---|---|
| COPD (n = 296) | COPD‐PH COMBINED (n = 1213) | Pc‐PH (n = 153) | Ipc‐PH (n = 408) | Cpc‐PH (n = 261) | U‐PH (n = 188) | |
| Age, years | 65.4 ± 10.2 | 63.2 ± 10.6∗ | 62.7 ± 10.6 | 64.3 ± 10.3 | 62.6 ± 10.6 | 62.1 ± 10.5 |
| Female | 116 (39.2%) | 522 (43.0%) | 67 (43.8%)† | 259 (63.5%) | 141 (54.0%) | 108 (57.4%) |
| BMI, kg/m2 | 28.14 ± 7.7 | 31.1 ± 17.0∗ | 28.8 ± 15.1† | 32.8 ± 17.9 | 31.1 ± 14.4 | 31.7 ± 24.4 |
| Race | ||||||
| White | 271 (91.6%) | 1022 (84.3%) | 120 (78.4%)† | 354 (86.8%) | 204 (78.2%) | 175 (93.1%) |
| Black | 18 (6.1%) | 154 (12.7%)∗ | 30 (19.6%)† | 41 (10.0%) | 47 (18.0%) | 10 (5.3%) |
| Other | 7 | 37 | 3 | 13 | 10 | 3 |
| Comorbidities | ||||||
| Hypertension | 257 (86.8%) | 1001 (82.5%)∗ | 111 (72.5%)† | 364 (89.2%) | 220 (84.3%) | 153 (81.4%) |
| Diabetes mellitus | 99 (33.4%) | 600 (49.5%)∗ | 59 (38.6%)† | 223 (54.7%) | 135 (51.7%) | 91 (48.4%) |
| CAD | 218 (73.6%) | 911 (75.1%) | 90 (58.8%)† | 344 (84.3%) | 199 (76.2%) | 133 (70.7%) |
| OSA | 87 (29.4%) | 410 (33.8%) | 37 (24.2%)† | 154 (37.7%) | 93 (35.6%) | 66 (35.1%) |
| Atrial fibrillation | 131 (44.6%) | 644 (53.1%)∗ | 58 (37.9%)† | 236 (57.8%) | 158 (60.5%) | 88 (46.8%) |
| Heart failure | 166 (56.1%) | 877 (72.3%)∗ | 92 (60.1%)† | 316 (77.5%) | 213 (81.6%) | 111 (59.0%) |
| Previous history of smoking | 133 (44.9%) | 459 (37.8%) | 55 (35.9%) | 149 (36.5%) | 92 (35.2%) | 90 (47.9%) |
| Medications | ||||||
| Anticoagulant agents | 89 (30.1%) | 495 (40.8%)∗ | 56 (36.6%)† | 174 (42.6%) | 131 (50.2%) | 56 (29.8%) |
| Lipid lowering medications | 215 (72.6%) | 764 (63.0%)∗ | 71 (46.4%)† | 291 (71.3%) | 167 (64.0%) | 117 (62.2%) |
| CCBs | 133 (44.9%) | 514 (42.4%) | 63 (41.2%)† | 197 (48.3%) | 87 (33.3%) | 82 (43.6%) |
| Beta‐blockers | 189 (63.9%) | 787 (64.9%) | 87 (56.9%)† | 287 (70.3%) | 188 (72.0%) | 111 (59.0%) |
| ACE inhibitors | 144 (48.6%) | 613 (50.5%) | 69 (45.1%)† | 230 (56.4%) | 152 (58.2%) | 82 (43.6%) |
| ARBs | 64 (21.6%) | 242 (20.0%) | 22 (14.4%) † | 95 (23.3%) | 48 (18.4%) | 35 (18.6%) |
| Diuretic agents | 164 (55.4%) | 929 (76.6%)∗ | 97 (63.4%)† | 346 (84.8%) | 232 (88.9%) | 117 (62.2%) |
| ERAs | 0 (0.0%) | 20 (1.6%)∗ | 7 (4.6%)† | 3 (0.7) | 3 (1.1%) | 2 (1.1%) |
| PDE5 inhibitors | 4 (1.4%) | 51 (4.2%)∗ | 14 (9.2%)† | 10 (2.5%) | 12 (4.6%) | 7 (3.7%) |
| Prostacyclin | 2 (0.7%) | 44 (3.6%)∗ | 11 (7.2%)† | 8 (2.0%) | 5 (1.9%) | 6 (3.2%) |
| ICS | 270 (91.2%) | 1162 (95.8%)∗ | 146 (95.4%) | 395 (96.8%) | 253 (96.9%) | 178 (94.7%) |
| LAMA | 177 (59.8%) | 899 (74.1%)∗ | 111 (72.5%) | 303 (74.3%) | 199 (76.2%) | 135 (71.8%) |
| SABA | 232 (78.4%) | 1076 (88.7%)∗ | 134 (87.6%) | 371 (90.9%) | 234 (89.7%) | 168 (89.4%) |
| LABA | 150 (50.7%) | 666 (54.9%) | 70 (45.8%)† | 242 (59.3%) | 145 (55.6%) | 104 (55.3%) |
| Oxygen | 27 (9.1%) | 147 (12.1%) | 23 (15.0%) | 46 (11.3%) | 43 (16.5%) | 17 (9.0%) |
| Laboratory tests | ||||||
| Bicarbonate, mEq/L (n = 1503) | 21.0 ± 14.6 | 25.4 ± 18.0∗ | 27.7 ± 5.0 | 27.3 ± 4.9 | 27.7 ± 4.5 | 27.6 ± 4.3 |
| Hemoglobin, g/dl (n = 1499) | 12.7 ± 1.8 | 12.4 ± 2.3∗ | 13.2 ± 2.3† | 12.0 ± 2.2 | 12.5 ± 2.2 | 12.5 ± 2.2 |
| RDW, % (n = 1499) | 14.4 ± 1.5 | 15.5 ± 2.3∗ | 15.7 ± 2.7† | 15.5 ± 2.2 | 16.0 ± 2.1 | 14.7 ± 1.8 |
| BNP, pg/ml (n = 1225) | 400.6 ± 557.5 | 802.9 ± 1136.0∗ | 521.6 ± 713.2† | 815.0 ± 1027.3 | 1059.9 ± 1191.0 | 538.5 ± 942.6 |
| GFR, ml/min/1.73 m2 (n = 1502) | 70.7 ± 28.2 | 66.6 ± 30.0∗ | 72.5 ± 31.6† | 63.2 ± 28.9 | 62.2 ± 27.9 | 73.2 ± 29.6 |
Note: Values are mean ± SD or percent.
Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; ASD, atrial septal defect; BMI, body mass index; BNP, B‐type natriuretic protein; CAD, coronary artery disease; CCB, calcium‐channel blocker; COPD, chronic obstructive pulmonary disease; Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; ERA, endothelin receptor antagonist; GFR, glomerular filtration rate; ICS, inhaled corticosteroid; Ipc‐PH, isolated postcapillary pulmonary hypertension; LABA, long‐acting beta agonist; LAMA, long‐acting muscarinic antagonist; OSA, obstructive sleep apnea; Pc‐PH, precapillary pulmonary hypertension; PDE5, phosphodiesterase‐5; PH, pulmonary hypertension; SABA, short‐acting beta agonist; U‐PH, undefined pulmonary hypertension.
p < 0.05 for COPD‐PH versus COPD.
p < 0.05 for means among Pc, Ipc, Cpc, and U PH.
We also observed clinical differences across COPD‐PH hemodynamic profiles. Individuals with COPD‐Pc‐PH were more likely to be male, Black, and have a lower BMI, compared to COPD patients with Ipc (all p < 0.05). Individuals with either COPD‐Ipc‐PH or COPD‐Cpc‐PH were more likely to have a higher prevalence of hypertension, diabetes mellitus, coronary artery disease (CAD), obstructive sleep apnea (OSA), atrial fibrillation, and heart failure compared to individuals with COPD‐Pc‐PH. Pulmo nary vasodilators were more likely used in individuals with COPD‐Pc‐PH compared to the other COPD‐PH subtypes (p < 0.001). There were no significant differences in ICS, LAMA, or SABA use among the COPD‐PH hemodynamic subtypes (p = 0.721). BNP was highest in the COPD‐Ipc‐PH and COPD‐Cpc‐PH groups and hemoglobin was highest in the Pc‐PH group.
Echocardiographic and hemodynamic data
Among patients with COPD referred to RHC, 1312/1509 (86.9%) patients had at least one transthoracic echocardiogram performed within 6 months of the RHC. The median time between echocardiogram and RHC was 1 day (IQR: −14, 1). Compared to COPD alone, individuals with COPD‐PH had higher right atrial pressure, reduced right ventricular function, and increased left atrial diameter. The degree of LV remodeling was less advanced in patients with Pc‐PH or U‐PH versus patients with either Cpc‐PH or Ipc‐PH (Table 3) as evident by smaller LV end‐diastolic and left atrial diameters (p < 0.05 for all comparisons). Tricuspid annular plane systolic excursion (TAPSE) was lower in COPD‐PH compared with COPD alone and was lowest among patients with Pc‐PH.
Table 3.
Echocardiographic characteristics of the COPD cohort
| COPD‐PH | |||||||
|---|---|---|---|---|---|---|---|
| COPD | COPD‐PH COMBINED | Pc‐PH | Ipc‐PH | Cpc‐PH | U‐PH | ||
| N | (n = 296 | (n = 1213) | (n = 153) | (n = 408) | (n = 261) | (n = 188) | |
| RVIDD, cm | 388 | 3.0 ± 0.6 | 3.3 ± 0.7∗ | 3.4 ± 0.8 | 3.3 ± 0.8 | 3.3 ± 0.7 | 3.1 ± 0.7 |
| TR peak velocity, m/s | 394 | 2.7 ± 0.6 | 3.2 ± 2.6∗ | 4.5 ± 7.3† | 2.9 ± 0.5 | 3.3 ± 0.7 | 2.9 ± 0.6 |
| RVSP, mmHg | 827 | 35.7 ± 12.0 | 50.5 ± 19.4∗ | 59.8 ± 25.3† | 43.5 ± 13.4 | 56.9 ± 18.3 | 39.9 ± 12.6 |
| TAPSE, cm | 136 | 1.9 ± 0.5 | 1.8 ± 1.3∗ | 1.6 ± 0.4† | 1.7 ± 0.5 | 2.0 ± 2.9 | 1.9 ± 0.5 |
| RA pressure, mmHg | 1054 | 6.3 ± 3.9 | 8.0 ± 4.7∗ | 7.3 ± 4.6† | 8.3 ± 4.7 | 9.5 ± 4.8 | 5.7 ± 3.3 |
| LA AP, cm | 1197 | 4.1 ± 0.9 | 4.3 ± 0.9∗ | 3.9 ± 0.9† | 4.6 ± 0.9 | 4.5 ± 0.8 | 4.1 ± 1.0 |
| LV Sys dimension, mm/m2 | 1212 | 3.6 ± 1.2 | 3.8 ± 1.4 | 3.2 ± 1.3† | 4.0 ± 1.3 | 4.1 ± 1.5 | 3.5 ± 1.2 |
| LV dia dimension, mm/m2 | 1240 | 4.9 ± 1.0 | 5.0 ± 1.1 | 4.5 ± 1.1† | 5.2 ± 1.0 | 5.3 ± 1.2 | 4.8 ± 0.9 |
| LVEF, % | 1312 | 45.1 ± 16.6 | 44.8 ± 17.0 | 50.4 ± 12.8† | 42.5 ± 17.1 | 40.1 ± 18.4 | 48.7 ± 15.4 |
Note: Values are mean ± SD or percent.
Abbreviations: Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; Ipc‐PH, isolated postcapillary pulmonary hypertension; LA AP, anteroposterior diameter of left atrium; LV, left ventricle; LVEF, Left ventricular ejection fraction; Pc‐PH, precapillary pulmonary hypertension; PH, pulmonary hypertension; RA, right atrium; RVIDD, right ventricular internal dimension‐diastole; RVSP, right ventricular systolic pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; U‐PH, undefined pulmonary hypertension.
p < 0.05 for COPD‐PH versus COPD.
p < 0.05 for means among Pc, Ipc, Cpc, and U PH.
