Comments
Abstract
Rationale: Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility.
Objectives: To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV–arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP).
Methods: We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure–volume loop analysis.
Measurements and Main Results: Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate.
Conclusions: In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.
In patients with pulmonary hypertension (PH), exercise tolerance is decreased with respect to control subjects. Whether or not this decreased exercise tolerance coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility is unknown.
In this prospective study we show that, in contrast to subjects with no PH, patients with PH have no exertional contractile reserve (as determined by the rest-to-exercise change in end-systolic elastance) to compensate for increase in load, leading to a decrease in RV–arterial coupling during exercise. An absent inotropic response to submaximal exercise warrants further study of the effects of inotropic drugs in RV dysfunction and failure. Because we also observed that the rest-to-exercise change in pulmonary artery pressure did not describe the exertional contractile reserve, but rather correlated to the heart rate response during exercise, it is also suggested that the rest-to-exercise change in pulmonary artery pressure should not be used as a surrogate measure for the contractile reserve.
Precapillary pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance (PVR), increasing the load on the right ventricle (RV). The RV’s ability to cope with the increased load is the most important determinant of survival in patients with PH (1). RV dysfunction tends to be more visible during exercise (2–5) and most patients with PH experience exercise intolerance caused by an inadequate increase in pulmonary blood flow during physical activity (2, 4). In healthy individuals, increased demand of oxygen is met by a proportional increase in cardiac output (CO) caused by an increase in stroke volume (SV) and heart rate (HR). In patients with PH, CO response is truncated during exercise because of a blunted maximal HR response together with an inability to increase SV (3, 5–10). It is unclear whether exercise intolerance and the impaired CO response to exercise in PH coincide with a failure to increase RV contractility during exercise (i.e., an impaired exertional contractile reserve).
The only way to assess the exertional contractile reserve is by determining end-systolic elastance (Ees): a load-independent measure of contractility that can be derived either from a family of pressure–volume loops or from the so-called single-beat method (11, 12). As such, the exertional contractile reserve can be described as the rest-to-exercise response in Ees (ΔEes). Pressure–volume loop analysis also provides the opportunity to determine arterial elastance (Ea), a measure of RV afterload. The matching of Ees to Ea is known as RV–arterial coupling and its preservation is important in terms of ventricular efficiency (13, 14). Because in PH, Ees is already considerably increased at rest (15), we hypothesized that patients with PH are unable to further increase Ees during exercise. Therefore, the increase in Ea will lead to a deterioration of RV–arterial coupling during exercise.
The aim of this study was to investigate in patients with PH and control subjects with no PH, the effects of exercise on RV contractility (Ees), Ea, and RV–arterial coupling (Ees/Ea). Additionally, the exertional contractile reserve was compared with a recently proposed surrogate measure, the rest-to-exercise change in pulmonary artery pressure (ΔPAP) (16). The findings of this study contribute to a better understanding of exercise intolerance and right heart failure in PH. Some of the results of this study has been previously reported in the form of an abstract (17).
We prospectively included patients with precapillary PH (idiopathic pulmonary arterial hypertension [IPAH], hereditary pulmonary arterial hypertension [HPAH], and chronic thromboembolic PH [CTEPH]) and control subjects without PH who performed an invasive cardiopulmonary exercise test (iCPET) in the VU University Medical Center from January 2013 until July 2014. Subjects with a history of left-sided heart failure, valvular heart disease, arrhythmias, or neuromuscular disease preventing the subject to exercise were excluded.
In total, 24 subjects performed an iCPET, including 17 patients with PH (13 IPAH, one HPAH, and three CTEPH patients) and 7 control subjects. The control group consisted of subjects in whom the iCPET did not confirm a previous suspicion of PH. In nine patients with IPAH, the iCPET was part of an ongoing clinical trial that was approved by the Medical Ethical Review Committee of the VU University Medical Center (Registration number: NL41878.029.13). In the remaining 15 subjects, the iCPET was part of their clinical evaluation. All subjects gave written informed consent for usage of the data for research purposes.
