CHEST

Original Research
PULMONARY VASCULAR DISEASE

Right Ventricular Load at Exercise Is a Cause of Persistent Exercise Limitation in Patients With Normal Resting Pulmonary Vascular Resistance After Pulmonary Endarterectomy
Diana Bonderman, MD; Amadea M. Martischnig, MD; Karin Vonbank, MD; Mariam Nikfardjam, MD; Brigitte Meyer, MD; Gottfried Heinz, MD; Walter Klepetko, MD; Robert Naeije, MD; and Irene M. Lang, MD

Background: Pulmonary endarterectomy (PEA) provides a potential cure for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, successfully operated patients can continue to suffer from a limitation of exercise capacity, despite normalization of pulmonary vascular resistance (PVR). The purpose of the present study was to explore the cardiopulmonary exercise test (CPET) prole and the pulmonary hemodynamic response to exercise in these patients. Methods: Thirteen successfully operated patients with CTEPH and persistent dyspnea and control subjects underwent a CPET and a right-sided heart catheterization at rest and during exercise. Results: The CPET prole of the patients was characterized by mild hyperventilation and . decreased peak oxygen uptake (Vo2). While there were no differences in resting hemodynamics between patients and control subjects, PVR was higher in the patients after 10 min of exercise (111 6 46 dynes/s/cm5 vs 71 6 42 dynes/s/cm5, P 5 .04), and pulmonary arterial compliance (Ca) was lower (5.5 6 2.3 mL/mm Hg vs 8.1 6 3.5 mL/mm Hg, P 5 .048). Ca under exercise correlated . with peak Vo2 in the patients (R2 5 0.825, P 5 .022). Conclusions: After successful PEA, patients with persistent exertional dyspnea display an abnormal pulmonary hemodynamic response to exercise, characterized by increased PVR and decreased Ca. Decreased Ca under exercise is a strong predictor of limited exercise capacity in these patients. CHEST 2011; 139(1):122127
Abbreviations: 6-MWT 5 6-min walk test; Ca 5 pulmonary arterial compliance; CPET 5 cardiopulmonary exercise test; CTEPH 5 chronic thromboembolic pulmonary hypertension; mPAP 5 mean pulmonary arterial pressure; O2 5 oxygen; PCWP 5 pulmonary capillary wedge pressure; PEA 5 pulmonary endarterectomy; PVR 5 pulmonary vascular resistance; RV 5 right ventricular; Vco2 5 CO2 output; Vd/Vt 5 pulmonary dead space fraction; Ve 5 minute ventilation; Vo2 5 oxygen uptake

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of pul-

monary embolism.1 If left untreated, the condition evolves, with progressive worsening of dyspnea and fatigue, eventual right-sided heart failure, and can be fatal after a few years. In carefully selected patients, thrombotic material can be removed by pulmonary endarterectomy (PEA). A successful PEA can normalize pulmonary vascular resistance (PVR) and return patients to a normal life.2-4 In some patients, PVR at rest can remain elevated. This is usu122

