Dobutamine Stress Echocardiography for the Assessment of Pressure-Flow Relationships of the Pulmonary Circulation

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1 [ Original Research Pulmonary Vascular Disease ] Dobutamine Stress Echocardiography for the Assessment of Pressure-Flow Relationships of the Pulmonary Circulation Edmund M. T. Lau, MD, FCCP ; Rebecca R. Vanderpool, PhD ; Preeti Choudhary, MD ; Lisa R. Simmons, PhD ; Tamera J. Corte, PhD ; Paola Argiento, MD ; Michele D Alto, MD ; Robert Naeije, PhD ; and David S. Celermajer, PhD BACKGROUND: Stress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mppa-q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mppa-q relationships. METHODS: DSE using an incremental dose protocol ( 20 m g/kg/min) was performed in 38 subjects (16 patients with pulmonary arterial hypertension [PAH] and 22 healthy control subjects). An additional 22 healthy control subjects underwent exercise stress echocardiography as a comparator group. Multipoint mppa-q plots were analyzed, and the pulmonary vascular distensibility coefficient a was calculated. RESULTS: DSE was feasible and informative in 93% of subjects. The average dobutamineinduced mppa-q slope was mm Hg/L/min in healthy control subjects and mm Hg/L/min in patients with PAH ( P,.001). The dobutamine-induced a was markedly reduced in patients with PAH ( mm Hg vs mm Hg in control subjects, P,.001). When exercise and dobutamine stress were compared in healthy control subjects, the exercise-induced mppa-q slope was modestly higher ( mm Hg/L/min, P 5.03 vs dobutamine). In patients with PAH, lower functional class status was associated with lower dobutamine-induced mppa-q slopes ( P 5.014), but not with resting total pulmonary vascular resistance. CONCLUSIONS: Noninvasive assessment of mppa-q relationships is feasible with dobutamine stress. DSE may potentially be a useful noninvasive technique for stress testing of the pulmonary vasculature. CHEST 2014; 146(4): Manuscript received October 7, 2013 ; revision accepted February 10, 2014; originally published Online First March 13, ABBREVIATIONS: DSE 5 dobutamine stress echocardiography; HR 5 heart rate; mppa 5 mean pulmonary artery pressure; PAH 5 pulmonary arterial hypertension; PH 5 pulmonary hypertension; Pla 5 left atrial pressure; Ppa 5 pulmonary artery pressure; Q 5 cardiac output; TPVR 5 total pulmonary vascular resistance AFFILIATIONS: From the Discipline of Medicine (Drs Lau, Choudhary, Corte, and Celermajer), Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Respiratory Medicine (Drs Lau and Corte), Department of Cardiology (Drs Lau, Choudhary, Simmons, and Celermajer), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Cardiology (Drs Argiento and D Alto), Second University of Naples, Naples, Italy; and Department of Pathophysiology (Drs Vanderpool and Naeije), Free University of Brussels, Brussels, Belgium. FUNDING/SUPPORT: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia Project [Grant to Dr Celermajer and Dr Corte] and a NHMRC and Heart Foundation Postgraduate Scholarship to Dr Lau [No ]. CORRESPONDENCE TO: Edmund M. T. Lau, MD, FCCP, Department of Respiratory Medicine, Royal Prince Alfred Hospital, Missendon Rd, Camperdown, NSW 2050, Australia; edmundmtlau@gmail.com 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest journal.publications.chestnet.org 959

2 Stress testing of pulmonary circulation has been used for. 60 years, since the introduction of the original hemodynamic definition of pulmonary hypertension (PH). 1 The rationale was that exercise would increase cardiac output (Q) with or without an increase in left atrial pressure (Pla) and that abnormally high mean pulmonary artery pressure (mppa)-q relationships during stress could be due to an increased incremental pulmonary vascular resistance (PVR) or an increase in Pla, or both. 2 Pioneer invasive studies in healthy volunteers led to the definition of PH with an mppa. 25 mm Hg at rest and. 30 mm Hg at exercise. These cutoff values were derived with a safety margin of 4 to 5 mm Hg added to the upper limits of normal values (mppa of 20 mm Hg at rest and 25 mm Hg at exercise). 3 Exercise measurements were withdrawn from the definition of PH at the World Symposium on Pulmonary Hypertension in 2008 because of insufficient certainty about the upper limits of normal mppa at exercise and levels of symptomatic mppa. 4 Since then, there has been accumulating evidence that mppa. 30 mm Hg at exercise is actually associated with dyspnea-fatigue symptoms. 