The day prior to the invasive exercise test, a maximal CPET was performed in the upright position using an electromagnetically braked cycle-ergometer (Ergoline GmbH, Bitz, Germany) according to the American Thoracic Society guidelines (18). Breath-by-breath measurements were made of o2, Vco2, and e (Vmax229; Sensormedica, Yorba Linda, CA).
A balloon-tipped, flow-directed 7.5F, triple-lumen Swan-Ganz catheter (Edwards Lifesciences LLC, Irvine, CA) was inserted in the pulmonary artery via the jugular vein under local anesthesia and constant ECG monitoring. The ports of the catheter were placed in the right atrium, RV, and pulmonary artery. The zero reference level for the pressure transducer was placed at midthoracic level in supine position. Subsequently, a second catheter was placed in the radial artery under local anesthesia. After placement of the pulmonary artery and radial artery catheters, patients were positioned on a recumbent bicycle (Lode, Groningen, the Netherlands) in supine position. After calibration of the equipment, resting hemodynamics (right atrial pressure, right ventricular pressure, PAP, and systemic blood pressure) were continuously recorded using a Powerlab data acquisition system (Chart 5 for Windows; AD Instruments, Sydney, Australia); resting mixed venous oxygen and arterial oxygen blood samples were drawn from the pulmonary artery and radial artery catheters; and breath-by-breath measurements were made of o2, Vco2, and e (Vmax229, Sensormedica).
The exercise protocol consisted of 1 minute of unloaded cycling followed by 2 minutes of submaximal exercise (40% of maximal workload [Wmax] during maximal CPET) with continuous recording of hemodynamics. Near the end of exercise, mixed venous and arterial blood samples were again drawn from the pulmonary artery and radial artery catheters.
For subjects whose Wmax was less than 150 W, submaximal workloads were immediately increased to 40% of Wmax after 1 minute of unloaded exercise. For subjects with a Wmax greater than 150 W, a direct increase to 40% of Wmax was too large and therefore these subjects were exercised at one additional intermediate step of 1 minute of exercise at 35 W in patients with PH and 45 W in control subjects. This intermediate step allowed data comparison at approximately similar absolute work rates in all subjects.
CO at rest and during exercise was measured using the direct Fick method. SV was calculated as CO divided by HR. CO and SV were indexed for body surface area. PAP was averaged over a period of 15 seconds to be sure that the PAP was measured over multiple respiratory cycles.
The Ees, a load-independent measure of RV contractility, was calculated at rest and during submaximal exercise as:
The load on the RV was calculated as:
Data are presented as mean ± SD unless stated differently. Comparisons of characteristics, CPET parameters, and resting hemodynamics between patients with PH and control subjects were performed using independent t tests for normally distributed data and Mann-Whitney U tests for not normally distributed data. Chi-square tests were used to analyze dichotomous variables. Comparisons of rest-to-exercise responses between patients with PH and control subjects were performed using two-way repeated measures analysis of variance with Bonferroni post hoc correction. The Pinteraction represents the P value for the effect of exercise in patients with PH in comparison with control subjects. Because patients with PH were significantly older than control subjects, the differences between patients with PH and control subjects in rest-to-exercise responses of HR, Ees, Ea, and RV–arterial coupling were adjusted for age using multivariate analysis of covariance. Simple linear regression was performed to describe the relationship between rest-to-exercise responses of different parameters in the PH group. Statistical analyses were performed using Graphpad Prism for Windows version 5 (GraphPad Software, Inc., San Diego, CA) and SPSS for Windows version 20 (IBM Corp., Armonk, NY). A P value less than 0.05 was considered statistically significant.
Of the 24 subjects that performed an iCPET, in 16 patients with PH and 5 control subjects, hemodynamic data at 40% of Wmax was of sufficient quality to analyze. In one patient with IPAH and in two control subjects the pressure signal was lost during exercise because of displacement of the pulmonary artery catheter. Ten of the 16 patients with PH used PH-specific treatment at the moment of the iCPET (Table 1). Final diagnosis and medication of the control subjects are described in Table 2.
