Pulmonary arterial hypertension (PAH) is a rapidly progressive condition associated with marked functional limitation, impaired quality of life (QOL), and poor prognosis. Patients typically present with exertional symptoms, but the diagnosis is based on abnormalities in resting hemodynamics (13).
Elevated pulmonary vascular resistance, an attenuated increase in cardiac output (CO) on exercise, and reduced peak oxygen consumption (V˙O2) have been reported in patients with a normal mean pulmonary artery pressure (mPAP) at rest but an mPAP > 30 mm Hg and pulmonary artery wedge pressure < 20 mm Hg on exercise (22). Historically, these pressures also defined PAH (6); however, a recent consensus statement on pulmonary hypertension excluded a diagnosis of PAH based on responses to exercise (13). Uncertainty exists regarding the utility of a specific threshold for mPAP during exercise to discriminate between patients with pulmonary hypertension and healthy individuals (10). However, recent studies have identified reduced exercise capacity associated with an exercise mPAP > 28 mm Hg (11) and progression from mPAP > 30 mm Hg on exercise to PAH at rest in subjects with connective tissue disease (2). These findings support the contention that mPAP > 30 mm Hg and pulmonary artery wedge pressure < 20 mm Hg on exercise, in patients with a clinical suspicion of PAH, may represent an early manifestation of the pathology underlying PAH (11,22).
Ventilatory and gas exchange abnormalities on exercise have been well described in PAH (5,21,24,26) and reflect the severity of the underlying functional impairment (21,26). Subjects with PAH have an elevated ventilatory equivalent for carbon dioxide (V˙E/V˙CO2) and reduced end-tidal carbon dioxide (PetcO2) at the anaerobic threshold (AT), a fall in PetcO2 from rest to AT, and reduced oxygen saturation at peak exercise. Therefore, concurrent evaluation of ventilatory and central hemodynamic responses during exercise may help identify patients with early pulmonary vascular disease and lead to earlier diagnosis of PAH. This is important, given that pharmacotherapy is more effective in earlier stages of PAH (14,25).
We studied a symptomatic cohort of patients, at risk of PAH, to determine whether an exercise mPAP > 30 mm Hg and pulmonary artery wedge pressure < 20 mm Hg (which we termed exercise-induced pulmonary arterial hypertension (EIPAH) for the purposes of this study) was associated with hemodynamic and ventilatory abnormalities typical of PAH. We also sought to determine the effect of EIPAH on exercise capacity and QOL.
Consecutive adult patients referred for investigation of possible PAH were recruited according to clinical, echocardiographic, and lung function criteria. Patients with clinical or echocardiographic evidence of left heart disease, a high probability of PAH at rest (pulmonary artery systolic pressure > 45 mm Hg) (17), symptoms of dyspnea and fatigue at rest, a body mass index > 35 kg·m−2, anemia (hemoglobin < 110 g·L−1), or musculoskeletal impairment were excluded.
Inclusion criteria were exertional dyspnea and risk factors for PAH, defined as scleroderma with a hemoglobin-corrected diffusing capacity for carbon monoxide < 70% predicted and normal lung volumes, and/or a first-degree relative with confirmed PAH and/or pulmonary artery systolic pressure 35-45 mm Hg on echocardiogram. Forty-five patients who met these criteria underwent further assessment, including high-resolution computed tomography and bronchial provocation testing, and six were subsequently excluded because of parenchymal lung or airway disease.
Thirty-nine subjects underwent evaluation of resting and exercise hemodynamics, exercise capacity, ventilatory response to exercise, and QOL. One subject was withdrawn because of myocardial ischemia on exercise and one because of an incomplete assessment. Seventeen subjects were found to have EIPAH, 6 had PAH (mPAP > 25 mm Hg, pulmonary artery wedge pressure < 15 mm Hg at rest), and 10 had noPAH (mPAP ≤ 25 mm Hg at rest and ≤30 mm Hg on exercise). Four subjects were found to have an mPAP ≤ 25 mm Hg at rest and an mPAP > 30 mm Hg and a pulmonary artery wedge pressure ≥ 20 mm Hg on exercise, suggesting exercise-induced left ventricular diastolic dysfunction (EILVDD). Twenty healthy controls, matched to the EIPAH group for age, gender, and body mass index, were recruited from the general population and evaluated for exercise capacity, ventilatory response to exercise, and QOL but not for central hemodynamics.