ally explained as the result of incomplete removal of thrombotic material, especially in the case of extension to more distal parts of the pulmonary arterial tree, and/or irreversible small vessel remodeling in overperfused, unobstructed lung areas.1 However, patients who have normalized resting PVR after successful PEA do not always regain their previous or predicted exercise capacity.5,6 This may be due to persistent alterations in gas exchange as sequelae of a previous embolism and surgical manipulation and to physical deconditioning. An additional
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possibility would be a pulmonary vascular restriction caused by persistent thrombotic material and/or postoperative scarring, leading to exercise-induced pulmonary hypertension and decreased pulmonary arterial compliance (Ca). As a consequence, excessive right ventricular (RV) afterload would occur during exercise, preventing the adaptive increase in cardiac output in response to the peripheral oxygen demand. Pulmonary arterial hydraulic load is determined using a measurement of the dynamic interaction between PVR and Ca, and is usually underestimated from single PVR determinations.7 Furthermore, it has recently been shown that the time constant of the pulmonary circulation, or PVR 3 Ca, remains unaltered at approximately 0.7 s in various types of pulmonary hypertension, including CTEPH.8 This implies a hyperbolic relationship between Ca and PVR, such that a PVR at the upper limit of normal can still be accompanied by a marked decrease in Ca and an increased RV afterload.8 In the present study, we explored pulmonary hemodynamics using right-sided heart catheterization at rest and during exercise to attempt to understand symptoms of persistent dyspnea and fatigue in patients at 1 year after a successful PEA under conditions of a normalized resting PVR. Materials and Methods
Setting and Study Design The study was performed at the Pulmonary Hypertension Unit of the Medical University of Vienna, Vienna, Austria, which has been a referral center for PEA and a tertiary referral center for pulmonary hypertension since 1992. Between January 2006 and June 2007, consecutive patients at 12 months after PEA with persistent exertional dyspnea rated as a Borg Dyspnea Score of 2, an echocardiographic examination documenting normal RV chamber sizes, and a systolic pulmonary arterial pressure , 36 mm Hg were Manuscript received February 10, 2010; revision accepted May 14, 2010. Afliations: From the Department of Cardiology (Drs Bonderman, Martischnig, Nikfardjam, Meyer, Heinz, and Lang), the Department of Pneumonology (Dr Vonbank), and the Department of Thoracic Surgery (Dr Klepetko), Medical University of Vienna, Vienna, Austria; and the Department of Pathophysiology (Dr Naeije), the Erasme University Hospital, Brussels, Belgium. Funding/Support: This research was in part supported by the Oesterreichischer Herzfonds and by the Fonds zur Frderung der wissenschaftlichen Forschung [Contract L513-B11] to Dr Bonderman. Parts of this study received nancial support from the European Commission under the 6th Framework Programme [Contract LSHM-CT-2005-018725, PULMOTENSION]. Correspondence to: Irene M. Lang, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Whringer Grtel 18-20, 1090 Vienna, Austria; e-mail: irene. lang@meduniwien.ac.at 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-0348
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asked to participate in the study. A time interval of 12 months was chosen on the basis of incremental functional improvement reported within the rst months after PEA.9 Patients underwent a cardiopulmonary exercise test (CPET). At the same study visit, a 6-min walk test (6-MWT) was performed and the serum N-terminal brain natriuretic peptide level was determined. In a second study visit, not later than 3 months after CPET, hemodynamic measurements were assessed using right-sided heart catheterization at rest and during submaximal supine bicycle exercise. Fourteen age- and body-dimension-matched control subjects were recruited for CPET. Control subjects for the invasive hemodynamic assessment were patients referred for clinical suspicion and echocardiographic evidence of pulmonary hypertension and a similar degree of exertional dyspnea in whom precapillary pulmonary hypertension at rest needed to be ruled out during a right-sided heart catheterization. The echocardiographic suspicion of pulmonary hypertension was based on a systolic pulmonary arterial pressure 36 mm Hg in the absence left ventricular or valvular abnormalities. All study participants gave written informed consent, and the Ethics Committee of the Medical University of Vienna approved the study. 6-MWT and Borg Dyspnea Score The 6-MWT was performed according to international diagnosis guidelines.10 The actual distance in meters walked in 6 min was compared with the distance that was predicted by the equation: 757 3 standing height 2 5.02 3 age 2 1.76 3 weight 2 309 for male patients; or 211 3 standing height 2 5.78 3 age 2 2.29 3 weight 1 667 for female patients.11 Standing height was entered in meters, age in years, and weight in kilograms. The Borg Dyspnea score is a patient-reported quantitative scaling method for scoring exertional dyspnea.12 Patients rate their breathlessness on a scale from 0 (no symptoms) to 10 (heavy breathlessness). We assessed the Borg Dyspnea Score immediately after a 6-MWT. Cardiopulmonary Exercise Testing In order to determine the individual working capacity and peak oxygen uptake (Vo2), each participant performed a physiciansupervised, standard, progressively increasing work rate CPET with gas exchange measurements. Every 2 min, the load was increased by 25 W until maximum working capacity was reached. Pedaling rate was constant at 70 to 80 rounds per min. Maximum working capacity was presented as the percentage of predicted value depending on age, gender, and body surface.13 Measured variables at each step and at maximum working capacity were heart rate by ECG and BP by sphygmomanometer, minute ventilation (Ve), Vo2, and CO2 output (Vco2). Vo2 and Vco2 were measured breath by breath (Sensormedics 2900 Metabolic Measurement Cart; Sensormedics; Hchberg, Germany). The oxygen (O2) pulse was calculated by dividing the Vo2 by the heart rate. Pulmonary dead space fraction (Vd/Vt) was calculated as arterial Pco2 minus mixed expired CO2 divided by Paco2. Hemodynamic Studies After introducing a Swan Ganz catheter via a jugular or subclavian access, hemodynamic measurements were performed at rest, including pulmonary arterial, right atrial, and ventricular pressures, pulmonary capillary wedge pressure (PCWP), and cardiac output (thermodilution method). Cardiac output was obtained as the mean of ve repetitive measurements after exclusion of the highest and lowest values. Systemic BP was recorded continuously using a permanent intraarterial line. ECG was monitored throughout the procedure. PVR, Ca, and systemic vascular resistance were
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calculated from measured values. PVR was calculated as the ratio of mean pulmonary arterial pressure (mPAP) to PCWP and cardiac output, and Ca as the ratio of stroke volume to pulse pressure. In addition, mixed venous and arterial saturations as well as blood lactate were determined. After exclusion of pulmonary hypertension at rest, dened as mPAP , 25 mm Hg and PVR , 240 dynes/s/cm5, patients performed bicycle exercise (Cyline 100; Medical Developpement; Andrezieux-Boutheon, France), which was performed in a supine position. After a 2-min step at 25 W, the load was increased to 50 W and continued for 10 min. Patients were instructed to pedal at a rate of 60 rounds per minute. All examinations were carried out under room air. After documentation of a steady state that was veried by a stable heart rate, hemodynamic measurements, mixed venous and arterial saturations, and blood lactate determinations were repeated. Statistical Analysis Statistical computations were performed using SPSS, version 15.0 (SPSS Inc; Chicago, Illinois). Continuous variables were described using means and standard deviations; groups were compared using the unpaired t test. Nominal variables were described using counts and percentages; groups were compared using the Fisher exact test. Correlations between measured values were assessed by means of Pearson correlation coefcients. All reported P values are the results of two-tailed tests, and P values , .05 were considered statistically signicant.