Patients with PH were significantly older than the control subjects (Table 1). As expected, patients with PH showed, during maximal CPET, significantly lower maximal oxygen consumption, workload, and HR compared with control subjects (Table 1). Resting hemodynamics showed significantly higher mean PAP (mPAP), PVR, and right atrial pressure and significantly lower cardiac index (CI), arterial, and mixed venous oxygen levels in patients with PH compared with the control subjects (Table 1). Between groups there was no difference in HR at rest. RV contractility (Ees) and RV afterload (Ea) at rest were significantly increased in patients with PH compared with control subjects, whereas no difference was seen in RV–arterial coupling (Table 1).
| Control Subjects (n = 5) | Pulmonary Hypertension (n = 16) | P Value | |
|---|---|---|---|
| Characteristics | |||
| Age, yr | 38 (12) | 57 (14) | 0.015 |
| Sex, n female | 3 | 11 | 0.717 |
| BSA, m2 | 1.853 (0.327) | 1.883 (0.181) | 0.850 |
| Diagnosis | 12 IPAH, 1 HPAH, 3 CTEPH | ||
| NYHA, II/III, n | 9/7 | ||
| Treatment, n | |||
| None | 5 | ||
| ERA | 2 | ||
| PDE5I | 1 | ||
| Prostanoids | 0 | ||
| ERA + PDE5I | 8 | ||
| Ca2+ antagonists | 1 | ||
| β-Blockers | 2 | ||
| CPET max | |||
| o2/kg, ml/kg/min | 31 (8) | 16 (5) | <0.001 |
| Work, W | 187 (87) | 90 (44) | 0.005 |
| HR, bpm | 174 (5) | 139 (15) | <0.001 |
| RHC rest | |||
| HR, bpm | 75 (14) | 77 (15) | 0.785 |
| CI, L/min | 4.7 (0.8) | 3.1 (0.6) | <0.001 |
| mPAP, mm Hg | 18 (2) | 53 (8) | <0.001 |
| PAWP, mm Hg | 11 (2) | 12 (2) | 0.475 |
| PVR, dyn/s/cm5 | 69 (14) | 582 (168) | <0.001 |
| mRAP, mm Hg | 4 (1) | 7 (4) | 0.015 |
| Sao2, % | 99 (0.5) | 95 (2) | <0.001 |
| So2, % | 82 (2) | 70 (4) | <0.001 |
| CMRI | |||
| RVEDV, ml | — | 151 (52) | |
| RVESV, ml | — | 88 (53) | |
| RVEF, % | — | 47 (13) | |
| LVEF, % | — | 61 (15) | |
| Load-independent RV function rest | |||
| Ees, mm Hg/ml/m2 | 0.47 (0.20) | 2.00 (0.50) | <0.001 |
| Ea, mm Hg/ml/m2 | 0.29 (0.05) | 1.36 (0.45) | <0.001 |
| Ees/Ea | 1.63 (0.74) | 1.61 (0.54) | 0.963 |
| Control Subject | Final Diagnosis | Medication |
|---|---|---|
| 1 | High-frequency ventilation and scoliosis | Long-acting β-agonist; inhalation glucocorticoid |
| 2 | Physical deconditioning after PE | Vitamin K antagonist |
| 3 | No cause found | None |
| 4 | No cause found | None |
| 5 | Physical deconditioning after PE | Vitamin K antagonist |
In control subjects 40% of Wmax was 70 ± 34 W and in patients with PH this was 39 ± 14 W (P = 0.009). From rest to exercise, both groups showed a significant increase in CI (Figure 1A), with a larger increase in CI in control subjects (Pinteraction = 0.003). During exercise, both groups showed a significant increase in HR, but no change in SVI (Figure 1B). The increase in HR was larger in control subjects compared with patients with PH (Pinteraction = 0.039), but not after correction for age (P = 0.300) (Figure 1C). The mPAP and RV systolic pressures (RV Psys) increased significantly during exercise in control subjects and patients with PH (Figures 1D and 1E), with larger increases seen in the PH group (mPAP, Pinteraction = 0.005; RV Psys, Pinteraction = 0.019). Pmax, derived from the single-beat method, was significantly higher than resting values in both groups (Figure 1F). Total PVR significantly decreased in patients with PH from rest to exercise (Figure 1G).