The study was approved by the human research ethics committees of the Royal Perth Hospital and Curtin University. Written informed consent was obtained from all subjects.
Exercise capacity was assessed by 6-min walk distance (6MWD) according to a standardized protocol (1) and a cardiopulmonary exercise test. The cardiopulmonary exercise test was performed using an electronically braked cycle ergometer attached to a customized imaging table (Lode BV, Groningen, The Netherlands) with the subject in a semirecumbent position (torso at 50° from the horizontal). An incremental symptom-limited protocol was used, which comprised a 3-min baseline period at rest followed by 15-W increments in workload every 3 min. The initial workload was individualized based on age, gender, and 6MWD. Standardized instructions and encouragement were provided to promote a maximum effort.
Breath-by-breath ventilation, oxygen and carbon dioxide concentrations, and derived minute ventilation, V˙O2, and carbon dioxide production were recorded (Vmax SensorMedics, Yorba Linda, CA). The maximum workload was defined as the highest workload sustained for >30 s. Peak V˙O2 was defined as the 30-s average centered on the highest V˙O2 measured at the maximum workload. Minute ventilation, V˙O2, carbon dioxide production, and RER were calculated in the same manner. Predicted values for maximum V˙O2 were those determined by Jones et al. (8).
Pulmonary artery pressure, pulmonary artery wedge pressure, and right atrial pressure were measured in the semirecumbent position. For transducer calibration, the zero position was taken as the fourth intercostal space in the midaxillary line. Pulmonary artery pressure and right atrial pressure were recorded continuously (Compact; Datex Engstrom, Helsinki, Finland), and CO was determined using thermal filament thermodilution, updated every 60 s (Vigilance; Baxter, Irvine, CA. Pulmonary artery wedge pressure was recorded at rest and every 3 min, immediately before an increase in workload and in the final minute of the test. If a subject performed <30 s of the final workload, the peak pulmonary artery pressure, pulmonary artery wedge pressure, right atrial pressure, and CO responses were taken as the values measured within the last 60 s of the previous workload.
Hemodynamic digital data were streamed from the Datex and Vigilance monitors to a data acquisition system (Powerlab; AD Instruments, Sydney, Australia). Storage of analog data (8-channel, 12-bit digital-to-analog converter (NI-DAQ 6008) using proprietary software written in LabVIEW 7.0; National Instruments, Austin, TX) allowed subsequent interrogation of the ECG and pulmonary artery pressure wave-form data and determination of pulmonary artery wedge pressure and pulmonary artery pressure at end expiration. All measurements were corrected for phase delay. Predicted peak CO was calculated assuming an arterial-venous O2 content difference of ([hemoglobin] × 10) (24). Systemic arterial pressure was measured manually at the brachial artery.
QOL was assessed using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36; Version 1) to determine the status and the transition from 12 months prior.
All data are presented as mean ± SD unless otherwise stated. A mixed model to allow for matching of control and EIPAH subjects was performed for the analysis of the differences in baseline characteristics between control and EIPAH groups, and a t-test was used to identify differences between these groups. One-way ANOVA and post hoc analysis with the Holm test was used to identify the difference in baseline characteristics between noPAH, EIPAH, and PAH groups. Conditional logistic regression for matched subjects was performed to determine the differences in hemodynamic, ventilatory, and exercise capacity outcome measures, and the Wilcoxon matched pairs signed-rank test was performed to determine the difference in QOL measures between the EIPAH and control groups. Multinomial regression was used to determine the difference in outcome measures between the noPAH, EIPAH, and PAH groups. Statistical analyses were performed using Stata Version 11 (Stata Corp., College Station, TX) or SPSS software version 18 (SPSS, Chicago, IL). P < 0.05 was accepted as significant.