Cardiopulmonary Exercise Testing All patients completed the CPET without incident (Table 1). Peak work rate, Vo2, and O2 pulse were decreased. The Ve/Vco2 slope (30.4 6 4.8 vs 27.4 6 3.5, P 5 .08) and Vd/Vt (0.28 6 0.06 vs 0.21 6 0.08, P 5 .02) were mildly increased, while peak Pao2 was decreased, along with an increase in the alveolar-to-arterial Po2 gradient. However, none of the patients became hypoxemic during the CPET, and maximal ventilation was within limits measured in control subjects, suggesting a preserved ventilatory reserve after successful surgery. Hemodynamic Measurements None of the study patients suffered from precapillary pulmonary hypertension at rest, and their hemodynamic variables did not differ from those of the control subjects. Data points at baseline and after 12 min of submaximal exercise were recorded for each study participant. At rest, both patients and control subjects were comparable with respect to PVR (106 6 43 dynes/s/cm5 in patients vs 107 6 47 dynes/s/cm5 in control subjects, P 5 .95) and Ca (6.5 6 1.9 mL/mm Hg in patients vs 7.8 6 2.9 mL/mm Hg in control subjects, P 5 .21) (Table 2). However, in response to exercise, opposite hemodynamic reactions were encountered between patients and control subjects (Fig 1). Mean PVR under exercise in patients was signicantly higher than in control subjects (111 6 46 dynes/s/cm5 vs 71 6 42 dynes/s/cm5, P 5 .04), and mean Ca under exercise behaved inversely (5.5 6 2.3 mL/mm Hg vs 8.1 6 3.5 mL/mm Hg, P 5 .04, Table 3). In search for an explanation for the marked peak Vo 2 reduction in patients with CTEPH, we correlated peak Vo 2 with Ca under exercise and found a strong relationship between these parameters (R 5 0.825, P 5 .02).

