Borderline Pulmonary Arterial Pressure Is Associated with Decreased Exercise Capacity in Scleroderma

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1 Borderline Pulmonary Arterial Pressure Is Associated with Decreased Exercise Capacity in Scleroderma Gabor Kovacs 1, Robert Maier 2, Elisabeth Aberer 3, Marianne Brodmann 4, Stefan Scheidl 1, Natascha Tröster 1, Christian Hesse 1, Wolfgang Salmhofer 3, Winfried Graninger 5, Ekkehard Gruenig 6, Lewis J. Rubin 7, and Horst Olschewski 1 1 Departments of Pulmonology, 2 Cardiology, 3 Dermatology, 4 Angiology, and 5 Rheumatology, Medical University Graz, Graz, Austria; 6 Department of Cardiology, University of Heidelberg, Heidelberg, Germany; and 7 University of California San Diego Medical Center, La Jolla, California Rationale: Pulmonary arterial hypertension is associated with impaired exercise capacity and decreased survival in patients with scleroderma. Randomized controlled studies showed significant benefit of targeted therapies in patients with a resting mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg. The clinical relevance of pulmonary arterial pressure values in the upper normal range is unknown. Objectives: To examine the clinical relevance of pulmonary arterial pressure in scleroderma patients. Methods: After a noninvasive screening program, 29 patients with systemic sclerosis without significant lung fibrosis and without known pulmonary arterial hypertension underwent right heart catheterization and simultaneous cardiopulmonary exercise test. A six-minute walk distance (6MWD) was determined within 48 hours. Measurements and Main Results: A resting MPAP above the median (17 mm Hg) was associated with decreased 6MWD ( vs m; P, 0.005) and peak VO 2 ( % vs %; P ). Resting pulmonary vascular resistance was inversely correlated with 6MWD (r ; P, 0.05). At 25 and 50W, MPAP above the median (23 and 28 mm Hg) was associated with decreased 6MWD (P, 0.005; P, ). At peak exercise, MPAP showed no association with 6MWD or peak VO 2 ; however, cardiac index was positively (r ; P, 0.05) and pulmonary vascular resistance was negatively correlated with 6MWD (r ; P, 0.05). Conclusions: MPAP and resistance in the upper normal range at rest and moderate exercise are associated with decreased exercise capacity and may indicate early pulmonary vasculopathy in patients with systemic sclerosis. Investigations on the prognostic and therapeutic implications of such borderline findings are warranted. Clinical trial registered with (NCT ). Keywords: exercise capacity; connective tissue disease; pulmonary arterial hypertension; pulmonary arterial pressure increase Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and leads to impaired right ventricular function, decreased exercise capacity, and death. Current guidelines define PAH as a mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise (1). According to measurements in healthy individuals, normal resting MPAP is mm Hg (2). The clinical relevance of MPAP values in the upper normal range is unknown. Previous studies on chronic obstructive pulmonary disease and lung fibrosis suggested that resting MPAP (Received in original form April 14, 2009; accepted in final form August 12, 2009) Supported by Actelion Austria. Correspondence and requests for reprints should be addressed to Horst Olschewski, M.D., Medical University Graz, Department of Pulmonology Austria 8036, Graz, Auenbruggerplatz horst.olschewski@meduni-graz.at This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 180. pp , 2009 Originally Published in Press as DOI: /rccm OC on August 13, 2009 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The presence of manifest pulmonary hypertension is associated with worse prognosis in systemic sclerosis. What This Study Adds to the Field Borderline elevation of mean pulmonary arterial pressure at rest and during exercise may represent early pulmonary vasculopathy and is associated with decreased exercise capacity in patients with systemic sclerosis. greater than 17 mm Hg may be associated with adverse events and reduced survival (3 5). There is scarce literature on the prognostic or functional implications of exercise values. Excessive elevation of pulmonary arterial pressure (PAP) during exercise in patients with normal resting PAP may be considered as an early manifestation