Effect size was calculated on the basis of an expected V˙E/V˙CO2 at AT of 29 ± 4 in healthy individuals (21) and a V˙E/V˙CO2 above 34 as a discriminating value for a pulmonary vascular limit to exercise (12) in the EIPAH group. Assuming 80% power and a 5% significance level, the sample size required to achieve a probability of 90% for detecting a difference between the EIPAH and control group was at least 14 subjects in each group.
Demographic data are presented in Table 1. The diffusing capacity for carbon monoxide was significantly reduced in the EIPAH and PAH groups, when compared with the reference range (3) and the control group. Subjects in the noPAH group were younger than those in the EIPAH, PAH, and EILVDD groups. There was a higher proportion of subjects with scleroderma in the EIPAH and PAH groups compared with the noPAH group.
No serious adverse events occurred. All cardiopulmonary exercise tests were symptom-limited. Dyspnea was the most common symptom limiting exercise in the PAH and EIPAH groups (Table 2).
Ventilatory comparisons between the EIPAH and matched control groups.
Compared with their matched control group, the EIPAH group demonstrated significant ventilatory abnormalities and impairment in exercise capacity. EIPAH was associated with an elevated V˙E/V˙CO2 and reduced PetcO2 at AT and an attenuated rise in PetcO2 from rest to AT. Further, EIPAH was associated with a significantly lower AT, peak V˙O2, and 6MWD (Table 2). These abnormalities were similar to the characteristic responses demonstrated by the PAH group, although less severe (Table 2).
There was an inverse correlation between V˙E/V˙CO2 at AT and peak V˙O2 (r = −0.63, P < 0.01) and between V˙E/V˙CO2 at AT and 6MWD (r = −0.59, P < 0.01) when data from the EIPAH and PAH groups were combined.
The EIPAH group had a significant impairment in QOL, with the greatest impairment in the physical domains (Table 3). Based on responses to the health transition item, a higher proportion of subjects in the EIPAH group than the control group reported that their health was worse compared with the previous year (24% vs 5%, respectively, P < 0.01).
QOL comparisons between PAH, EIPAH, EILVDD, and noPAH groups.
There were no significant differences in QOL between the PAH, EIPAH, EILVDD, and noPAH groups, including the health transition responses (all P > 0.05).
Hemodynamic comparisons between the EIPAH, PAH, and noPAH groups.
When adjusted for age, there was no significant difference in peak exercise CO between groups. Peak exercise CO was lower than predicted in all groups (Table 4). At rest, the EIPAH group demonstrated a higher mPAP, pulmonary vascular resistance, and right ventricular stroke work index than the noPAH group. The EIPAH and PAH groups had a significantly greater rise in mPAP (Table 4), and the PAH group had a steeper slope in the relationship between mPAP and CO (Fig. 1) from rest to peak exercise than the noPAH group. By definition, the PAH group had a higher mPAP at rest, and the EIPAH group had a higher mPAP at peak exercise than the noPAH group. Stratification by mPAP prevented statistical analysis of the difference in mPAP, or measures derived from mPAP, between PAH and noPAH groups at rest and between EIPAH and noPAH groups at peak exercise.
Comparisons between the EIPAH and EILVDD groups.
The EIPAH group had a significantly higher V˙E/V˙CO2 at AT (P = 0.03) and a lower PetcO2 at AT (P = 0.008) compared with the EILVDD group. There were no statistically significant differences in resting or exercise hemodynamic responses between the EIPAH and EILVDD groups, although by definition, the group with EILVDD had a higher pulmonary artery wedge pressure at peak exercise than the EIPAH group. Similarly, there were no differences in AT, peak V˙O2, or 6MWD between these groups.
Influence of age and diagnosis of scleroderma.
