To the Editor:
Pulmonary hypertension (PH) due to chronic lung disease, classified as World Health Organization (WHO) group 3 PH (1), is the second most common cause of PH after left-heart disease (2). Group 3 patients have a lower quality of life, higher medical costs, and worse survival compared with patients with chronic lung disease but without PH (3). Despite the large clinical burden and poor prognosis of group 3 PH, its long-term outcomes and clinical, echocardiographic, and hemodynamic characteristics are not well described. Furthermore, despite the large clinical burden of this disease, there are no approved therapies for patients with group 3 PH. Thus, we need to better understand the clinical characteristics and outcomes of group 3 PH to identify possible therapeutic targets.
We examined 122 patients with group 3 PH and 155 patients with group 1 PH from the University of Minnesota Pulmonary Hypertension Repository (4). Group 3 PH and group 1 PH were defined according to the WHO classification criteria (1, 5). In the group 3 population, PH was associated with interstitial lung disease in 55 patients, chronic obstructive pulmonary disease (COPD) in 45, obstructive sleep apnea or obesity-hypoventilation syndrome in 11, and combined pulmonary fibrosis and emphysema in 11. The etiology of PH in the group 1 population included idiopathic, heritable, or drug-induced disease (n = 48), connective tissue disease (n = 59), liver disease (n = 24), congenital heart disease (n = 18), human immunodeficiency virus infection (n = 2), and other causes (n = 4). Fifty-two group 3 patients (43%) and 65 group 1 patients (42%) were incident cases.
Compared with group 1, the group 3 cohort was older, had a higher proportion of males, and had more comorbidities, including hypertension, diabetes, hyperlipidemia, coronary artery disease, obesity, and atrial fibrillation, resulting in a significantly higher Charlson comorbidity score (Table 1). There was no difference in WHO functional class between the groups. At the time of referral, group 3 patients were more likely to be on supplemental oxygen and digoxin, and less likely to be on pulmonary vasodilator therapy. Use of diuretics did not differ between the groups. Group 3 patients had lower 6-minute-walk distances and more exercise-induced hypoxemia. On pulmonary function tests, group 3 patients had lower lung volumes and lower DlCO values. There were no intergroup differences in serum N-terminal pro–B-type natriuretic peptide levels or serum creatinine (Table 1).
Table 1.
Comparison of Clinical, Echocardiographic, and Hemodynamic Characteristics of Patients with Group 3 and Group 1 Pulmonary Hypertension
| Characteristics | Group 3 PH (n = 122) | Group 1 PH (n = 155) | P Value |
|---|---|---|---|
| Age, yr | 65 ± 11 | 53 ± 17 | <0.001 |
| Female, n (%) | 64 (53) | 116 (75) | <0.001 |
| Body mass index, kg/m2 | 30 ± 7 | 28 ± 7 | 0.015 |
| WHO functional class (n = 230), n (%) | 0.151 | ||
| I | 0 (0) | 3 (2) | |
| II | 8 (8) | 19 (15) | |
| III | 79 (77) | 87 (68) | |
| IV | 15 (15) | 19 (15) | |
| Comorbidities, n (%) | |||
| Hypertension | 86 (70) | 63 (41) | <0.001 |
| Diabetes | 36 (30) | 28 (18) | 0.025 |
| Hyperlipidemia | 65 (53) | 37 (24) | <0.001 |
| Coronary artery disease | 39 (32) | 16 (10) | <0.001 |
| Atrial fibrillation | 25 (20) | 9 (6) | <0.001 |
| Charlson comorbidity index | 5.1 ± 2.3 | 3.9 ± 3.1 | <0.001 |
| Medications, n (%) | |||
| Oxygen | 82 (67) | 28 (18) | <0.001 |
| Diuretics | 64 (52) | 72 (46) | 0.321 |
| Digoxin | 12 (10) | 5 (3) | 0.023 |
| Coumadin | 19 (16) | 28 (18) | 0.583 |
| Calcium channel blockers | 23 (19) | 30 (19) | 0.916 |
| Phosphodiesterase-5 inhibitors | 12 (10) | 42 (27) | <0.001 |
| Endothelin receptor antagonists | 1 (1) | 9 (6) | 0.046 |