Figure 1. (A) Cardiac index (CI) significantly increased in both groups during exercise, with a larger increase in CI in the control subjects (P = 0.003). (B) Stroke volume index (SVI) did not increase in both groups. (C) *Pinteraction adjusted for age. Heart rate (HR) significantly increased during exercise in both groups during exercise, with a larger increase in HR in the control subjects (Pinteraction = 0.039). After correction for age, the rest-to-exercise response in HR between groups was not different (P = 0.300). (D) Mean pulmonary artery pressure (mPAP) significantly increased in both groups during exercise, with a larger increase in mPAP in patients with PH (Pinteraction = 0.005). (E) Right ventricular systolic pressure (RVPsys) significantly increased in both groups during exercise, with a larger increase in RVPsys in patients with PH (Pinteraction = 0.019). (F) Maximal isovolumic pressure (Pmax) significantly increased in both groups during exercise. (G) Total pulmonary vascular resistance (TPVR) significantly decreased in patients with PH during exercise. (H) o2 significantly increased in both groups during exercise, with a larger increase in o2 in control subjects (Pinteraction = 0.006). (I) So2 significantly decreased in both groups during exercise. Data are presented as mean ± SE. Blue bars represent the data at rest, and red bars represent the data during exercise at 40% of Wmax. PH = pulmonary hypertension.
[More] [Minimize]From rest to exercise, RV contractility (Ees) increased significantly in control subjects, but not in patients with PH (Pinteraction ≤ 0.001), implying an impaired exertional contractile reserve (Figure 2).
Figure 2. (A) End-systolic elastance (Ees) significantly increased in control subjects during exercise, but not in patients with pulmonary hypertension (PH) (Pinteraction < 0.001). (B) Arterial elastance (Ea) significantly increased in both groups during exercise. (C) Right ventricular–arterial coupling (Ees/Ea) significantly decreased in patients with PH during exercise, but not in control subjects (Pinteraction = 0.013). Data are presented as mean and SE. The blue bars represent the data at rest, and the red bars represent the data during exercise at 40% of Wmax. *Pinteraction adjusted for age.
[More] [Minimize]RV afterload (Ea) increased significantly during exercise in both groups (Figure 2). As a result, RV–arterial coupling during exercise decreased in patients with PH, but remained stable in control subjects (Pinteraction = 0.013) (Figure 2).
There was no relation between the rest-to-exercise response in Ees (ΔEes) and PAPs (ΔEes and change in systolic PAP [ΔsPAP], r = 0.350, R2 = 0.123, P = 0.184; ΔEes and ΔmPAP, r = 0.182, R2 = 0.033, P = 0.500), and neither was ΔEes related to ΔHR (r = 0.055; R2 = 0.003; P = 0.838) or ΔSVI (r = 0.373; R2 = −0.139; P = 0.155).
ΔsPAP and ΔmPAP were both related to ΔHR (ΔsPAP and ΔHR, r = 0.579, R2 = 0.335, P = 0.019; ΔmPAP and ΔHR, r = 0.788, R2 = 0.621, P < 0.001) (Figure 3), but not to SVI.
Figure 3. There was a significant correlation between the change in pulmonary artery pressure and the change in heart rate (HR) from rest to exercise (bottom, ΔsPAP and ΔHR, r = 0.579, R2 = 0.335, P = 0.019; top, ΔmPAP and ΔHR, r = 0.788, R2 = 0.621, P < 0.001). mPAP = mean pulmonary artery pressure; sPAP = systolic pulmonary artery pressure.
[More] [Minimize]This is the first study to describe the RV exertional contractile reserve in patients with PH and the effects of exercise on RV–arterial coupling. We showed that patients with PH have an impaired exertional contractile reserve and that the failure to increase contractility during exercise in response to the increased RV afterload led to a deterioration of RV–arterial coupling.