5,6 Furthermore, noninvasive and invasive exercise measurements in a large number of normal subjects have allowed better delineation of exerciseinduced PH by a mppa. 30 mm Hg at a Q, 10 L/min or slope of mppa-q relationship. 3 mm Hg/L/min. 7 It is hoped that these criteria will help in the much-needed identification of early pulmonary vascular disease. 8 As noninvasive testing is preferable to invasive measurements for the purposes of screening or initial diagnostic evaluation, an accurate and reproducible noninvasive measure of an individual s mppa-q relationship is desirable. Exercise echocardiography for the assessment of multipoint mppa-q relationships is feasible but technically challenging. 9,10 These technical demands limit the FOR EDITORIAL COMMENT SEE PAGE 876 application of exercise echocardiography to very few centers with sufficient expertise in this technique. Furthermore, the optimal exercise protocol for the assessment of the pulmonary circulation has not been established. 11 Dobutamine is an inochronotropic stress agent commonly used for the study of coronary artery disease 12 and offers potential advantages over exercise stress, as image acquisition is facilitated by reduced patient movement and cooperation with exercise is not required. Furthermore, studies in intact animals suggest that doses of dobutamine 20 m g/kg/min are without intrinsic vasomotor effects on the functional state of the pulmonary circulation. 13,14 The purpose of the present study was, therefore, to investigate the effects of an infusion of dobutamine on mppa-q relationships, as assessed by Doppler echocardiography in healthy volunteers and in patients with pulmonary arterial hypertension (PAH). We also compared the effects of exercise vs dobutamine stress on mppa-q relationships in the normal pulmonary circulation. Materials and Methods Subjects A total of 60 subjects participated in the study. Dobutamine stress echocardiography (DSE) was performed in healthy control subjects (n 5 22) and patients with PAH (n 5 16). An additional group of healthy control subjects (age- and sex-matched to the healthy control subjects who underwent DSE) who had undergone exercise echocardiography (n 522) were used as a comparison group to understand any differences in the mppa-q relationships during exercise vs dobutamine stress in the normal pulmonary circulation. Subjects in the exercise echocardiography group represented new analyses of previously reported studies. 9,15 A l l healthy control subjects were nonsmokers with no history of cardiac or respiratory diseases. All patients with PAH had their diagnosis confirmed by invasive, right-sided heart catheterization. The study was approved by the local institutional ethics review committees (Royal Prince Alfred Hospital Zone, RPAH-X ; Erasme University Hospital, P2011/101), and all participants provided informed consent. Stress Echocardiography Echocardiography images were acquired by either the Vivid system (General Electric Co) or ie33 (Koninklijke Philips NV). Dobutamine was given as a continuous infusion at incremental doses of 5, 10, 15, and a maximum of 20 m g/kg/min. Each infusion stage was for 3 min, and measurements for systolic pulmonary artery pressure (Ppa) and Q were taken during the last 30 s of each stage. The prespecified infusion end points were either reaching the maximum dobutamine dose or a heart rate (HR). 120 beats/min. A HR. 120 beats/min was chosen to avoid inducing very high HR in patients with PAH for safety reasons. Echocardiography data were recorded and analyzed offline by two independent observers. Exercise echocardiography was performed on a semirecumbent cycle ergometer (Model 900 EL; Ergoline GmbH), and workload was increased by 20 to 30 W every 2 min until the maximal tolerable workload, as previously described. 