Results Clinical Characteristics of Study Participants Out of 101 patients undergoing PEA between 1996 and 2006, 68% were free from postoperative pulmonary hypertension. Of these, 85% reported persistent exertional dyspnea of some degree. Between January 2006 and June 2007, 14 consecutive CTEPH patients fullling inclusion criteria were asked to participate in the study, 13 of which were consented. Mean time after PEA was 57 6 37 months (range 12-118 months). Limitation in exercise capacity was evident from a shorter-than-predicted11 6-MWT distance (439 6 104 m vs 571 6 113 m, P , .0001) and a Borg Dyspnea Score ranging from 2 to 7. Ten patients in whom precapillary pulmonary hypertension had been excluded by a right-sided heart catheterization consented to be control subjects for the hemodynamic study and underwent right-sided heart catheterization under exercise. Final diagnoses of the control subjects were normal hemodynamic performance with systemic hypertension (n 5 8) and mild postcapillary pulmonary hypertension due to left ventricular diastolic dysfunction (n 5 2). None of the control subjects suffered from pulmonary disease. No differences between patients and control subjects were encountered with respect to age (53 6 13 years vs 53 6 14 years, P 5 .97), sex (8 out of 13 women vs 6 out of 10 women, P 5 .98), 6-MWT distance (439 6 104 m vs 380 6 79 m, P 5 .39) or serum N-terminal brain natriuretic peptide levels (154 6 189 pg/mL vs 58 6 75 pg/mL, P 5 .15).
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Discussion Successful PEA with normalized resting PVR can be complicated by persistent exertional dyspnea. In the present study, CPET demonstrated a cardiac rather than a ventilatory limitation of exercise capacity that was explained as the result of abnormal PVR and Ca responses to exercise. Outcome reports of large surgical series suggest that CTEPH can be cured by PEA.2 In particular, patients with postoperative normalization of hemodynamic parameters display a sustained benet with respect to functional status, RV function,14 and survival.4 However, many patients do not experience a complete return to normal of their functional state and exercise capacity.6 Exercise capacity in our patients could have been limited by increased dead space ventilation
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Table 1Cardiopulmonary Exercise Testing

Variable Sex, F(M) Age, y BMI Respiratory ratio Lactate, mmol/L Peak exercise lactate, mmol/L Peak exercise O2 uptake, L/min Peak exercise O2 uptake, % of predicted Peak work rate, W Peak work rate, % of predicted Peak O2 pulse, mL/beat Peak heart rate, beats/min Peak ventilation, L/min Vd/Vt Ve/Vco2 slope Baseline AaDo2, mm Hg Peak AaDo2, mm Hg Baseline Sao2, % Peak Sao2, % Baseline Pao2, mm Hg Peak Pao2, mm Hg Patients (n 5 13) 8(5) 53 6 13 26.7 6 4.8 1.1 6 0.1 5.0 6 1.7 5.8 6 1.8 1.8 6 0.7 89.6 6 35.3 110 6 51 73.8 6 16.6 11.6 6 3.7 152 6 19 39.8 6 5.0 0.28 6 0.06 30.4 6 4.8 26 6 5 42 6 10 96.6 6 0.5 93.8 6 2.2 83 6 7 74 6 11 Control Subjects (n 5 14) 5(9) 50 6 10 25.4 6 3.6 1.2 6 0.1 5.3 6 1.7 6.0 6 1.7 2.3 6 0.6 108.9 6 10.7 167 6 49 97.4 6 13.7 14.6 6 3.1 161 6 22 35.8 6 8.8 0.21 6 0.08 27.4 6 3.5 24 6 6 29 6 7 96.0 6 1.0 95.1 6 1.3 84 6 8 85 6 10 P value .17 .32 .48 .56 .71 .73 .03 .05 .01 .001 .04 .31 .21 .02 .08 .18 .001 .19 .07 .86 .02

AaDo2 5 alveolar-arterial oxygen difference; F 5 female; M 5 male; O2 5 oxygen; Sao2 5 arterial oxygen saturation; Vco2 5 CO2 output; Vd/Vt 5 pulmonary dead space fraction; Ve 5 minute ventilation.