In line with previous studies, RV contractility (Ees) measured at rest was larger in patients with PH than in control subjects (15, 22). Here we show that patients with PH are unable to increase RV contractility during exercise and this suggests that RV contractility is already maximally increased at rest.
As far as we know, the rest-to-exercise response in a load-independent measure of RV contractility has never been studied in healthy subjects. In the left ventricle of healthy humans, the increase in load-independent measures of contractility during exercise (23–25) is largely caused by an increase in β-adrenergic stimulation (26). The impaired rest-to-exercise response in RV contractility in patients with PH could relate to the down-regulation and desensitization of β-adrenergic receptors, which has been shown in PH rat models (27) and patients with PH (28). It has been suggested that the increased catecholamine levels at rest in PAH (29) may lead to an inability to increase catecholamine levels during exercise (30). Interestingly, an impaired inotropic RV response was also observed in a recent study using different PH rat models treated with several inotropic agents (27). The impaired exertional contractile reserve found in our study adds to the debate whether it is useful to treat patients with PH with RV failure with inotropic agents (30). Although a degree of caution has to be taken into account regarding the extrapolation of our findings during submaximal exercise to a situation of RV failure, the usefulness of inotropic agents in patients with PH with RV failure should be studied in a randomized controlled trial. Absence of a contractile reserve suggests that it may be more useful to treat RV failure with agents that reverse maladaptive RV remodeling.
We found a significant increase in load (Ea) on the RV in patients with PH and control subjects during exercise, whereas total PVR (= Ea ∙ HR) significantly decreased in patients with PH and remained stable in control subjects. Most hemodynamic exercise studies measured load as PVR and showed a decrease or stable PVR during exercise in both patients with PH and healthy control subjects (2, 31–34). The difference between both measures of load is explained by the way in which they are calculated: PVR as pressure divided by CO, and Ea as pressure divided by SV. Despite the larger RV afterload in patients with PH at rest, no differences in RV–arterial coupling between patients with PH and control subjects were found, implying that RV–arterial coupling at rest was well maintained. It was shown in a large cohort of patients with IPAH that RV–arterial coupling at rest was maintained in stable patients with PH and decreased in patients with PH with a more progressive disease (15). Another study showed a decrease in RV–arterial coupling at rest in patients with PH compared with control subjects (35). In this study, the calculation of Ees was simplified as end-systolic pressure divided by end-systolic volume (measured by magnetic resonance imaging), assuming the volume at zero pressure (V0) is zero. However, it has been shown that V0 depends on RV dilatation and therefore that the assumption of V0 = 0 leads to an underestimation of Ees and RV–arterial coupling (21).
The insufficient response in RV contractility to the increase in load resulted in a deterioration in RV–arterial coupling during exercise in patients with PH, whereas in control subjects the exertional contractile reserve was sufficient to maintain RV–arterial coupling. Studies of the LV showed that at an Ees/Ea ratio of 1, ventricular stroke work is optimal (14), although maximal ventricular efficiency, defined as ventricular stroke work divided by myocardial oxygen consumption, is reached at an Ees/Ea ratio of 2 (13). Theoretically, the decrease in RV–arterial coupling in patients with PH suggests that the coupling is shifted to an optimal ventricular stroke work at the cost of ventricular efficiency, although this cannot be determined from the current data.
A recent study in patients with PH defined the contractile reserve as the increase in systolic PAP during exercise (16). In this study, a larger increase in sPAP was associated with a better survival. The rationale for using ΔsPAP as a measure of contractile reserve was derived from the pressure–flow relation. The authors stated that a greater increase in pressure allows the ejection of a higher SV and that, therefore, the contractile reserve can be described by the increase in pressures. In our study ΔPAP did not correlate with ΔEes or with ΔSVI. Because it is known that the increase in SV in patients with PH during exercise is only minor (3, 5–9), the increase in CI during exercise is highly HR dependent. Our data showed significant relations between the increases in PAP and ΔHR. This is in line with a recent study showing a strong relation between ΔmPAP and ΔHR during exercise in patients with PAH (7). Therefore, a large increase in PAP during exercise seems not to indicate an intact contractile reserve, but rather a more preserved HR response. The ability to increase HR is a well-known predictor of survival (36, 37) and the better survival found by Grünig and coworkers (16) in patients with PH with a larger increase in PAP during exercise could reflect a relatively intact HR response.