10 Systolic Ppa was measured from the peak tricuspid regurgitation jet. Right atrial pressure was assigned at 5 mm Hg for all healthy control subjects and estimated from the inferior vena cava diameter and collapsibility for patients with PAH. 16 The mppa was calculated as systolic Ppa An agitated air-blood-saline mixture was used to enhance the Doppler signal of the tricuspid regurgitation jet 18 from baseline through to peak stress in eight healthy control subjects in the dobutamine stress group. No subjects with PAH required agitated saline enhancement, as they all had sufficient tricuspid regurgitation jet. Q was estimated from the velocity time integral of the left ventricular outflow tract, together with HR and left ventricular outflow tract diameter. As no subjects had significant shunts present, total pulmonary vascular resistance (TPVR) was calculated as mppa/q. The interobserver variabilities of systolic Ppa and Q were determined to be 5.2% and 8.8%, respectively, for DSE. The interobserver variabilities of exercise stress echocardiography for systolic Ppa and Q were 7.9% and 13.9%, respectively. 10 Th e linearity of mppa-q curves was analyzed qualitatively and quantitatively. Linear regression was used to determine the slope 960 Original Research [ 146 # 4 CHEST OCTOBER 2014 ]

3 of best fit and intercept at zero flow. The pulmonary vascular distensibility coefficient a (percentage change in diameter per mm Hg increase in transmural pressure) was derived from each multipoint mppa-q plot by fitting into the following equation, as previously described 19 : where R 0 is the TPVR at rest ar0q [(1 alap) 5 ] 1 mppa a Statistical Analysis All data are presented as mean SD unless otherwise stated. Leastsquares linear regression was used to calculate the mppa-q slope. Between-group comparisons were made with one-way analysis of variance, and if significant differences were observed, subgroups were compared using independent samples t test analyses. Proportions were evaluated using the Fisher exact test. A Poon-adjusted mean slope was used to allow for similar linear or mildly nonlinear data from subjects to be grouped together for analyses. 20 A two-sided P,.05 was considered statistically significant. Results Baseline characteristics of the study groups are presented in Table 1. Two healthy control subjects and one patient with PAH who had undergone dobutamine stress were excluded from final analysis due to insufficient quality of echocardiographic measurements. The overall success rate for DSE was 93%. The diagnosis of patients with PAH included idiopathic PAH (n 5 6), connective tissue-associated PAH (n 5 9), and portopulmonary hypertension (n 5 1). Patients with PAH encompassed a range of disease severity. All TABLE 1 ] Baseline Characteristics of Study Subjects Characteristic Patients With PAH Dobutamine Stress (n 5 16) Dobutamine Stress (n 5 22) Control Subjects Exercise Stress (n 5 22) Age, y 56 9 a Male patients, % 25 b N/A Height, cm Weight, kg BMI, kg/m BSA, m Echocardiographic parameters LVEF, % 71 8 b ,.0001 TAPSE, mm 17 4 b ,.0001 Invasive hemodynamics c Systolic Ppa, mm Hg Diastolic Ppa, mm Hg 27 9 Mean Ppa, mm Hg Ppw, mm Hg 8 2 Mean RAP, mm Hg 9 5 NYHA functional class (No. in I:II:III:IV) P Value (2:6:7:1) 6-min walk distance, m PH-specific therapy Endothelin antagonist, % 75 Phosphodiesterase-5 inhibitor, % 56 Prostanoid, % 19 Combination therapy, % 44 Data given as mean (SD) unless otherwise indicated. BSA 5 body surface area; LVEF 5 left ventricular ejection fraction; N/A 5 not applicable; NYHA 5 New York Heart Association; PAH 5 pulmonary arterial hypertension; PH 5 pulmonary hypertension; Ppa 5 pulmonary artery pressure; Ppw 5 pulmonary artery wedge pressure; RAP 5 right atrial pressure; TAPSE 5 tricuspid annular plane systolic excursion. a P,.05 compared with exercise-stress control subjects. b P,.05 compared with dobutamine- and exercise-stress control subjects. c Invasive hemodynamics measured at time of initial diagnosis. journal.publications.chestnet.org 961

4 patients were receiving PH-specific therapy at the time of study. Hemodynamic Response to Dobutamine Infusion The peak dobutamine dose reached was similar for both control subjects and PAH groups ( mg/kg/min vs m g/kg/min), with an average of data points per multipoint mppa-q plot per subject. Resting and peak dobutamine hemodynamics are shown in Table 2. Resting Q was not significantly different between control subjects and patients with PAH, but peak Q was higher in control subjects ( L/min vs L/min, P 5.04) due to higher stroke volume at peak dobutamine dose (99 22 ml vs ml, P,.001). The HR and stroke volume responses during dobutamine infusion are