Patients with COPD‐PH exhibited hemodynamics distinct from individuals with COPD alone (Table 4). In addition to elevated right heart pressures, individuals with COPD‐PH had decreased stroke volume and PA oxygen saturation compared to patients with COPD alone. Patients with Cpc‐PH had the highest mean PA pressure and the lowest stroke volume, mixed venous saturation, and pulmonary compliance among PH subgroups. All hemodynamic measures of cardiac function were less severe in COPD‐U‐PH individuals compared with the other COPD‐PH subtypes. However, the COPD‐U‐PH did display evidence of subclinical left heart and pulmonary vascular disease based on a wedge pressure of 12.3 ± 3.8 and PVR of 2.2 ± 0.6, both of which were significantly different from patients with COPD without PH (p < 0.001).
Table 4.
Hemodynamic characteristics of the COPD cohort
| COPD‐PH | |||||||
|---|---|---|---|---|---|---|---|
| COPD | COPD‐PH combined | Pc‐PH | Ipc‐PH | Cpc‐PH | U‐PH | ||
| N | (n = 296) | (n = 1213) | (n = 153) | (n = 408) | (n = 261) | (n = 188) | |
| Heart rate, beats/min | 861 | 74.2 ± 14.9 | 78.5 ± 16.9∗ | 78.8 ± 13.9 | 78.0 ± 17.3 | 80.6 ± 18.1 | 77.4 ± 16.1 |
| Systolic BP, mmHg | 1364 | 123.1 ± 25.6 | 125.7 ± 25.4 | 125.3 ± 28.1 | 125.2 ± 24.1 | 126.1 ± 26.4 | 127.5 ± 24.6 |
| Diastolic BP, mmHg | 1509 | 68.7 ± 12.6 | 72.3 ± 13.6∗ | 74.5 ± 16.4 | 71.1 ± 12.9 | 74.0 ± 14.1 | 71.6 ± 12.3 |
| Mean RA pressure, mmHg | 1302 | 3.8 ± 3.0 | 10.5 ± 6.3∗ | 6.9 ± 4.3† | 11.9 ± 6.3 | 13.9 ± 6.7 | 6.9 ± 3.3 |
| Systolic PA pressure, mmHg | 1509 | 26.1 ± 5.0 | 51.2 ± 17.6∗ | 55.4 ± 19.1† | 47.4 ± 12.7 | 64.5 ± 16.8 | 36.3 ± 6.5 |
| Diastolic PA pressure, mmHg | 1509 | 8.9 ± 4.2 | 23.2 ± 8.5∗ | 23.1 ± 8.4† | 22.3 ± 6.2 | 29.7 ± 8.3 | 16.4 ± 4.4 |
| Mean PA pressure, mmHg | 1509 | 16.2 ± 3.2 | 34.4 ± 10.7∗ | 35.9 ± 11.2† | 32.6 ± 7.1 | 43.4 ± 10.3 | 24.7 ± 2.5 |
| PAWP, mmHg | 1392 | 8.0 ± 4.0 | 19.0 ± 7.7∗ | 9.9 ± 3.1† | 23.0 ± 6.2 | 23.2 ± 5.7 | 12.4 ± 2.5 |
| DPG, mmHg | 1392 | 2.1 ± 2.4 | 5.6 ± 6.9∗ | 13.4 ± 8.5† | 1.8 ± 2.1 | 7.2 ± 7.1 | 4.4 ± 3.6 |
| TPG, mm Hg | 1377 | 8.2 ± 3.3 | 15.2 ± 8.9∗ | 25.0 ± 10.1† | 9.7 ± 4.2 | 19.6 ± 8.0 | 12.3 ± 3.8 |
| PVR, Wood units | 1284 | 1.8 ± 1.0 | 3.3 ± 2.3∗ | 5.7 ± 2.8† | 1.8 ± 0.7 | 4.9 ± 2.1 | 2.2 ± 0.6 |
| TDCO, L/min | 1291 | 4.9 ± 1.5 | 5.0 ± 1.6 | 4.6 ± 1.2† | 5.4 ± 1.7 | 4.2 ± 1.4 | 5.7 ± 1.6 |
| Stroke volume, ml | 832 | 71.5 ± 24.9 | 67.1 ± 26.9∗ | 61.9 ± 19.5† | 73.1 ± 28.7 | 55.2 ± 22.9 | 77.7 ± 28.0 |
| PA oxygen saturation, % | 1280 | 69.0 ± 7.0 | 64.2 ± 9.9∗ | 66.2 ± 8.5† | 64.0 ± 8.5 | 58.3 ± 10.7 | 69.9 ± 7.4 |
| PA compliance, ml/mmHg | 832 | 4.4 ± 2.2 | 2.9 ± 1.8∗ | 2.2 ± 1.1† | 3.3 ± 1.9 | 1.8 ± 1.0 | 4.4 ± 1.9 |
Note: Values are mean ± SD or percent.
Abbreviations: BP, blood pressure; Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; DPG, diastolic pulmonary gradient; Ipc‐PH, isolated postcapillary pulmonary hypertension; PA, pulmonary artery; PAWP, pulmonary artery wedge pressure; Pc‐PH, precapillary pulmonary hypertension; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrium; TDCO, thermodilution cardiac output; TPG, transpulmonary pressure gradient; U‐PH, undefined pulmonary hypertension.
p < 0.05 for COPD‐PH versus COPD.
p < 0.05 for means among Pc, Ipc, Cpc, and U‐PH.
Pulmonary function data
Among patients with COPD referred for RHC, 338 (26.0%) underwent PFT within 1 year of RHC. The distribution of patients with COPD‐PH by GOLD stages was: I: 19.9% (51), II: 45.9% (118), III: 21.0% (54), and IV: 13.2% (34) (Figure S2). The distribution of patients with COPD, but lacking PH by GOLD stage were: I: 33.3% (27), II: 42.0% (34), III: 14.8% (12), and IV: 9.9% (8). The distribution of mPAP by GOLD stage among those with COPD‐PH is shown in Figure S3. Patients with COPD‐PH had a reduced FVC compared to individuals with COPD alone (Table 5). Percent forced expiratory volume in 1 s (FEV1) was significantly lower in COPD‐PH compared to COPD alone. DLCO was not significantly different compared to COPD alone (p = .06), however, all subtypes of COPD‐PH except for Ipc‐PH had lower DLCO compared to COPD. COPD‐Pc‐PH had a significantly reduced DLCO compared to all other PH subgroups.