| Prostacyclins | 0 (0) | 10 (6) | 0.003 |
| Six-minute-walk test | |||
| Distance, m (n = 162) | 237 ± 108 (n = 73) | 335 ± 136 (n = 89) | <0.001 |
| Rest oxygen saturation, % (n = 151) | 97 ± 2 (n = 71) | 97 ± 3 (n = 80) | 0.494 |
| Nadir exercise oxygen saturation, % (n = 152) | 87 ± 5 (n = 70) | 90 ± 6 (n = 82) | 0.001 |
| Pulmonary function test, % predicted | |||
| FEV1 (n = 196) | 56 ± 23 (n = 99) | 75 ± 19 (n = 97) | <0.001 |
| FVC (n = 190) | 64 ± 23 (n = 98) | 78 ± 19 (n = 92) | <0.001 |
| FEV1/FVC (n = 191) | 69 ± 19 (n = 98) | 77 ± 9 (n = 93) | <0.001 |
| TLC (n = 127) | 80 ± 25 (n = 61) | 87 ± 15 (n = 66) | 0.078 |
| DlCO (n = 165) | 35 ± 19 (n = 80) | 60 ± 26 (n = 85) | <0.001 |
| Lab | |||
| Serum hemoglobin, g/dl (n = 272) | 13.5 ± 2.1 (n = 121) | 13.4 ± 2.7 (n = 151) | 0.752 |
| Serum creatinine, mg/dl (n = 274) | 0.9 (0.7–1.1) (n = 121) | 0.9 (0.7–1.1) (n = 153) | 0.802 |
| Serum NT-proBNP, pg/dl (n = 230) | 1,324 (223–3,350) (n = 102) | 806 (238–2,628) (n = 128) | 0.393 |
| Echocardiography | |||
| Left ventricular ejection fraction, % (n = 247) | 60 ± 10 (n = 116) | 60 ± 8 (n = 131) | 0.885 |
| Left ventricular mass index, g/m2 (n = 182) | 158 ± 57 (n = 88) | 130 ± 48 (n = 94) | <0.001 |
| Left ventricular end diastolic diameter, cm (n = 218) | 4.3 ± 0.8 (n = 101) | 4.0 ± 0.8 (n = 117) | 0.014 |
| Left atrial diameter, mm (n = 185) | 4.0 ± 0.9 (n = 81) | 3.8 ± 1.0 (n = 104) | 0.221 |
| Right ventricular enlargement, n (%) (n = 251) | 83 (73) (n = 114) | 108 (79) (n = 137) | 0.265 |
| Right atrial enlargement, n (%) (n = 247) | 68 (60) (n = 113) | 98 (73) (n = 134) | 0.031 |
| Right ventricular FAC, % (n = 190) | 28 ± 10 (n = 85) | 33 ± 11 (n = 105) | 0.006 |
| Right ventricular FAC <35%, n (%) (n = 190) | 58 (68) (n = 85) | 55 (52) (n = 105) | 0.027 |
| Pericardial effusion, n (%) (n = 251) | 12 (10) (n = 115) | 41 (30) (n = 136) | <0.001 |
| Hemodynamics | |||
| Heart rate, beats/min (n = 229) | 79 ± 16 (n = 98) | 77 ± 16 (n = 131) | 0.347 |
| Mean right atrial, mm Hg (n = 273) | 7 ± 4 (n = 121) | 8 ± 5 (n = 152) | 0.244 |
| Mean PAP, mm Hg (n = 277) | 40 ± 10 (n = 122) | 47 ± 14 (n = 155) | <0.001 |
| PCWP, mm Hg (n = 277) | 10 ± 3 (n = 122) | 9 ± 3 (n = 155) | 0.029 |
| Cardiac output, L/min (n = 265) | 4.8 ± 1.5 (n = 121) | 4.2 ± 1.5 (n = 144) | 0.006 |
| Cardiac index, L/min/m2 (n = 189) | 2.6 ± 0.7 (n = 92) | 2.4 ± 0.8 (n = 97) | 0.093 |
| PVR, Wood units (n = 265) | 6.9 ± 3.4 (n = 121) | 10.3 ± 5.6 (n = 144) | <0.001 |
| Diastolic pulmonary gradient, mm Hg (n = 277) | 15 ± 8 (n = 122) | 21 ± 12 (n = 155) | <0.001 |
| PAC, ml/mm Hg (n = 224) | 2.0 ± 1.1 (n = 97) | 1.5 ± 1.0 (n = 127) | <0.001 |
| Vasodilator response, n (%) (n = 277) | 4 (3) (n = 122) | 8 (5) (n = 155) | 0.559 |
Definition of abbreviations: FAC = fractional area change; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PAC = pulmonary arterial compliance; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; WHO = World Health Organization.
Data are presented as n (%) for categorical variables and as mean ± SD or median (25th to 75th percentiles) for continuous variables.
Group 3 patients had higher left ventricular mass and end-diastolic diameters (Table 1). There was no difference in right ventricular (RV) dimensions (Table 1), but group 3 patients had lower RV fractional area change (RVFAC) values (Figure 1A, top). When RVFAC was plotted against mean pulmonary artery pressure (mPAP), the rate of decline in RVFAC with increasing mPAP was similar between the two PH groups (Figure 1A, bottom). However, group 3 patients had lower RVFAC values for any given mPAP than group 1 patients (Figure 1A, bottom). Despite the lower RVFAC values, group 3 patients had a lower prevalence of right atrial enlargement and pericardial effusion than group 1 patients.