Neither age (r = −0.05, 95% CI = −0.26 to 0.15, P = 0.6) nor the presence of scleroderma (r = 0.76, 95% CI = −4.9 to 6.4, P = 0.8) had an influence on peak exercise mPAP, but both were significant factors in determining peak exercise CO, with older age (r = −0.08, 95% CI = −0.14 to −0.03, P = 0.005) and a diagnosis of scleroderma (r = −1.9, 95% CI = −3.6 to −0.4, P = 0.02) being associated with a lower peak exercise CO. Subjects with scleroderma (n = 20) were older than those without a clinical diagnosis (mean age = 58 ± 12 vs 40 ± 14 yr, P < 0.01). Scleroderma was associated with impaired QOL (social functioning domain; P < 0.05). Neither age nor a diagnosis of scleroderma had a significant influence on any other outcome measure (all P > 0.05).
This study describes exercise abnormalities associated with EIPAH in symptomatic patients, at risk of PAH. EIPAH (mPAP > 30 mm Hg and a pulmonary artery wedge pressure < 20 mm Hg on exercise) was associated with ventilatory abnormalities and a clinically important reduction in exercise capacity, consistent with a pulmonary vascular limitation to exercise and typical of PAH. These exercise impairments were accompanied by a marked reduction in QOL.
Reduced exercise capacity and a low AT, in the presence of an elevated V˙E/V˙CO2 and reduced oxygen saturation, identify a pulmonary vascular limitation to exercise, according to a well-accepted diagnostic algorithm for exercise interpretation (24). Reduced PetcO2 at AT and a fall, rather than a rise, in PetcO2 from rest to AT have also been shown to be associated with PAH (5,26). Our data confirm these findings in the group with PAH. Compared with healthy controls, similar but milder ventilatory abnormalities were evident in the EIPAH group. These abnormalities in the EIPAH group, in whom there was a clinical suspicion of PAH, are consistent with a mild, or early, pulmonary vasculopathy, similar to that present in subjects with PAH. The abnormal ventilatory responses demonstrated by the EIPAH group were not seen in the group with EILVDD. This finding supports the suggestion that the abnormalities demonstrated by the EILVDD group were more likely to be related to left heart dysfunction than a pulmonary vasculopathy. Further, these results lend weight to the suggestion that a cardiopulmonary exercise test may help differentiate these groups. Our findings contrast with those of Walkey et al. (23), who found no difference in the V˙E/V˙CO2 at AT between subjects with scleroderma and an elevated pulmonary artery wedge pressure at peak exercise (EILVDD, n = 4) compared with those with a peak exercise pulmonary artery wedge pressure <18 mm Hg and evidence of a pulmonary vascular limit to exercise (n = 3). However, according to our calculations, the study of Walkey et al. (23) was not powered to detect differences between groups comprising numbers of three and four. There was no overlap of V˙E/V˙CO2 at AT between groups with a pulmonary vascular limit to exercise or EILVDD, with all subjects in the pulmonary vascular group having a higher V˙E/V˙CO2 at AT than those with an elevated pulmonary artery wedge pressure.
The EIPAH group demonstrated a significant impairment in exercise capacity in both peak V˙O2 and 6MWD. Although reduced peak V˙O2 has previously been reported in EIPAH (22), this is the first study to demonstrate that 6MWD is decreased. The 6MWD is a measure of submaximal exercise tolerance that is considered to reflect the capacity to perform activities of daily living (20). The inverse relationship between V˙E/V˙CO2 at AT and both peak V˙O2 and 6MWD in our study suggests an association between ventilatory abnormalities and impaired maximal and submaximal exercise capacity in PAH and EIPAH.
When compared with healthy controls, the subjects with EIPAH had marked reductions in QOL, with a greater magnitude of impairment in the physical health domains than in the mental health domains. In PAH, exertional symptoms affect the ability to perform activities of daily living, which is reflected in the physical domains of the SF-36 (9). Our study demonstrates similar results in the EIPAH group, with exertional symptoms negatively affecting QOL, particularly in the physical domains. The cause of the QOL impairment in the noPAH group is uncertain. However, the finding of diminished QOL in this group is consistent with the significant, persistent exertional symptoms reported by these subjects.