Table 5.
Pulmonary characteristics of the COPD cohort
| COPD‐PH | |||||||
|---|---|---|---|---|---|---|---|
| COPD | COPD‐PH combined | Pc‐PH | Ipc‐PH | Cpc‐PH | U‐PH | ||
| N | (n = 296) | (n = 1213) | (n = 153) | (n = 408) | (n = 261) | (n = 188) | |
| DLCO, % (mL/min/mmHg) | 269 |
53.4 ± 20.3 |
48.3 ± 20.1 |
35.5 ± 16.1† |
54.9 ± 19.0 |
47.4 ± 19.9 |
46.9 ± 19.8 |
|
(13.0 ± 5.5) |
(12.0 ± 5.4) |
(8.6 ± 4.9)† |
(13.6 ± 5.3) |
(11.7 ± 5.4) |
(12.0 ± 5.0) |
||
| FEV1, % (L) | 338 |
66.7 ± 24.2 |
60.6 ± 24.1∗ |
61.5 ± 24.5 |
61.4 ± 24.7 |
62.1 ± 18.9 |
56.1 ± 26.5 |
|
(1.8 ± 0.8) |
(1.7 ± 0.8) |
(1.7 ± 0.8) |
(1.8 ± 0.8) |
(1.8 ± 0.7) |
(1.7 ± 0.8) |
||
| FVC, % (L) | 338 |
75.4 ± 18.8 |
69.0 ± 19.6∗ |
71.6 ± 21.2 |
69.0 ± 19.5 |
67.0 ± 15.0 |
67.0 ± 20.9 |
|
(2.7 ± 1.0) |
(2.6 ± 0.9) |
(2.5 ± 1.0) |
(2.6 ± 1.0) |
(2.5 ± 0.8) |
(2.7 ± 0.9) |
||
| FEV1/FVC, % | 338 | 65.4 ± 14.1 | 65.7 ± 16.0 | 64.0 ± 15.7 | 66.2 ± 16.4 | 69.6 ± 11.5 | 62.4 ± 19.4 |
| FRC, % (L) | 254 |
111.6 ± 38.2 |
108.7 ± 43.9 |
123.3 ± 46.5 |
108.5 ± 48.3 |
94.8 ± 25.4 |
124.4 ± 55.5 |
|
(3.5 ± 1.3) |
(3.4 ± 1.5) |
(3.7 ± 1.4)† |
(3.5 ± 1.6) |
(2.9 ± 0.9) |
(4.0 ± 1.9) |
||
| RV, % (L) | 257 |
121.3 ± 56.2 |
124.2 ± 63.3 |
131.8 ± 64.8 |
124.0 ± 66.1 |
105.3 ± 33.6 |
151.1 ± 89.2 |
|
(2.6 ± 1.2) |
(2.7 ± 1.4) |
(2.8 ± 1.4) |
(2.7 ± 1.4) |
(2.2 ± 0.8) |
(3.3 ± 1.9) |
||
| TLC, % (L) | 257 |
93.7 ± 20.4 |
90.0 ± 23.4 |
95.8 ± 24.0† |
89.5 ± 24.6 |
82.6 ± 16.1 |
98.6 ± 28.6 |
|
(5.5 ± 1.5) |
(5.3 ± 1.6) |
(5.4 ± 1.6)† |
(5.4 ± 1.6) |
(4.8 ± 1.4) |
(6.1 ± 2.0) |
||
| VC, % (L) | 254 |
77.1 ± 18.2 |
75.0 ± 22.3 |
75.0 ± 22.3 |
72.0 ± 19.4 |
69.8 ± 14.3 |
69.3 ± 18.6 |
|
(2.8 ± 1.0) |
(2.5 ± 1.0) |
(2.5 ± 1.0) |
(2.7 ± 0.9) |
(2.6 ± 0.8) |
(2.8 ± 0.9) |
||
Note: Values are mean ± SD or percent.
Abbreviations: Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; DLCO, diffusion capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; Ipc‐PH, isolated postcapillary pulmonary hypertension; Pc‐PH, precapillary pulmonary hypertension; PH, pulmonary hypertension; RV, residual volume; TLC, total lung capacity; U‐PH, undefined pulmonary hypertension; VC, vital capacity.
p < 0.05 for COPD‐PH versus COPD.
p < 0.05 for means among Pc, Ipc, Cpc, and U PH.
When adjusting for age, sex, and race, FEV1 is inversely associated with mean PA and right atrium (RA) (Table 6, p < 0.025). As a noninvasive estimate of pulmonary pressure, RVSP was similarly inversely associated with FEV1 (p < 0.004). Additionally, as FEV1 is reduced, cardiac output and PA oxygen saturation decrease. When modeled as a nonlinear association, a relationship between FEV1 and continuous hemodynamic variables is evident until FEV1 decreased to ~50%, at which point there was no clear association (Figure S4). Similarly, as DLCO is reduced, mean PA pressure, PVR, and RVSP increase (p < 0.001) along with significant reductions in cardiac output and PA oxygen saturation. Unlike FEV1, the association of DLCO to clinical correlates of PH was present throughout the physiologic scale of DLCO (0‐100%, Figure S4).
Table 6.
Multivariate hemodynamic associations with FEV1 and DLCO
| Age‐, sex‐, and race adjusted β‐coefficient (β‐range) | p value | |
|---|---|---|
| FEV1 | ||
| Mean PA pressure, mm Hg | −2.4 (−3.5 to −1.4) | <0.001 |
| PVR, wood units | −0.3 (−0.5 to −0.1) | 0.015 |
| RVSP | −3.5 (−5.9 to −1.1) | 0.004 |
| Mean RA pressure, mm Hg | −0.7 (−1.3 to −0.1) | 0.025 |
| TDCO | 0.0 (−0.2 to −0.1) | 0.886 |
| PA oxygen saturation, % | 0.9 (−0.0 to −1.7) | 0.051 |
| DLCO | ||
| Mean PA pressure, mm Hg | −2.3 (−3.4 to −1.1) | <0.001 |
| PVR, wood units | −0.8 (−1.0 to −0.5) | <0.001 |
| RVSP, mmHg | −4.5 (−6.9 to −2.0) | <0.001 |
| Mean RA pressure, mm Hg | 1.0 (−0.7 to −0.7) | 0.948 |
| TDCO | 0.3 (0.2–0.5) | <0.001 |
| PA oxygen saturation, % | 1.8 (0.9–2.7) | <0.001 |
Note: Values are reflected as beta‐coefficient of continuous variables (PVR, RVSP, mean RA pressure, RDCO, and PA oxygenation when FEV1 or DLCO increase from 25th to 75th percentile).