shown in Figure 1. Dobutamine-Induced Multipoint mppa-q Relationships Th e average dobutamine-induced mppa-q slope in control subjects was mm Hg/L/min. After Poon adjustment, the slope of the best-fit line to pooled data was 1.0 mm Hg/L/min with an intercept of 10.7 mm Hg. At peak dobutamine, only one control subject had mppa. 30 mm Hg, occurring at a corresponding Q of 11.9 L/min. In the PAH group, the average mppa-q slope was mm Hg/L/min ( P,.001 vs control subjects), with a Poon-adjusted mppa-q slope of 4.8 mm Hg/L/min and an intercept of 27.3 mm Hg ( Fig 2 ). Using the curvilinear fit model, the average distensibility coefficient a was markedly reduced in patients with PAH compared with control subjects ( mm Hg vs mm Hg, P,.001). Within the PAH group, patients in New York Heart Association functional classes I or II had lower mppa-q slopes compared with those in functional classes III or IV ( mm Hg/L/min vs mm Hg/L/min, P 5.01), whereas resting TPVR was not associated with functional class status ( Fig 3 ). TABLE 2 ] Noninvasive Pulmonary and Systemic Hemodynamics at Rest and Peak Stress Measurement Condition Patients With PAH Dobutamine Stress (n 5 16) Dobutamine Stress (n 5 22) Control Subjects Exercise Stress (n 5 22) mppa, mm Hg Rest a ,.0001 P Value Peak stress a 20 4 b 35 6,.0001 Q, L/min Rest Peak stress a b ,.0001 Cardiac index, L/min/m 2 Rest Peak stress a b ,.0001 TPVR, dyn/s/cm 5 Rest a ,.0001 Peak stress a ,.0001 TPVRI, dyn/s/cm 5 /m 2 Rest 1, a ,.0001 Peak stress 1, a ,.0001 SBP, mm Hg Rest Peak stress b b ,.0001 DBP, mm Hg Rest Peak stress b b 94 6,.0001 HR, per min Rest a Peak stress a b ,.0001 RPP (SBP 3 HR) Rest 9,901 2,440 a 7,979 1,579 8,375 1, Peak stress 14,020 3,128 b 13,600 2,604 b 23,630 3,128,.0001 Data given as mean ( SD) unless otherwise indicated. DBP 5 diastolic BP; HR 5 heart rate; mppa 5 mean Ppa; Q 5 cardiac output; RPP 5 rate pressure product; SBP 5 systolic BP; TPVR 5 total pulmonary vascular resistance; TPVRI 5 total pulmonary vascular resistance index. See Table 1 legend for expansion of other abbreviation. a P,.05 compared with both dobutamine-stress control subjects and exercise-stress control subjects. b P,.05 compared with exercise-stress control subjects. 962 Original Research [ 146 # 4 CHEST OCTOBER 2014 ]

5 Figure 1 Hemodynamic response to incremental-dose dobutamine infusion in healthy control subjects and patients with PAH. A, Plot of mean (SD) values for heart rate. B, Plot of mean stroke volume values. *P,.05; **P,.01; ***P,.001. bpm 5 beats per min; PAH 5 pulmonary arterial hypertension. Dobutamine vs Exercise Stress in Healthy Control Subjects Baseline demographics and hemodynamics were well matched between the two healthy control groups who underwent exercise and dobutamine stress. Exercise stress achieved greater peak Q augmentation than dobutamine stress ( L/min vs L/min, P,.001). Compared with dobutamine stress, exercise stress was associated with a higher slope of the mppa-q relationship ( mm Hg/L/min vs mm Hg/L/min, P 5.03) and lower distensibility coefficient a ( mm Hg vs mm Hg, P 5.001). As exercise achieved significantly higher peak Q compared with dobutamine stress in healthy control subjects, a reanalysis of the exercise data were taken by limiting exercise Q to similar flow ranges achieved by peak dobutamine stress (exercise Qlimit L/min, P 5.6 vs peak dobutamine stress Q). This re-analysis enabled direct comparison between dobutamine and exercise stress over similar ranges of physiologic flows. This resulted in an exercise mppa-q slope of mm Hg/L/min ( P vs dobutamine stress) and a of /mm Hg ( P 5.06 vs dobutamine stress) (Fig 4 ). Discussion Our study demonstrates that it is feasible to derive meaningful mppa-q relationships using dobutamine stress to augment Q to assess the functional state of the pulmonary circulation. Subjects with PAH revealed markedly elevated mppa-q slopes compared with healthy control subjects under dobutamine stress. In addition, poor functional class status in patients with PAH was associated with higher dobutamine-induced mppa-q slopes. The novel application of DSE for the pulmonary circulation is a noninvasive technique that can potentially be applied to detect abnormal mppa-q responses from pulmonary vascular disease. Multipoint mppa-q Relationships The clinical utility of multipoint mppa-q assessment