of pulmonary vasculopathy (6) but can also be caused by left ventricular impairment, intrathoracic pressure elevation, or a combination of these factors. Exercise hemodynamics may be considered to be important for the understanding of the individual exercise-limiting factors (6, 7) and the different diagnostic and therapeutic consequences. In patients at risk for PAH, such as scleroderma, exercise-induced PAH may represent an intermediate stage between normal pulmonary circulation and manifest PAH. However, the prognostic or clinical relevance of this condition is unknown. It is also unknown if the maximal PAP during exercise, the dynamics of PAP increase, or any other parameter describing pulmonary hemodynamics during exercise is of clinical relevance. Systemic sclerosis may be considered a risk factor for PAH. Recent studies suggested that up to 50% of patients with connective tissue disease had an abnormal PAP increase during exercise (8 13). Most of these studies, however, used stressechocardiography, and few applied right heart catheterization (RHC) to all patients (10, 11, 14). The goal of this study was to investigate the impact of resting and exercise PAP on exercise capacity in patients with systemic sclerosis. We enrolled patients without significant pulmonary fibrosis, left heart dysfunction, and manifest PAH. We applied right heart catheterization for measurement of pulmonary hemodynamics and assessed 6-minute walk distance (6MWD) and peak VO 2 representing those objective measures with the highest prognostic relevance in PAH patients (15, 16). We found that mild elevations in resting PAP and pulmonary vascular resistance (PVR) were associated with both elevated PAP during slight exercise levels and reduced exercise capacity. METHODS Patients with systemic sclerosis as the only risk factor for PAH were enrolled into a screening program for PAH where they underwent

2 882 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL exercise doppler echocardiography and cardiopulmonary exercise test (CPET) (11). All patients were diagnosed and classified by an expert panel that included rheumatologists, dermatologists, angiologists, cardiologists, and pulmonologists. The study was approved by the local ethics committee. Patients with manifest PAH, symptomatic obstructive or restrictive pulmonary disease (prebronchodilator FEV 1, 65% predicted), systolic or diastolic left ventricular failure (ejection fraction, 50%, diastolic failure. mild [17]), hemodynamically significant valvular disease, or systemic arterial hypertension or patients with significant arthritis, myositis, or joint problems that might have substantially influenced the exercise tests were excluded. At the initial screening, systolic PAP was calculated at rest and during exercise using the Bernoulli equation: systolic PAP v 2 1 right atrial pressure, where v is the peak velocity of the tricuspid regurgitation jet (m/s), and the right atrial pressure is estimated from the diameter and breathinginduced variability of the inferior vena cava (in all cases 5 mm Hg in our study). Peak VO 2 was adjusted to age, sex, and weight and is given as % predicted. Patients who revealed a significant increase in systolic PAP greater than 40 mm Hg during exercise doppler echocardiography or a decreased exercise capacity (peak VO 2, 75% predicted) at CPET were eligible for this study and were invited to undergo RHC. All patients who agreed and gave informed written consent were investigated. RHC examinations were combined with a simultaneous symptomlimited CPET (25W increase every 2 minutes) on a semi-recumbent cycle ergometer. The same CPET equipment and protocol and the same blood gas analyzer (ABL 825 Radiometer; Bronshoj, Denmark) was used for noninvasive screening and during right heart catheterization. For the RHC examinations, a 7F quadriple-lumen, balloon-tipped, flow-directed Swan-Ganz catheter (Baxter, Deerfield, IL) was introduced using the transjugular approach. Hemodynamic measurements were performed at rest and at each level of exercise. These measurements included systolic, diastolic and mean PAP (MPAP), pulmonary arterial wedge pressure (PAWP), right atrial pressure, and cardiac output (CO) measured by the thermodilution technique and calculated using an analog computer system. Pulmonary vascular resistance