Abbreviations: DLCO, diffusion capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 s; PA, pulmonary artery; PVR, pulmonary vascular resistance; RA, right atrium; RVSP, right ventricular systolic pressure; TDCO, thermodilution cardiac output.
Outcomes of COPD‐PH
After adjusting for age, sex, and race, the risk of death was significantly increased in individuals with COPD‐PH compared to COPD (hazard ratio [HR]: 1.70; 95% CI: 1.28–2.26; p = 0.001) (Figure 2). Among COPD‐PH subtypes, patients with COPD‐Cpc‐PH displayed the highest risk of death, (HR: 2.39; 95% CI: 1.64–3.47; p < 0.001), compared to individuals with COPD alone. Similar significant elevations in risk of death were noted in COPD‐Pc‐PH (HR: 1.92, 95% CI: 1.22–3.02; p = 0.018) and COPD‐Ipc‐PH (HR: 1.60, 95% CI: 1.16–2.22, p = 0.013) compared to individuals with COPD alone. COPD‐U‐PH was not significantly associated with a higher risk of death compared to COPD alone (HR: 1.44; 95% CI: 0.93–2.24, p = 0.172). Using Sixth World Symposium on PH definition of PH severity, survival outcomes were also assessed by defining COPD‐PH as mPAP 21–24 mmHg with PVR ≥ 3 WU, or mPAP 25–34 mmHg, and COPD with severe PH as mPAP ≥ 35 mmHg, or mPAP ≥ 25 mmHg with low cardiac index (<2.0 L/min/m2) (Figure S5). Significant elevations in risk of death were noted in individuals with these definitions, COPD‐PH (HR: 1.61, 95% CI: 1.20–2.21; p < 0.001) and COPD‐PH, severe (HR: 2.06, 95% CI: 1.50–2.82, p < 0.001) compared to individuals with COPD alone. Elevations in mPAP revealed decreased survival probability at 5 years in both COPD‐PH and COPD (Figure S6).
Figure 2.
Forest plot of adjusted hazard ratio for mortality in COPD‐PH compared to COPD without PH. Mortality adjusted for the following variables determined within 6 months of right heart catheterization: age, sex, race. HR, hazard ratio; 95% CI, confidence interval. Cpc‐PH, combined postcapillary and precapillary pulmonary hypertension; Ipc‐PH, isolated postcapillary pulmonary hypertension; Pc‐PH, precapillary pulmonary hypertension; U‐PH, undefined pulmonary hypertension
DISCUSSION
We describe the clinical, hemodynamic, and pulmonary function features of unselected patients with COPD referred for RHC, a departure from prior studies which focused on patients with COPD‐PH only or used echocardiographic data to define PH status. We found that PH was common in this population, comprising over 80% of our cohort. Patients with PH had an increased prevalence of cardiometabolic disease and evidence of LV remodeling with reduced RV function. Over half of the COPD‐PH cohort had elevated LV filling pressure demonstrating a high prevalence of mixed WHO Group II/III PH. Among a subset with PFT data, more severe COPD was associated with higher mean PA pressure and PVR. FEV1 (β = −2.4, p = <0.001) and DLCO (β = −2.3, p = <0.001) were associated with mean PA pressure when adjusted for age, sex, and race, which may provide some insight into the observations of others that low DLCO is a predictor of mortality. 24 Finally, we demonstrated that COPD‐PH is associated with a 70% increased risk of mortality compared with COPD alone and a 139% increased risk among COPD patients with a Cpc‐PH profile. These data are important to patients and their providers because they raise awareness of PH as a complication of COPD and suggest the need to focus management not only on COPD but also on comorbidities, particularly left heart disease.
This study builds on prior work in this area in several ways. First, the large sample size of greater than 1200 patients with COPD‐PH allows for more robust clinical characterization. Many of the prior studies investigating the clinical characteristics of COPD‐PH patients were relatively small and/or limited to hospitalized subjects, which reduces generalization to more stable patients. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 25 Second, this study is performed using the definitions developed at the last World Symposium on Pulmonary Hypertension, defining PH as an mPAP greater than 20 mmHg. Third, we included individuals with COPD and without PH on RHC as a reference group. The absence of a similar group in prior studies limited inferences about the etiology of PH and related risk factors in patients with COPD. Finally, the inclusion of RHC, echocardiogram, PFT, and vital status data allowed for a complete cardio‐pulmonary interrogation of our cohort.
The prevalence of PH in patients with COPD is poorly understood because right heart catheterization is not routinely performed on this patient population and echocardiography has diagnostic limitations. The left heart contribution to COPD‐PH was debated at the First World PH Symposium devoted to “cor pulmonale” in 1963 and evaluated by radionuclide angiographic studies in the 1980s. 26 In this prior patient population, abnormal left ventricular function made up at least 20% of the study population.
Our report contributes to growing recognition that isolated precapillary COPD‐PH is relatively uncommon and that most patients have a component of left heart disease, leading to a mixed etiology. 27 Previous studies have shown that up to 30% of patients with COPD have evidence of systolic or diastolic left heart failure. 28 , 29 , 30 These studies were limited to echocardiographic data within COPD cohorts and generally focused on patients with severe COPD. We found that only 12.6% of our COPD‐PH cohort had isolated precapillary disease, and approximately 55% had some aspect of postcapillary disease (Ipc‐ and Cpc‐PH). These subtype percentages were similar amongst individuals with reduced or preserved ejection fractions. We also identified a previously uncharacterized hemodynamic profile of patients with PH with wedge <15 mmHg and PVR < 3 WU, which we called “undefined PH.” As a whole, these patients had mild elevations in wedge pressure and PVR (compared with normative values) indicating a degree of subclinical LV and pulmonary vascular disease, which may warrant longitudinal surveillance. The marked overlap between COPD and cardiometabolic disease in our cohort suggests the potential for shared risk factors (e.g., smoking, sedentary behavior) that may be particularly fruitful targets to reduce the risk of COPD‐PH.