has previously been shown by Castelain et al 21 in a study on the hemodynamic effects of IV prostacyclin therapy in idiopathic PAH. Despite an increase in exercise capacity as assessed by 6-min walk distance at 6 weeks, resting TPVR remained unchanged, but the slope of the mppa-q relationship during exercise decreased significantly. Similarly, Provencher et al 22 demonstrated that changes in 6-min walk distance were associated with changes in exercise isoflow mppa but not resting measurements. Thus, there is accumulating evidence to suggest that the assessment of the pulmonary circulation under dynamic stress provides important clinical information in addition to resting measurements. This concept is supported by our finding that mppa-q slope, but not resting TPVR, correlated with functional class status in patients with PAH. Figure 2 A, Individual, dobutamineinduced, multipoint mppa and cardiac output (mppa-q) plots. B, Poon-adjusted pooled data of mppa-q relationships. The pooled mppa-q slope was 1.0 mm Hg/L/min with an intercept of 10.7 mm Hg in healthy control subjects and 4.8 mm Hg/L/min with an intercept of 27.3 mm Hg in patients with PAH. mppa 5 mean pulmonary artery pressure. See Figure 1 legend for expansion of other abbreviation. journal.publications.chestnet.org 963

6 Figure 3 A, B, Relationship between New York Heart Association FC status to mppa-q slope and resting TPVR in patients with PAH. Data shown are means and SD. FC was significantly associated with dobutamine-induced mppa-q slope ( mm Hg/L/min vs mm Hg/L/min for FC I-II vs FC III-IV, respectively; P 5.014). In comparison, FC status was not associated with resting TPVR ( P 5.13). FC 5 functional class; TPVR 5 total pulmonary vascular resistance. See Figure 1 and 2 legends for expansion of other abbreviations. Exercise vs Dobutamine Stress: Physiologic Considerations We compared the pulmonary hemodynamic response of exercise vs dobutamine stress in matched, healthy control subjects. As peak exercise can augment Q more than dobutamine stress, it is important that mppa-q relationships from exercise and dobutamine stress are compared over the same range of flows (approximately 5-10 L/min). In healthy control subjects, we found that dobutamine stress was associated with a lower mppa-q slope and a trend toward a higher distensibility coefficient a. This difference is most likely to be explained by dobutamine-induced pulmonary vasodilatation. Dobutamine has predominant b-adrenoceptor agonist activity, although lesser a-adrenorecptor effects do occur, particularly at higher doses. 23 Although previous studies suggest that dobutamine has minimal intrinsic Figure 4 Multipoint mppa-q plots at rest and during exercise stress (blue), and dobutamine stress (black) in healthy control subjects. Dobutamine- and exercise-induced mppa-q relationships were compared over similar physiologic flow ranges. The prediction bands of normal exercise response are shown in gray. See Figure 2 legend for expansion of abbreviations. effects on pulmonary vasomotor tone, these were performed in anesthetized animals with dobutamine doses generally less than those used in the present study. 13,14 Our more relevant human data would be in agreement with prior studies demonstrating a pulmonary vasoconstrictor response following sympathetic neural blockade in intact, conscious dogs. 24,25 The difference in mppa-q response between exercise and dobutamine stress could potentially be explained, alternatively, by exercise-induced vasoconstriction or exercise-related increase in Pla. However, we feel that these mechanisms are unlikely to be operational. By limiting the analysis of mppa-q relationships in the exercise group to the same flow ranges achieved by dobutamine infusion (peak Q of around 10 L/min), this corresponds to mild-moderate exercise workloads in healthy individuals. Significant exercise-induced vasoconstriction is unlikely to occur at this level of exercise. It has been shown that at Q of around 10 L/min, Pla changes little compared with resting values, but a brisker rise can occur at higher workloads when Q exceeds 20 L/min. 26 Finally, dobutamine should not significantly alter left ventricular filling pressures in subjects without coronary artery disease and with normal left ventricular function and normal baseline filling pressures Invasive exercise hemodynamic studies in patients with PAH have revealed mppa-q slopes ranging from 6 to 15 mm Hg/L/min, depending on the severity of the underlying pulmonary vascular disease. This is considerably higher than the mppa-q slopes found in our study. The comparative effects of dobutamine and exercise on mppa-q slopes were directly compared by Kafi et al 31 in an invasive study involving 11 patients with idiopathic PAH. In this study, the pooled, exerciseinduced mppa-q slope was 15 mm Hg/L/min vs a 964 Original Research [ 146 # 4 CHEST OCTOBER 2014 ]