was derived from the difference of MPAP and PAWP divided by CO. Cardiac index (CI) was determined as the ratio of CO to body surface area. 6MWD was measured within 48 hours from RHC. Examiners performing the 6MWD were blinded to the RHC data. All examinations were performed by the same experienced team. No complications were observed. Statistics The primary objective of this study was to assess the association between MPAP and exercise capacity. We tested 6MWD and peak VO 2 for this association at rest and at 25W, 50W, and maximal exercise. Due to the explorative nature of this study, the relatively homogeneous population, and the limited number of subjects, we did not correct for covariates and multiple testing. Results are expressed as means 6 SD. All t tests were two sided. P values less than 0.05 were considered significant. Statistical analysis was performed using SPSS software version 14.0 (SPSS, Chicago, IL). RESULTS A total of 63 consecutively referred patients with systemic sclerosis were screened for this study. Fifteen patients were excluded: five due to significant lung involvement, four due to left ventricular impairment, two due to systemic arterial hypertension, and four due to significant arthritis, myositis, or joint problems (n 5 4). Eleven patients presented with SPAP less than 40 mm Hg during rest and exercise and a peak VO 2 greater than 75% predicted and according to our protocol were not suggested to undergo RHC. The remaining 37 patients were invited to participate in this study. Six patients did not agree with RHC. Patients in whom a manifest PAH (mean PAP. 25 mm Hg at rest; n 5 2) was diagnosed at RHC did not undergo further exercise testing and were excluded from analysis. A total of 29 patients with systemic sclerosis were included in the analysis (Table 1). Patients were classified as following: 15 patients had diffuse cutaneous systemic sclerosis, 7 patients had limited cutaneous systemic sclerosis, and 7 patients had overlap syndrome including scleroderma. At rest, MPAP was below 25 mm Hg in all patients ( mm Hg). VO 2, right atrial pressure, and PAWP were in the normal range in all patients (Table 1). Resting Hemodynamics Resting MPAP greater than 17 mm Hg (median) was associated with decreased 6MWD (P, 0.005), peak VO 2 (P ), and maximal work rate (P, 0.05) (Table 2). Resting PVR was inversely correlated with 6MWD (r ; P, 0.05). Resting MPAP was strongly correlated with MPAP values at slight exercise levels (rest vs. 25W, r ; rest vs. 50W, r ) but showed a weak correlation with maximal MPAP (r ). Resting PAWP, right atrial pressure, CO, CI, or systemic blood pressure showed no significant correlation with 6MWD or peak VO 2. Hemodynamics during Slight Exercise All patients completed at least the 50W exercise level. At 25W, MPAP greater than 23 mm Hg (median) (Table 3) and at 50W, MPAP greater than 28 mm Hg (median) (Table 4) were associated with decreased 6MWD (P, and P, ) and lower maximal work rate (P, and P, 0.005). The comparison of 6MWD results of patients with MPAP values below and above the median are represented in Figures 1 and 2. Hemodynamics during Maximal Exercise At maximal exercise, MPAP was not associated with exercise capacity. However, CI was positively (r ; P, 0.05) and PVR was negatively correlated with 6MWD (r ; P, 0.05). DISCUSSION In this exploratory study, we hypothesized that resting and exercise PAP may have an impact on exercise capacity in patients with systemic sclerosis at risk for PAH. To our knowledge, the TABLE 1. MAIN CLINICAL AND HEMODYNAMIC DATA OF 29 PATIENTS WITH SYSTEMIC SCLEROSIS All Patients Mean 6 SD Age, years Disease duration, yr Height, cm Weight, kg DL CO, % predicted Hb, g/dl HR, bpm Mean PAP, mm Hg PAWP, mm Hg RAP, mm Hg PVR, dyns cm CI, L/min/m SPAP, mm Hg Mean SAP, mm Hg SSAP, mm Hg DSAP, mm Hg Max WR VO 2, % predicted MWD, m Definition of abbreviations: bpm5 beats per minute; CI 5 cardiac index; DSAP 5 diastolic systemic arterial pressure; Hb 5 hemoglobin concentration; HR 5 heart rate; PAP 5 pulmonary arterial pressure; PAWP 5 pulmonary arterial wedge pressure; PVR 5 pulmonary vascular resistance; RAP 5 right atrial pressure; SAP 5 systemic arterial pressure; SPAP 5 systolic pulmonary arterial pressure; SSAP 5 systolic systemic arterial pressure; WR 5 work rate; 6MWD 5 6-min walk distance.