An mPAP between 21 and 34 mmHg is a common finding in COPD patients, including 46.8% of our cohort of unselected patients referred for RHC. Burrows et al. first reported on 50 patients with COPD than those with severe airflow limitation had an average mPAP of 25 mmHg. 31 Weitzenblum et al. found that 35% of patients with moderate‐to‐severe COPD who underwent right heart catheterization had a mean pulmonary artery pressure of >20 mmHg. 4 Among those with end‐stage COPD (average FEV1: 27%), 91% of patients had mPAP > 20 mmHg. 9 Other studies reported similar results in smaller (n = 200–300) cohorts of emphysema, lung transplantation candidates, and candidates for lung volume reduction surgery. 9 , 10 , 32 The largest series to date of 998 hospitalized patients with COPD found the mPAP to be 20.3 ± 8.1 mmHg with a 50% prevalence of mPAP > 20 mmHg. 12 We found the prevalence of PH among patients with COPD increased from 66% using the historical definition to 80% when applying the revised definition, which was largely driven by increases in COPD‐ Ipc‐ and U‐PH. Although the treatment implications of the revised definition remain unclear, awareness of any degree of PH is important given the consistent association of even mild PH with adverse outcomes. 33 , 34
COPD‐PH is associated with increased mortality, but risk according to hemodynamic profile has not been reported. PVR has been implicated in the progression of COPD 35 and 5‐year survival is reduced among COPD patients with mPAP ≥ 25 mmHg, appearing to relate more strongly to pulmonary hemodynamics than FEV1, hypoxemia, or hypercapnia. 36 , 37 For COPD patients with mPAP > 40 mmHg, the unadjusted 5‐year survival is only about 15%. 12 , 38 A recent study found that individuals with COPD‐PH had worse survival than patients with idiopathic pulmonary arterial hypertension, despite similar hemodynamic impairment. 39 Among COPD‐PH hemodynamic subgroups, we found that the adjusted risk of mortality was highest in the Cpc‐PH group. Moreover, we found that individuals with the U‐PH profile had a trend toward an increased risk of mortality compared to COPD patients with mPAP < 20 mmHg. Several mechanisms may contribute to mortality risk in COPD‐PH. Precapillary PH may be driven by parenchymal loss and accompanying alveolar hypoxia, hypoxemia and hypercapnia, air‐trapping and hyperinflation, polycythemia (leading to hyperviscosity and hypervolemia), and inflammation‐induced vascular remodeling related to smoking. 10 , 13 The extent to which those with Ipc‐PH and COPD have elevated PA pressure due to LV disease versus COPD‐related mechanisms is difficult to ascertain. Similarly, the degree to which COPD versus a potential molecular predisposition to pulmonary vascular disease leads to the Cpc‐PH phenotype is unknown. Molecular interrogation of the different COPD‐PH profiles is warranted to help prioritize and potentially personalize therapies.
Our study has several limitations. Our data are derived from a single center, although the large and heterogeneous population strengthens the generalizability of our findings. To select a population with right heart catheterization data for hemodynamic subgrouping, we utilized an RHC referral population. This population, therefore, may lead to inherit subgroup bias, but importantly no subgroup differences were seen in those with and without left heart disease (Figure S1) suggesting generalizability of the findings. Exercise testing during RHC was not performed but likely would have increased the number of patients with PH in our COPD population. Treatment options and guidelines for COPD management have evolved throughout the course of our 17‐year study, and we were unable to account for this in our analysis. TAPSE data is limited as this value was not routinely measured until 2014. Binary smoking status is limited to approximately 50% of our COPD cohort. We used an algorithmic approach irrespective of PFT data to define COPD patients, as many patients within our cohort lack reviewable PFT data. For those that do have PFT data, COPD severity was based on GOLD criteria for measured airflow obstruction, as we are unable to reliably determine the level of dyspnea/exacerbation within our EMR. 40 This approach adds rigor by excluding patients with indeterminate ICD coding as well as coding for restrictive or reversible obstructive disease. Using this approach likely increased specificity for COPD at the expense of sensitivity as no doubt some of the excluded individuals deemed indeterminate likely had COPD.
CONCLUSION
PH is common among patients with COPD referred for RHC. The etiology of PH in patients with COPD is often mixed due to multimorbidity and is associated with high mortality, which may have implications for risk factor management. These results support an integrated approach to objectively identify both diseases at an early stage and to optimize control of respiratory and cardiovascular conditions. Additional studies providing new data on the pathogenesis and management of patients with COPD and PH are needed.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
ETHICS STATEMENT
The Vanderbilt University Institutional Review Board (IRB #140544) approved this study. Data for this study were extracted from Vanderbilt's Synthetic Derivative database, a deidentified version of Vanderbilt's electronic medical record.
AUTHOR CONTRIBUTIONS
The authors take responsibility for the integrity of the work as a whole, contributed to the writing and reviewing of the manuscript, and have given final approval for the version to be published. All authors had full access to the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Daniel P. Cook and Evan L. Brittain conception and design of research. Daniel P. Cook and Evan L. Brittain drafted the manuscript and designed figures. Daniel P. Cook, Meng Xu, Meng Xu, and Jeffrey S. Annis processed experimental data and performed analysis. Daniel P. Cook prepared figures. Melinda C. Aldrich and Anna R. Hemnes aided in interpreting the results and worked on the manuscript. Daniel P. Cook, Meng Xu, Meng Xu, Jeffrey S. Annis, Melinda C. Aldrich, Anna R. Hemnes, and Evan L. Brittain edited, reviewed, and approved final version of manuscript.
Supporting information
Supporting information.
Supporting information.