because of persistent pulmonary vascular obstruction. It has been long recognized that more than half of the pulmonary circulation needs to be obstructed to drive pulmonary hemodynamic performance to the upper limits of normal.15,16 Thus, a normal PVR does not exclude the presence of a signicant degree of vascular obstruction. However, persistent vascular obstruction would have caused increases in Vd/Vt and ventilatory equivalents at exercise.17 Incomplete return of pulmonary hemodynamic performance to normal after PEA has been shown to be associated with increased dead space ventilation and dyspnea in proportion to persistently increased PVR.17 However, gas exchange in our patients was near normal, with exercise-induced decreases in Pao2 paralleled by a decrease in mixed venous Po2 as a consequence of an insufcient cardiac output response. There was no

increased chemosensitivity that could have been caused by mild exercise-induced hypoxemia, and there was no abnormal dead space ventilation, indicating that the patients had an ample ventilatory reserve until peak Vo2. Thus, a ventilatory limitation to exercise capacity can be reasonably excluded. Our results are in keeping with previous studies on lung function and gas exchange in patients with CTEPH, which showed preserved resting lung mechanics and diffusion capacity for carbon monoxide and only mildly altered ventilation/perfusion matching, with no diffusion limitation to gas exchange, at rest and during exercise.18,19 In these studies, decreased arterial oxygenation, at rest and more so at exercise, was essentially explained as the result of decreased mixed venous oxygenation. This was also observed in our successfully operated patients with CTEPH.

Table 2Resting Hemodynamics

Variable Serum lactate, mmol/L O2 saturation, % Mixed venous saturation, % Heart rate, beats/min Mean arterial pressure, mm Hg SVR, dynes/s/cm5 Cardiac output, L/min mPAP, mm Hg PCWP, mm Hg PVR, dynes/s/cm5 Ca, mL/mm Hg Patients (n 5 13) 0.8 6 0.3 96.3 6 1.4 71.9 6 6.0 72 6 12 88 6 14 1,154 6 150 7.1 6 1.3 18 6 5 963 106 6 43 6.5 6 1.9 Control Subjects (n 5 10) 1.0 6 0.6 95.3 6 1.9 69.6 6 4.4 78 6 16 92 6 17 1,094 6 385 7.3 6 2.7 19 6 6 11 6 6 107 6 47 7.8 6 2.9 P Value .30 .15 .31 .29 .62 .34 .80 .54 .26 .95 .21

Ca 5 pulmonary arterial compliance; mPAP 5 mean pulmonary arterial pressure; PCWP 5 pulmonary capillary wedge pressure; PVR 5 pulmonary vascular resistance; SVR 5 systemic vascular resistance. See Table 1 for expansion of the other abbreviation.
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Figure 1. Changes in mean pulmonary vascular resistance (PVR) and pulmonary arterial compliance (Ca) in response to submaximal exercise. As previously shown,8 we found an inverse relationship between PVR and Ca at rest and during exercise, with data points following a hyperbolic relationship. As a physiologic reaction, PVR decreases and Ca increases during exercise (control subjects, gray arrow). By contrast, the opposite reaction occurs in patients (black arrow). Arrow origins represent mean values of PVR-Ca pairs at rest; arrowheads represent mean values of PVR-Ca pairs during exercise.

We examined the possibility of a cardiovascular limitation, in spite of a normal resting PVR. Because standard hemodynamic measurements at rest were not different between patients and control subjects, we performed an exercise stress protocol that permits an optimal assessment of RV afterload using Ca calculations. Inverse directional changes of PVR and Ca in patients vs control subjects were suggestive of an abnormal pulmonary hemodynamic response to exercise and pinpointed excessive afterloading of the right ventricle as a possible cause of exercise limitation. PVR is a ratio of mean pressure to mean ow. Steady ow hemodynamic measurements allow for the measurement of arteriolar resistance but are insufficient for the evaluation of RV afterload as defined by arterial impedance or by the ratio of pulsatile pressure to pulsatile ow. Pulmonary arterial impedance results from a dynamic interplay