7 dobutamine-induced mppa-q slope of 8.3 mm Hg/L/min. This supports the notion that dobutamine-induced mppa-q relationships result in a lower slope compared with exercise stress in patients with PAH, similar to the observations in the healthy control subjects. Apart from the likely effects of dobutamine-induced vasodilatation, pulmonary vasoconstriction can occur in patients with PAH even at relatively low workloads, due to early development of acidosis and decreased, mixed venous P o 2. Potential Utility of Dobutamine Stress for the Pulmonary Circulation The large reserve of the normal pulmonary circulation suggests that PAH is usually diagnosed late in its course and a latent (and relatively asymptomatic) stage precedes the onset of markedly reduced exercise capacity and right ventricular failure. 8 Thus, subjects with early PAH may present with normal or near-normal resting hemodynamics but an abnormal mppa response when stressed by an increase in pulmonary blood flow. 6,32 In our study, we demonstrated that subjects with established PAH had an average dobutamine-induced mppa-q slope of mm Hg/L/min compared with mm Hg/L/min in healthy control subjects. Furthermore, the dobutamine-induced distensibility coefficient a was markedly reduced in patients with PAH compared with control subjects ( vs /mm Hg). a derived from exercise echocardiography has been shown to be sensitive to subtle changes in pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. 33 Further studies are required to determine whether dobutamine stress can reveal abnormal a and mppa-q response in at-risk populations who might have early pulmonary vascular disease but have not yet lost sufficient microvascular reserves to produce resting PAH (such as those with scleroderma disorders or carriers of BMPR2 mutations). Although dynamic exercise remains the most physiologic stressor as patient symptoms are replicated, the use of dobutamine as an alternative stressor of the pulmonary circulation has theoretical advantages. Exercise echocardiography requires very experienced echosonographers in dedicated centers and images must be acquired during the exercise, as pulmonary hemodynamics change rapidly once exercise is ceased. 10 Finally, analogous to stress testing for suspected coronary artery disease, exercise may not be feasible in patients with lower-limb musculoskeletal or neurologic diseases, and in those with suboptimal cooperation with exercise protocols. It is important to appreciate that mppa-q relationships generated by dobutamine and exercise stress may not be interchangeable, as suggested by the subtle differences in response found between the two stressors in the present study. Therefore, further validation studies in larger samples of healthy control subjects are required to determine the upper limits of normal for dobutamine-induced mppa-q relationships. Study Limitations It would be ideal to validate noninvasive mppa-q relationships against concurrent invasive measurements, but there is ethical concern regarding right-sided heart catheterization in healthy control subjects. We thus could not identify comparison data in the literature on invasively determined multipoint mppa-q relationships in healthy control subjects during incremental dobutamine infusion. The same control subjects were not subjected to both dobutamine and exercise stresses. However, the control groups were matched for age, sex, and BMI to reduce confounding factors. We cannot exclude that the difference in dobutamine- and exercise-stress response of the pulmonary circulation could be due to chance differences between the two control groups, but this appears unlikely. Furthermore, the PAH group was slightly older and tended toward a higher BMI compared with both control subjects. Although increasing age