3 Kovacs, Maier, Aberer, et al.: Impact of Borderline Pulmonary Pressure in Scleroderma 883 TABLE 2. HEMODYNAMIC CHARACTERISTICS OF PATIENTS WITH MEAN PULMONARY ARTERIAL PRESSURE VALUES ABOVE AND BELOW MEDIAN AT REST TABLE 4. HEMODYNAMIC CHARACTERISTICS OF PATIENTS WITH MEAN PULMONARY ARTERIAL PRESSURE VALUES ABOVE AND BELOW MEDIAN AT 50W MPAP at rest.17 mm Hg (n 5 14) MPAP at rest < 17 mm Hg (n 5 15) P Value MPAP at 50W. 28 mm Hg (n 5 13) MPAP at 50W < 28 mm Hg (n 5 16) P Value Mean PAP, mm Hg PVR, dyns cm SPAP, mm Hg PAWP, mm Hg ,0.05 CO, L/min NS RAP, mm Hg NS Mean SAP, mm Hg NS Max WR, W ,0.05 VO 2, % predicted MWD, m ,0.005 Age, years NS Height, cm NS Weight, kg NS Female:male 12:2 14:1 Definition of abbreviations: CO5 cardiac output; MPAP 5 mean pulmonary arterial pressure; NS 5 not significant; PAWP 5 pulmonary arterial wedge pressure; PVR 5 pulmonary vascular resistance; RAP 5 right atrial pressure; SAP 5 systemic arterial mean pressure; SPAP 5 systolic pulmonary arterial pressure; WR 5 work rate; 6MWD 5 six-minute-walk distance. Mean PAP, mm Hg PVR, dyns cm SPAP, mm Hg CO, L/min NS PAWP, mm Hg NS RAP, mm Hg ,0.05 Mean SAP, mm Hg NS Max WR, W ,0.005 VO 2, % predicted NS 6MWD, m , Age, years ,0.05 Height, cm NS Weight, kg NS Female:male 11:2 15:1 Definition of abbreviations: CO 5 cardiac output; MPAP 5 mean pulmonary arterial pressure; NS 5 not significant; PAWP 5 pulmonary arterial wedge pressure; PVR 5 pulmonary vascular resistance; RAP 5 rightatrialpressure;sap5 systemic arterial mean pressure; SPAP 5 systolic pulmonary arterial pressure; WR 5 work rate; 6MWD 5 six-minute-walk distance. association of resting and exercise pulmonary hemodynamics to exercise capacity in patients with scleroderma has not been investigated. Our results suggest that MPAP values around 14 mm Hg at rest and around 25 mm Hg during mild exercise levels identified patients with a higher exercise capacity compared with patients with MPAP around 20 mm Hg at rest and 30 mm Hg during mild exercise. This suggests that only patients with the average PAP of a control population may be considered unaffected by pulmonary vasculopathy and that this might have an impact on prognosis. Clinical Relevance of Resting PAP Resting MPAP greater than 17 mm Hg was associated with decreased 6MWD and peak VO 2. This finding is in accordance TABLE 3. HEMODYNAMIC CHARACTERISTICS OF PATIENTS WITH MEAN PULMONARY ARTERIAL PRESSURE VALUES ABOVE AND BELOW MEDIAN AT 25W MPAP at 25W. 23 mm Hg (n 5 14) MPAP at 25W < 23 mm Hg (n 5 15) P Value Mean PAP, mm Hg PVR, dyns cm SPAP, mm Hg CO, L/min NS PAWP, mm Hg ,0.05 RAP, mm Hg NS Mean SAP, mm Hg NS Max WR, W ,0.005 VO 2, % predicted NS 6MWD, m ,0.005 Age, years ,0.05 Height, cm NS Weight, kg NS Female:male 12:2 14:1 Definition of abbreviations: CO 5 cardiac output; MPAP 5 mean pulmonary arterial pressure; NS 5 not significant; PAWP 5 pulmonary arterial wedge pressure; PVR 5 pulmonary vascular resistance; RAP 5 rightatrialpressure;sap5 systemic arterial mean pressure; SPAP 5 systolic pulmonary arterial pressure; WR 5 work rate; 6MWD 5 six-minute-walk distance. with previous studies in other patient populations at risk for pulmonary hypertension. Patients with lung fibrosis and a resting MPAP greater than 17 mm Hg had a decreased survival (5-year survival, 16.7%) compared with those with a resting MPAP less than 17 mm Hg (5-year survival, 62.2%) (3), and patients with chronic obstructive pulmonary disease had an increased risk of hospitalization if MPAP was above 18 mm Hg (4) and increased mortality if MPAP was above 20 mm Hg (5). Clinical Relevance of PAP at Slight Exercise In our study, the association between 6MWD and hemodynamics appeared even tighter during low levels of exercise as compared with rest. This suggests that particularly patients with a steeper rise of PAP during slight levels of exercise have a lowered exercise capacity and might thus represent a population with worse prognosis. The association between PAP and peak VO 2 was similar but not as consistent. A sharp rise in PAP with exercise may be due to pulmonary vasculopathy (decreased compliance of the vessels) or impaired left ventricular diastolic function. Our data did not support the clinical relevance of left ventricular diastolic dysfunction because PAWP did not significantly correlate with 6MWD or peak VO 2 at rest or exercise. Furthermore, Figure 1. Six-minute-walk distance (mean 6 SD) in patients with mean pulmonary arterial pressure values above (white) andbelow(black) the median as measured at rest (P, 0.005), at 25W (P, 0.005), at 50W (P, ), and at maximal exercise (not significant). *P, 0.005; **P,