ACKNOWLEDGMENTS
All data generated or analyzed during this study are included in this published article and its supplementary information files. This study was supported by the following funding organizations: NIH: R01 HL146588, 5 P01 HL 108800‐03, 1RO1 HL 142720‐01A1, T32GM007347, and T32GM080178, F30HL140756. CFF: COOK20L0. The project was supported by Clinical Translational Science Award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Cook DP, Xu M, Martucci VL, Annis JS, Aldrich MC, Hemnes AR, Brittain EL. Clinical insights into pulmonary hypertension in chronic obstructive pulmonary disease. Pulmonary Circulation. 2022;12:e12006. 10.1002/pul2.12006
REFERENCES
- 1. Awerbach JD, Stackhouse KA, Lee J, Dahhan T, Parikh KS, Krasuski RA. Outcomes of lung disease‐associated pulmonary hypertension and impact of elevated pulmonary vascular resistance. Respir Med. 2019;150:126–30. 10.1016/j.rmed.2019.03.004 [DOI] [PubMed] [Google Scholar]
- 2. Hurdman J, Condliffe R, Elliot CA, Swift A, Rajaram S, Davies C, Hill C, Hamilton N, Armstrong IJ, Billings C, Pollard L, Wild JM, Lawrie A, Lawson R, Sabroe I, Kiely DG. Pulmonary hypertension in COPD: results from the ASPIRE registry. Eur Respir J. 2013;41:1292–301. 10.1183/09031936.00079512 [DOI] [PubMed] [Google Scholar]
- 3. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. 10.1183/13993003.01913-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J, Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax. 1981;36:752–8. 10.1136/thx.36.10.752 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Oswald‐Mammosser M, Apprill M, Bachez P, Ehrhart M, Weitzenblum E. Pulmonary hemodynamics in chronic obstructive pulmonary disease of the emphysematous type. Respiration. 1991;58:304–10. 10.1159/000195950 [DOI] [PubMed] [Google Scholar]
- 6. Kessler R, Faller M, Weitzenblum E, Chaouat A, Aykut A, Ducoloné A, Ehrhart M, Oswald‐Mammosser M. “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164:219–24. 10.1164/ajrccm.164.2.2006129 [DOI] [PubMed] [Google Scholar]
- 7. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, Pochettino A, Kotloff RM. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735–40. 10.1164/rccm.200210-1130OC [DOI] [PubMed] [Google Scholar]
- 8. Doi M, Nakano K, Hiramoto T, Kohno N. Significance of pulmonary artery pressure in emphysema patients with mild‐to‐moderate hypoxemia. Respir Med. 2003;97:915–20. 10.1016/s0954-6111(03)00115-x [DOI] [PubMed] [Google Scholar]
- 9. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE, National Emphysema Treatment Trial (NETT) G. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med. 2002;166:314–22. 10.1164/rccm.2107027 [DOI] [PubMed] [Google Scholar]
- 10. Thabut G, Dauriat G, Stern JB, Logeart D, Lévy A, Marrash‐Chahla R, Mal H. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest. 2005;127:1531–6. 10.1378/chest.127.5.1531 [DOI] [PubMed] [Google Scholar]
- 11. Stevens D, Sharma K, Szidon P, Rich S, McLaughlin V, Kesten S. Severe pulmonary hypertension associated with COPD. Ann Transplant. 2000;5:8–12. [PubMed] [Google Scholar]
- 12. Chaouat A, Bugnet A‐S, Kadaoui N, Schott R, Enache I, Ducoloné A, Ehrhart M, Kessler R, Weitzenblum E. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172:189–94. 10.1164/rccm.200401-006OC [DOI] [PubMed] [Google Scholar]
- 13. Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, Gibbs S, Martinez FJ, Semigran MJ, Simonneau G, Wells AU, Vachiéry JL. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62:D109–16. 10.1016/j.jacc.2013.10.036 [DOI] [PubMed] [Google Scholar]
- 14. Kovacs G, Agusti A, Barberà JA, Celli B, Criner G, Humbert M, Sin DD, Voelkel N, Olschewski H. Pulmonary vascular involvement in chronic obstructive pulmonary disease. is there a pulmonary vascular phenotype? Am J Respir Crit Care Med. 2018;198:1000–11. 10.1164/rccm.201801-0095PP [DOI] [PubMed] [Google Scholar]
- 15. Gologanu D, Stanescu C, Ursica T, Balea MI, Ionita D, Bogdan MA. Prevalence and characteristics of pulmonary hypertension associated with COPD–a pilot study in patients referred to a pulmonary rehabilitation program clinic. Maedica (Buchar). 2013;8:243–8. [PMC free article] [PubMed] [Google Scholar]
- 16. Holverda S, Bogaard HJ, Groepenhoff H, Postmus PE, Boonstra A, Vonk‐Noordegraaf A. Cardiopulmonary exercise test characteristics in patients with chronic obstructive pulmonary disease and associated pulmonary hypertension. Respiration. 2008;76:160–7. 10.1159/000110207 [DOI] [PubMed] [Google Scholar]
- 17. Christensen CC, Ryg MS, Edvardsen A, Skjønsberg OH. Relationship between exercise desaturation and pulmonary haemodynamics in COPD patients. Eur Respir J. 2004;24:580–6. 10.1183/09031936.04.00118303 [DOI] [PubMed] [Google Scholar]
- 18. Pulley J, Clayton E, Bernard GR, Roden DM, Masys DR. Principles of human subjects protections applied in an opt‐out, de‐identified biobank. Clin Transl Sci. 2010;3:42–8. 10.1111/j.1752-8062.2010.00175.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, Masys DR. Development of a large‐scale de‐identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther. 2008;84:362–9. 10.1038/clpt.2008.89 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Assad TR, Hemnes AR, Larkin EK, Glazer AM, Xu M, Wells QS, Farber‐Eger EH, Sheng Q, Shyr Y, Harrell FE, Newman JH, Brittain EL. Clinical and biological insights into combined post‐ and pre‐capillary pulmonary hypertension. J Am Coll Cardiol. 2016;68:2525–36. 10.1016/j.jacc.2016.09.942 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Martucci J, Liu H, Kerchberger VE, Osterman TJ, Torstenson E, Richmond B, Aldrich MC. A clinical phenotyping algorithm to identify cases of chronic obstructive pulmonary disease in electronic health records. bioRxiv. 2019;716779. 10.1101/716779 [DOI] [Google Scholar]