Although a direct link between exercise capacity and RV contractile reserve was not investigated in this study, our findings suggest that a decreased exercise capacity in PH is not only the direct result of an increased pressure in the lung circulation, but also caused by intrinsic changes in RV contractility. Moreover, our study results imply that inotropic drugs may have little value in improving RV dysfunction in PH. Studies are warranted to identify interventions that could restore RV contractile reserve by reversing maladaptive remodeling.
Because the rest-to-exercise response in PAP was not related to the rest-to-exercise response in Ees, but rather reflected an intact HR response, the rest-to-exercise response in PAP should not be used as a surrogate measure of the exertional contractile reserve.
For safety reasons, we exercised subjects only at submaximal workloads (40% of Wmax). In a subanalysis hemodynamic data were compared at comparable submaximal workloads of 37 W ± 12 in patients with PH and 46 W ± 5 in control subjects (P = 0.096). Differences between patients with PH and control subjects in rest-to-exercise responses of hemodynamics and load-independent measures of RV function were similar in direction and magnitude as in the data at 40% of Wmax (results not shown). From our results, we cannot determine whether the observed differences at submaximal exercise can be extrapolated to maximal exercise testing.
In the calculation of Ees, we used mPAP as a surrogate for RV end-systolic pressure based on a study of Chemla and coworkers (38) who found that in normal subjects mPAP was closely related to RV end-systolic pressure. It is possible that in a pressure-overloaded RV, RV end-systolic pressure is more closely related to the systolic RV pressure (39), which would have led to an overestimation of Ees. However, mPAP and systolic RV pressure were strongly related at rest and during exercise, implying that the choice of pressure does not influence the direction of the rest-to-exercise response.
Although the single-beat method has been developed and validated for the left ventricle (12), validation of the method in PH has been restricted to animals (11). The results of that study showed, in a wide range of Pmax values, that an excellent relation exists between Pmax determined by the single-beat method and the Pmax values determined after clamping of the pulmonary artery.
We used relatively deconditioned control subjects, because the primary indication to perform iCPET in these subjects was unexplained dyspnea. Based on the literature (3, 40–42), including a previous study from our institute (3), we did not expect to find an unchanged SV in healthy subjects during submaximal exercise. The difference in SV response in control subjects between the current study and our previous study (3) can probably be explained by the fact that the control subjects in our previous study were healthy volunteers in good condition. Several previous studies showed physiologic explanations for an unchanged SV from rest to exercise. A reduced filling time caused by an increase in HR can result in an inability to increase SV in healthy subjects. Furthermore, in the upright position, the venous return is increased from rest to exercise via the muscle pump. When exercise is performed in the supine position, the venous return is already increased at rest because of the return of pooled blood caused by gravity, resulting in an inability to increase SV during exercise (6, 43–49).
Because we already found large differences in the hemodynamic rest-to-exercise responses between patients with PH and relatively deconditioned control subjects, the inclusion of relatively deconditioned control subjects only strengthens our findings.
Patients with PH had no RV exertional contractile reserve, which resulted in RV–arterial uncoupling during submaximal exercise. Rest-to-exercise responses in PAPs rather reflected the rest-to-exercise response in HR than an exertional contractile reserve and should therefore not be used as a surrogate measure of exertional contractile reserve.
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Supported by the NWO, Vidi Grant, project number 91.796.306 (A.V.-N.).
Author Contributions: All authors contributed significantly to the submitted work. O.A.S. and H.-J.B. contributed to the conception and design of the study, the analysis and interpretation of data, and the writing of the manuscript. F.S.d.M., H.G., F.O., N.W., and A.V.-N. contributed to the conception and design of the study, the analysis and interpretation of data, and revising the manuscript. All authors gave their final approval.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201412-2271OC on February 24, 2015
Author disclosures are available with the text of this article at www.atsjournals.org.