4 884 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 2. Six-minute-walk distance (6MWD) in patients with mean pulmonary arterial pressure values (MPAP) below and above median (A) at rest, (B) at 25W, (C) at 50W, and (D) at maximal exercise. there was no association between systemic blood pressure values (systolic, diastolic, or mean) and 6MWD, suggesting that pulmonary vasculopathy might be the main factor contributing to the association between PAP and exercise capacity. Pulmonary parenchymal involvement might influence PAP values in patients with systemic sclerosis. Our study did not address this issue because patients with significant pulmonary fibrosis or obstruction were excluded from this study. Patients with MPAP below Median at Rest and Mild Exercise Our patients with scleroderma who had MPAP values below median at rest and mild exercise levels showed average PAP values similar to the healthy control subjects (2). This was associated with significantly increased 6MWD, peak VO 2, and CI and lower PVR compared with patients with MPAP above the median values, suggesting that they were not affected by pulmonary vasculopathy (Table 5; Figure 3). PVR showed a slight decrease with maximal exercise in the low PAP group but was unchanged in the elevated PAP group. This also suggests increased vascular stiffness in the elevated PAP group. MPAP at Maximal Exercise MPAP at maximal exercise did not significantly differ between the two groups (Figure 3) and showed no significant correlation with 6MWD or peak VO 2 (Figures 1 and 2D). These findings suggest that MPAP values at rest and mild exercise may be key hemodynamic variables for patients with scleroderma, indicating pulmonary vasculopathy, whereas MPAP at maximal exercise is not. An explanation may be that vasculopathy (i.e., impaired distension/recruitment) was the driving force accounting for the level of pressure at lower exercise levels, whereas flow-dependent physiologic pressure increase determined PAP at maximal exercise. Patients with higher MPAP at mild exercise reached significantly lower CO values at maximal exercise and therefore had a reduced flow-induced PAP increase. Such patients may represent an intermediate stage between normal and PAH. This finding is in agreement with a recent study by Tolle and colleagues (6). Pressure Flow Relationship In our study, we found virtually linear PAP/CO and PAP/VO 2 slopes in all patients (Figure 3). This is in contrast to the study of Tolle and colleagues, who found very different hemodynamic patterns in response to exercise, with curvilinear slopes between PAP and VO 2. This difference may be due to the fact that we included a relatively homogeneous group of patients with scleroderma where obvious diseases of the heart and the lungs had been excluded. Our data suggest that in such patients, resting hemodynamics are highly predictive of exercise hemodynamics and exercise capacity. This implies that they might also be prognostically relevant. The only patient with an out-of-proportion increase in MPAP during exercise was a patient with mild obstructive lung disease with a dramatic increase in all intratho-