between PVR, Ca, and wave reection. Most recently, Lankhaar et al8,20 have shown that the time constant of the pulmonary circulation, or PVR 3 Ca, remains unchanged at approximately 0.7 s in various types of pulmonary hypertension, including CTEPH, and is not even affected by treatment. Accordingly, the relationship between PVR and Ca is hyperbolic, with a proportionally more important decrease of Ca at close to normal PVR and little further decrease of Ca in severe pulmonary hypertension. On the other hand, the fact that the time constant of the pulmonary circulation is little affected by the severity and nature of pulmonary vascular disease strongly suggests that the response of the pulmonary circulation to insults is most often monotonous and that the contribution of wave reections can be neglected. In other words, the hydraulic load imposed on the right ventricle is predominantly dened by a combination of changes in Ca and PVR. In the present study, the hemodynamic response of patients post-PEA was clearly abnormal, with a mild but signicant increase instead of a decrease in PVR and a decrease instead of an increase in Ca. The normal response to exercise is characterized by a decreased PVR and an increased Ca, as seen in the control subjects. The fact that the increase in PVR at exercise was mild in absolute terms gave relatively more importance to Ca, and this is probably why exercise Ca turned out to be the only independent predictor of decreased exercise capacity in the patients. One of the limitations of the present study is that the control subjects for the hemodynamic measurements were not healthy individuals but patients referred for clinical and echocardiographic suspicion of pulmonary hypertension. The reported exercise-induced changes in PVR and Ca therefore relate to patients with systemic arterial hypertension or left ventricular diastolic dysfunction rather than to healthy individuals. However, in the absence of pulmonary vascular disease or impaired cardiac output, their changes in PVR and Ca are comparable to those in healthy individuals.21

Table 3Exercise Hemodynamics

Variable Serum lactate, mmol/L O2 saturation, % Mixed venous saturation, % Heart rate, beats/min Mean arterial pressure, mm Hg SVR, dynes/s/cm5 Cardiac output, L/min mPAP, mm Hg PCWP, mm Hg PVR, dynes/s/cm5 Ca, mL/mm Hg Patients (n 5 13) 1.7 6 0.7 94.4 6 2.4 50.7 6 8.9 97 6 19 108 6 12 686 6 109 11.5 6 2.3 30 6 8 14 6 5 111 6 46 5.5 6 2.3 Control Subjects (n 5 10) 1.7 6 0.9 94.9 6 13.7 58.0 6 7.5 104 6 28 106 6 16 879 6 345 10.8 6 4.4 25 6 7 15 6 7 71 6 42 8.1 6 3.5 P Value .87 .67 .04 .54 .73 .18 .65 .14 .48 .04 .04

See Table 1 and 2 legends for expansion of abbreviations. 126

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Indeed, Ca under exercise in healthy volunteers ranged from 5 to 10 mL/mm Hg and PVR under exercise from 35 to 86 dynes/s/cm5,21 which are similar to the values of control subjects in this study (Ca under exercise: 4-12 mL/mm Hg, and PVR under exercise: 28-98 dynes/s/cm5). Another limitation is that the exact pathophysiologic substrate for the dysfunctional pulmonary vasculature has not been determined. Most likely, a combination of residual thrombi in subsegmental pulmonary arteries and microvascular changes contribute to the inability to adequately recruit vascular territories under exercise conditions. A further limitation is the fact that Ca is posture dependent because leg elevation results in an increase in stroke volume.22 However, Ca was measured in a supine position in both patients and control subjects and yielded opposite changes during conditions of exercise. Taken together, patients after successful PEA demonstrate a pathologic hemodynamic response to exercise. This information is important, especially in patients with diminished exercise capacity despite normalization of resting hemodynamic parameters. Acknowledgments
Author contributions: Dr Bonderman: is responsible for data analysis and has drafted the manuscript. Dr Martischnig: contributed to data acquisition and interpretation. Dr Vonbank: contributed to data acquisition and interpretation. Dr Nikfardjam: contributed to data acquisition and interpretation. Dr Meyer: contributed to data acquisition and interpretation. Dr Heinz: contributed to data acquisition and interpretation. Dr Klepetko: contributed to data acquisition and interpretation. Dr Naeije: approved the nal version. Dr Lang: approved the nal version. Financial/nonnancial disclosures: The authors have reported to CHEST that no potential conicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: This publication reects only the authors views, and the European Community is in no way liable for any use that may be made of the information contained therein.

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