Figure 1.
Worse right ventricular (RV) function and increased mortality in group 3 pulmonary hypertension (PH). (A) Top: reduced RV fractional area change (RVFAC) in group 3 PH compared with group 1 PH (28 ± 10% vs. 33 ± 11%, P = 0.006). Bottom: plot of RVFAC versus mean pulmonary artery pressure (mPAP) in group 1 and group 3 patients. Group 3 patients had worse RV function at all mPAPs, as demonstrated by a significantly different y intercept (group 3: 44.2 ± 4.3, group 1: 47.9 ± 4.2, P < 0.0001). However, there was an equivalent response to increasing afterload, as shown by the similar slope of best-fit regression lines (group 3: −0.38 ± 0.10, group 1: −0.33 ± 0.09, P = 0.70). *P < 0.05 (t test). (B) Survival analysis shows significantly worse survival for group 3 PH in the total cohort (top) and incident cohort (bottom). CI = confidence interval; WHO = World Health Organization.
A hemodynamic evaluation showed that group 3 patients had lower mPAP and pulmonary vascular resistance, with higher pulmonary arterial compliance, pulmonary capillary wedge pressure, and cardiac output when compared with group 1 patients. Right atrial pressure and cardiac index did not differ between the two PH populations (Table 1).
The patients were followed routinely in the clinic every 3–6 months. Vital statistics were obtained from the Minnesota death index and chart review. No patient was lost to follow-up. There were 59 deaths in group 3 and 52 deaths in group 1 over a median follow-up of 2.3 years. Survival was significantly worse in group 3 patients compared with group 1 patients. The 1-, 3-, and 5-year survival rates in group 3 and group 1 patients were 80% and 95%, 48% and 82%, and 30% and 62%, respectively (hazard ratio [HR], 2.5 [95% confidence interval (CI), 1.7–3.7; P < 0.001]; Figure 1B, top). This remained significant after adjusting for age, sex, and Charlson comorbidity index (HR, 1.5 [95% CI, 1.0–2.3; P = 0.046]). The 1- and 2-year survival rates in the incident cohort were also worse in group 3 PH compared with group 1 PH (80% vs. 90%, and 55% vs. 82%, respectively; HR, 2.5 [95% CI, 1.1–5.6; P = 0.026]; Figure 1B, bottom). In the group 3 PH population, there was no difference in survival when COPD PH was compared with interstitial lung disease PH.
Consequently, although they had less severe pulmonary vascular disease, group 3 patients had worse RV function, reduced exercise capacity, and worse survival than group 1 patients. The mechanisms underlying the worse RV function in group 3 PH are unclear, but there are several possible explanations. First, patients with COPD but without PH have impaired RV function (6). This afterload-independent RV dysfunction is hypothesized to result from hypoxemia, inflammation, lung hyperinflation, and/or endothelial dysfunction (6). Thus, patients with group 3 PH may have additional, nonhemodynamic insults to the RV resulting in RV dysfunction that is disproportionate to the PH severity. Another possible reason for the worse RV function in group 3 patients is the higher proportion of males in this group. Consistent with this hypothesis, healthy males were found to have lower cardiac magnetic resonance–calculated RV ejection fraction values than females in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort (7). Further studies are needed to define the mechanisms that underlie the RV dysfunction in group 3 PH, as therapies that improve RV function may benefit these patients. This is particularly important because current pulmonary arterial hypertension–specific therapies neither improve symptom burden nor increase exercise capacity in group 3 patients (8).
Our study has several limitations. This was a single-center study and most patients were entered retrospectively. However, we collected the baseline variables at the time of the referral to our practice rather than at the time of enrollment in the registry, which reduces survival bias. Although we adjusted for age, sex, and Charlson comorbidity index, we did not adjust for all characteristics that were different between group 3 and group 1 PH in the survival analysis.
In conclusion, patients with group 3 PH have greater functional limitations, worse RV function, and increased mortality compared with those with group 1 PH. These data highlight the requirement for further exploration of RV dysfunction in group 3 PH and the need for effective therapies to improve survival for this vulnerable patient population.
Footnotes
K.W.P. is funded by NIH F32 HL129554. S.L.A. is supported by the Canada Foundation for Innovation (229252 and 33012), NIH RO1 HL113003, a Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine (950-229252), and a grant from the William J. Henderson Foundation. T.T. is funded by AHA Scientist Development Grant 15SDG25560048.
Author Contributions: K.W.P. and T.T. conceived the study. K.W.P., L.R., F.K., and T.T. collected and analyzed the data. J.R.M. analyzed the data. K.W.P., S.L.A., M.P., E.K.W., and T.T. interpreted the results and wrote the manuscript.
Originally Published in Press as DOI: 10.1164/rccm.201712-2405LE on January 23, 2018
Author disclosures are available with the text of this letter at www.atsjournals.org.
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