5 Kovacs, Maier, Aberer, et al.: Impact of Borderline Pulmonary Pressure in Scleroderma 885 TABLE 5. HEMODYNAMICS AT MAXIMAL EXERCISE IN PATIENTS WITH MEAN PULMONARY ARTERIAL PRESSURE (PAP) VALUES BELOW MEDIAN AT REST AND AT 25W AND AT 50W VERSUS PATIENTS WITH MEAN PAP AT REST OR AT 25W OR AT 50W MPAP. median at rest or at 25W or at 50W (n 5 15) MPAP < median at rest and at 25W and at 50W (n 5 14) P Value Mean PAP max, mm Hg NS PVR max, dyns cm ,0.005 CI max, L/min ,0.005 PAWP max, mm Hg NS RAP max, mm Hg NS Mean SAP max, mm Hg NS Max WR, W ,0.005 VO 2, % predicted MWD, m ,0.005 Age, yr NS Time since disease NS onset, years Height, cm NS Weight, kg NS Female:male 13:2 13:1 Definition of abbreviations: CO5 cardiac output; MPAP 5 mean pulmonary arterial pressure; NS 5 not significant; PAWP 5 pulmonary arterial wedge pressure; PVR 5 pulmonary vascular resistance; RAP 5 right atrial pressure; SAP 5 systemic arterial mean pressure; SPAP 5 systolic pulmonary arterial pressure; WR 5 work rate; 6MWD 5 6-min walk distance. racic pressures (PAP, PAWP, and right atrial pressure) during higher levels of exercise accompanied by high breathing frequency and large breath-dependent changes in all pressure measures. Based on our clinical observations, the cause of the pressure increase in this case was air entrapment; after cessation of exercise, all pressure values quickly returned to normal. Limitations A limitation of this study is the relatively small number of patients precluding a detailed analysis and correction for covariates. Therefore, these findings need confirmation. Another limitation is that long-term follow-up results have not been available. Because the prognostic value of 6MWD and peak VO 2 in patients with scleroderma without manifest PAH have not been investigated, our results should be interpreted with caution. However, we believe that our data provide a good rationale for further clinical studies addressing the prognostic role of borderline PAP values and its possible implications for early targeted therapy. In conclusion, resting and exercise pulmonary pressure values in the upper normal level are associated with decreased exercise capacity in patients with systemic sclerosis and pulmonary pressures below 25 mm Hg. Further studies including patients with borderline PAP at rest or slight exercise are warranted. Conflict of Interest Statement: G.K. received lecture fees from AstraZeneca, Actelion of $1,001 $5,000 and from GlaxoSmithKline of up to $1,000. He received grant support from Actelion of $10,001 $50,000 and has a patent from Siemens. R.M. received lecture fees and grant support from Actelion Pharmaceuticals of $10,001 $50,000. E.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.B. served on the Board or Advisory Board for Bayer Austria and Actelion and received up to $1,000. She received lecture fees from Bayer Austria, from Sanofi Aventis Austria of $1,001 $5,000 and from Actelion of up to $1,000. She received grant support from Actelion of $10,001 $50,000. S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.T. received lecture fees from Air Liquide and Actelion of up to $1,000. C.H. received lecture fees from Actelion and Encysive of $1,001 $5,000. W.S. received lecture fees from Wyeth, Jansen-Cileg, and Abbott of $1,001 $5,000. W.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.G. served on the Advisory Board for GlaxoSmithKline and Actelion and received $1,001 $5,000. He received lecture fees from GlaxoSmithKline, Actelion, Pfizer, Bayer, and Encysive of $1,001 $5,000. He received grant support from Bayer, Actelion of $10,001 $50,000, from Pfizer of $1,001 $5,000, from MondoGen of $10,001 $50,000, from GlaxoSmithKline of $1,001 $5,000, and a Self Help Group ph ev of $50,001 $100,000. L.J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.O. served as a consultant for Myogen and received $5,001 $10,000 and $100,001 or more from Unither. He served on the Board or Advisory Board for Bayer Schering Pharma and received $10,001 $50,000, GlaxoSmithKline, and Novartis and received $1,001 $5,000. He received lecture fees from Actelion, Bayer Schering of $10,001 $50,000, from Encysive of $5,001 $10,000, from GlaxoSmithKline, and from Pfizer of $1,001 $5,000. He received grant support from Actelion of $100,001 or more and from Encysive of $50,001 $100,000. Acknowledgment: The authors thank Dr. Petra Ofner-Kopeinig and Prof. Dr. Andrea Berghold (Institute for Medical Informatics, Statistics and Documentation of the Medical University Graz) for statistical consultation. Figure 3. (A) MPAP flow diagram of 29 patients at rest and during exercise. 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