- 22. Gottesman O, Kuivaniemi H, Tromp G, Faucett WA, Li R, Manolio TA, Sanderson SC, Kannry J, Zinberg R, Basford MA, Brilliant M, Carey DJ, Chisholm RL, Chute CG, Connolly JJ, Crosslin D, Denny JC, Gallego CJ, Haines JL, Hakonarson H, Harley J, Jarvik GP, Kohane I, Kullo IJ, Larson EB, McCarty C, Ritchie MD, Roden DM, Smith ME, Böttinger EP, Williams MS, eMERGE N. The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet Med. 2013;15:761–71. 10.1038/gim.2013.72 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Wells QS, Farber‐Eger E, Crawford DC. Extraction of echocardiographic data from the electronic medical record is a rapid and efficient method for study of cardiac structure and function. J Clin Bioinforma. 2014;4:12. 10.1186/2043-9113-4-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Rose L, Prins KW, Archer SL, Pritzker M, Weir EK, Misialek JR, Thenappan T. Survival in pulmonary hypertension due to chronic lung disease: influence of low diffusion capacity of the lungs for carbon monoxide. J Heart Lung Transplant. 2019;38:145–55. 10.1016/j.healun.2018.09.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Portillo K, Torralba Y, Blanco I, Burgos F, Rodriguez‐Roisin R, Rios J, Roca J, Barberà JA. Pulmonary hemodynamic profile in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:1313–20. 10.2147/copd.S78180 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Matthay RA, Berger HJ, Davies RA, Loke J, Mahler DA, Gottschalk A, Zaret BL. Right and left ventricular exercise performance in chronic obstructive pulmonary disease: radionuclide assessment. Ann Intern Med. 1980;93:234–9. 10.7326/0003-4819-93-2-234 [DOI] [PubMed] [Google Scholar]
- 27. Rischard FP. A105 glory days: the latest clinical research in PAH. Insights from the Pulmonary Vascular Phenomics Project (PVDOMICS): the effect of multiple pulmonary vascular groups on hemodynamics in pulmonary hypertension. Am J Respir Crit Care Med. 2019;199:A2505. [Google Scholar]
- 28. Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J. 2005;26:1887–94. 10.1093/eurheartj/ehi291 [DOI] [PubMed] [Google Scholar]
- 29. Funk GC, Lang I, Schenk P, Valipour A, Hartl S, Burghuber OC. Left ventricular diastolic dysfunction in patients with COPD in the presence and absence of elevated pulmonary arterial pressure. Chest. 2008;133:1354–9. 10.1378/chest.07-2685 [DOI] [PubMed] [Google Scholar]
- 30. Rennard SI, Locantore N, Delafont B, Tal‐Singer R, Silverman EK, Vestbo J, Miller BE, Bakke P, Celli B, Calverley PM, Coxson H, Crim C, Edwards LD, Lomas DA, MacNee W, Wouters EF, Yates JC, Coca I, Agustí A, Evaluation of COPD Longitudinally to Identify Predictive Surrogate E. Identification of five chronic obstructive pulmonary disease subgroups with different prognoses in the ECLIPSE cohort using cluster analysis. Ann Am Thorac Soc. 2015;12:303–12. 10.1513/AnnalsATS.201403-125OC [DOI] [PubMed] [Google Scholar]
- 31. Burrows B, Earle RH. Course and prognosis of chronic obstructive lung disease. A prospective study of 200 patients. N Engl J Med. 1969;280:397–404. 10.1056/nejm196902202800801 [DOI] [PubMed] [Google Scholar]
- 32. Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest. 1998;113:576–83. 10.1378/chest.113.3.576 [DOI] [PubMed] [Google Scholar]
- 33. Assad TR, Maron BA, Robbins IM, Xu M, Huang S, Harrell FE, Farber‐Eger EH, Wells QS, Choudhary G, Hemnes AR, Brittain EL. Prognostic effect and longitudinal hemodynamic assessment of borderline pulmonary hypertension. JAMA Cardiol. 2017;2:1361–8. 10.1001/jamacardio.2017.3882 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Maron BA, Hess E, Maddox TM, Opotowsky AR, Tedford RJ, Lahm T, Joynt KE, Kass DJ, Stephens T, Stanislawski MA, Swenson ER, Goldstein RH, Leopold JA, Zamanian RT, Elwing JM, Plomondon ME, Grunwald GK, Barón AE, Rumsfeld JS, Choudhary G. Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the veterans affairs clinical assessment, reporting, and tracking program. Circulation. 2016;133:1240–8. 10.1161/circulationaha.115.020207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Burrows B, Kettel LJ, Niden AH, Rabinowitz M, Diener CF. Patterns of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med. 1972;286:912–8. 10.1056/nejm197204272861703 [DOI] [PubMed] [Google Scholar]
- 36. Klinger JR. Group III pulmonary hypertension: pulmonary hypertension associated with lung disease: epidemiology, pathophysiology, and treatments. Cardiol Clin. 2016;34:413–33. 10.1016/j.ccl.2016.04.003 [DOI] [PubMed] [Google Scholar]
- 37. Oswald‐Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, Kessler R. Prognostic factors in COPD patients receiving long‐term oxygen therapy Importance of pulmonary artery pressure. Chest. 1995;107:1193–8. 10.1378/chest.107.5.1193 [DOI] [PubMed] [Google Scholar]
- 38. Mueller‐Mottet S, Stricker H, Domenighetti G, Azzola A, Geiser T, Schwerzmann M, Weilenmann D, Schoch O, Fellrath JM, Rochat T, Lador F, Beghetti M, Nicod L, Aubert JD, Popov V, Speich R, Keusch S, Hasler E, Huber LC, Grendelmeier P, Tamm M, Ulrich S. Long‐term data from the Swiss pulmonary hypertension registry. Respiration. 2015;89:127–40. 10.1159/000370125 [DOI] [PubMed] [Google Scholar]
- 39. Vizza CD, Hoeper MM, Huscher D, Pittrow D, Benjamin N, Olsson KM, Ghofrani HA, Held M, Klose H, Lange T, Rosenkranz S, Dumitrescu D, Badagliacca R, Claussen M, Halank M, Vonk‐Noordegraaf A, Skowasch D, Ewert R, Gibbs J, Delcroix M, Skride A, Coghlan G, Ulrich S, Opitz C, Kaemmerer H, Distler O, Grünig E. Pulmonary hypertension in patients with COPD: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Chest. 2021;160:678–89. 10.1016/j.chest.2021.02.012 [DOI] [PubMed] [Google Scholar]
- 40. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez‐Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187:347–65. 10.1164/rccm.201204-0596PP [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting information.
Supporting information.
Data Availability Statement
For additional information, see the Methods section in the Supporting Information. All data generated or analyzed during this study are included in this published article and its supplementary information files.