The finding of ventilatory abnormalities in the EIPAH group in the current study contrasts with the observations made by Tolle et al. (22), who identified hemodynamic abnormalities and reduced aerobic capacity in EIPAH but no ventilatory differences between the EIPAH and control groups. This contrasting finding is likely related to the characteristics of the control groups used in the two studies. Subjects in the "normal" group in the study by Tolle et al. (22) were symptomatic patients. In that study, the V˙E/V˙CO2 at AT was not sensitive in discriminating between subjects with and without EIPAH; however, the reported mean V˙E/V˙CO2 at AT of 36 for the "normal" group (mean age = 45.9 yr) is unlikely to represent a healthy response (12). Our inclusion of an asymptomatic control group allowed evaluation of the ventilatory response of subjects with EIPAH against responses in healthy age-, gender-, and body mass index-matched control subjects and identified indisputable ventilatory abnormalities associated with EIPAH. In our study, there were significant hemodynamic differences between the EIPAH and noPAH groups. However, the younger, symptomatic noPAH group demonstrated impairments in peak exercise CO and exercise capacity, compared with age-appropriate reference values, confirming that they would not have been an appropriate control group for this study.
PAH is known to be a progressive condition, although the rate of progression is variable (4). The clinical course of subjects with elevated mPAP on exercise is unknown. The finding that 24% of subjects with EIPAH in this study reported worsening QOL during the previous year raises the possibility that EIPAH may be associated with disease progression and represents an early phase of PAH. This is consistent with the recent findings by Condliffe et al. (2), who reported that EIPAH associated with connective tissue disease progressed to PAH at rest in 19% of subjects and that death related to pulmonary hypertension and/or right-sided heart failure occurred in 10% of subjects during a mean period of 3.3 yr.
The question whether EIPAH progresses to PAH remains unanswered. However, regardless of progression, the current study identified marked functional impairments associated with EIPAH, suggesting that this condition warrants consideration for therapy. Clinical benefits that include an improvement in 6MWD and functional class have recently been described after pharmacologic therapy for "exercise-uncovered" PAH (defined as mPAP < 25 mm Hg at rest but mPAP > 30 mm Hg and a pulmonary artery wedge pressure ≤ 15 mm Hg on exercise) in an open-label trial (16). These findings demonstrate that, for selected patients with an mPAP > 30 mm Hg on exercise, PAH-specific therapy is beneficial. Furthermore, these findings would be consistent with EIPAH being part of a continuum in pulmonary vascular disease.
We specifically chose a group with a high pretest probability of EIPAH to optimize the diagnostic yield of EIPAH in our investigation. Patients with scleroderma are known to be at increased risk of PAH (15). Scleroderma was present in 54% of the patient subjects in our study, and 81% of these had PAH or EIPAH. Our results and those of Condliffe et al. (2) suggest a high incidence of a pulmonary vascular dysfunction and progression in subjects who have scleroderma, a reduced diffusing capacity for carbon monoxide, and exertional symptoms of dyspnea and fatigue. In our study, scleroderma was associated with a lower peak exercise CO and impaired social functioning; however, there was no association between any of the other identified functional limitations and a diagnosis of scleroderma. These impairments, therefore, seem to reflect a pulmonary vasculopathy rather than other morbidities associated with scleroderma. Kovacs et al. (11) also reported an association between increased exercise mPAP and impaired exercise capacity in subjects with scleroderma and suggested a pulmonary vasculopathy as the likely cause for their findings.
To accommodate the possibility that age would be a confounding factor in the difference between the patient groups, we recruited an age-matched control group. In comparison with this control group, clear and indisputable ventilatory, exercise capacity, and QOL impairments were identified in the EIPAH group.
Previous studies reporting invasive central hemodynamics to describe the development of pulmonary hypertension on exercise in symptomatic subjects with an mPAP < 25 mm Hg at rest (7,18,19,22) have significant limitations. Early studies neither measured pulmonary artery wedge pressure on exercise (18,19) nor excluded subjects with an abnormal pulmonary artery wedge pressure at rest or on exercise (7) and, therefore, were unable to exclude postcapillary pulmonary hypertension. The lack of a healthy control group in the study by Tolle et al. (22) prevented an adequate description of the clinical sequelae of EIPAH. The current study has addressed these limitations.
We have demonstrated that combining the assessment of central hemodynamic and ventilatory responses during exercise can identify a likely pulmonary vasculopathy that is not evident at rest. This analysis of pulmonary vascular function under stress provides the potential to improve early diagnosis of PAH, if EIPAH is found to be an early stage of PAH.
Limitations and general applicability of this study.
No central hemodynamic data were collected for control subjects because this was considered unethical owing to the invasive nature of the procedure. This precluded comparison of hemodynamic responses in the EIPAH group with those of healthy controls.
We examined a carefully selected group of patients referred to a regional pulmonary hypertension center, which services a population of 1.5 million people. We believe that our findings cannot be applied to all patients presenting with unexplained dyspnea. Nonetheless, the group we studied represents a dilemma with which clinicians are often faced, namely, a patient presenting with risk factors and a clinical suspicion of PAH but who does not meet diagnostic criteria for PAH at rest.
It is likely that the significance of a rise in mPAP on exercise is influenced by age and the pretest probability of a pulmonary vasculopathy as shown by others (2,10). Although the general applicability of our findings is uncertain, we believe that the abnormalities identified on exercise, in the subjects with EIPAH, are clinically significant. They suggest that, in a selected group, a rise in mPAP with exercise to > 30 mm Hg should not be dismissed even if mPAP is < 25 mm Hg at rest.
We have presented cross-sectional data only. Longitudinal follow-up of the cohort with EIPAH is being undertaken.
This study was not powered to detect a difference in outcome measures between groups of 4 to 10 subjects. Therefore, findings of no difference between the noPAH, EILVDD, and PAH groups with other groups should be interpreted with caution.
The loss of independence of the control group, by individual matching of control and EIPAH subjects, precluded statistical comparison of the noPAH, EILVDD, and PAH groups with the control group.
Hemodynamic findings on exercise, in isolation, may be difficult to interpret because of a wide range of normal responses. However, the combination of hemodynamic and ventilatory measures in the assessment of selected symptomatic patients can identify abnormalities that are characteristic of PAH, may represent early manifestations of a pulmonary vasculopathy, and may therefore facilitate earlier diagnosis of PAH.
The authors thank Dr. Martin Thomas, Dr. Alexandra Higton, Dr. Matthew Best, Min Ding, and the Cardiac Catheter Suite, Royal Perth Hospital, for their assistance with data collection; Christopher Reed, Monty Brydon, and Alan Dick for their technical support; and Michael Phillips and Peter McKinnon for their assistance with statistical analyses.
This research was supported by Bayer Schering Pharmaceuticals and Actelion Pharmaceuticals Australia in the form of unrestricted research grants. R.M.F. has received travel support from Bayer Schering, Actelion, and CSL and an Honorarium from Pfizer Australia. A.M. has received travel support from Actelion. E.G. has received travel support from Actelion, GlaxoSmithKline, Pfizer, and Bayer Schering. E.G. is on the Advisory Board and has received Honoraria and research funding, to a total value of <$20,000 per annum, from GlaxoSmithKline, Actelion, Pfizer, CSL, and Bayer Schering. These funding bodies had no influence on the planning of this study, data collection, analysis, or interpretation. S.C.J., K.R.G., and G.O'D. have no financial relationships with a commercial entity that has a commercial interest in the subject of this article or other conflicts of interest to disclose.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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