and possibly BMI are associated with higher mppa-q slopes,9,34 this would not have accounted for the marked differences observed. The present study was not large. It was designed as a proof-of-principle study to validate that DSE can be used for the study of the pulmonary circulation and can reveal the expected pathophysiologic abnormalities in those with established PAH. Future studies are required in healthy subjects over a larger age spectrum; in at-risk populations without resting PAH, such as asymptomatic carriers of BMPR2 mutations; and in those with cardiopulmonary conditions other than PAH. Conclusions By using dobutamine stress to augment pulmonary flow, multipoint mppa-q plots can be generated to noninvasively assess the functional status of the pulmonary circulation. This is potentially more prac tical than exercise stress echocardiography, and dobutamine stress reveals substantial differences between healthy subjects and those with PAH. Further validation studies are required to determine the potential utility of measuring mppa-q response during dobutamine stress for early diagnosis, prognostication, and monitoring of therapeutic response in PAH. journal.publications.chestnet.org 965

8 Acknowledgments Author contributions: E. M. T. L. served as principal author, had access to all of the data in the study, and takes responsibility for the integrity of the study data. E. M. T. L., L. R. S., T. J. C., R. N., and D. S. C. contributed to study concept and design; E. M. T. L., R. R. V., P. C., P. A., and M. D. contributed to data collection and analysis; R. N. and D. S. C. contributed to manuscript preparation; E. M. T. L. contributed to the drafting of the manuscript; R. R. V., P. C., L. R. S., T. J. C., P. A., and M. D. contributed to the review of the manuscript; and R. R. V., P. C., L. R. S., T. J. C., P. A., M. D., R. N., and D. S. C. contributed to the final approval of the manuscript. Financial/nonfinancial disclosures : The authors have reported to CHEST the following conflicts of interest: Dr Vanderpool reports receiving consulting fees from United Therapeutics Corp. Dr Corte has received an unrestricted educational grant for research from Actelion Pharmaceuticals Ltd. Drs Lau, Choudhary, Simmons, Argiento, D Alto, Naeije, and Celermajer have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: We acknowledge all echosonographers at Royal Prince Alfred Hospital for their technical assistance in the project. References 1. Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J ;20(4): Lewis GD, Bossone E, Naeije R, et al. Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation ;128(13): Naeije R, Chesler N. Pulmonary circulation at exercise. Compr Physiol ;2(1): Galiè N, Hoeper MM, Humbert M, et al ; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J ;30(20): Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation ;118(21): Kovacs G, Maier R, Aberer E, et al. Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma. Am J Respir Crit Care Med ; 180 ( 9 ): Naeije R, Vanderpool R, Dhakal BP, et al. Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. Am J Respir Crit Care Med ;187(6): Lau EM, Manes A, Celermajer DS, Galiè N. Early detection of pulmonary vascular disease in pulmonary arterial hypertension: time to move forward. Eur Heart J ;32(20): Argiento P, Vanderpool RR, Mulè M, et al. Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest ;142(5): Argiento P, Chesler N, Mulè M, et al. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J ;35(6): Bossone E, D Andrea A, D Alto M, et al. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr ;26(1): Geleijnse ML, Fioretti PM, Roelandt JR. Methodology, feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol ;30(3): Pagnamenta A, Fesler P, Vandinivit A, Brimioulle S, Naeije R. Pulmonary vascular effects of dobutamine in experimental pulmonary hypertension. Crit Care Med ;31(4): Lejeune P, Naeije R, Leeman M, Melot C, Deloof T, Delcroix M. Effects of dopamine and dobutamine on hyperoxic and hypoxic pulmonary vascular tone in dogs. Am Rev Respir Dis ;136(1): Lalande S, Yerly P, Faoro V, Naeije R. Pulmonary vascular distensibility predicts aerobic capacity in healthy individuals. J Physiol ;590(Pt 17 ): Milan A, Magnino C, Veglio F. Echocardiographic indexes for the non-invasive evaluation of pulmonary hemodynamics. J Am Soc Echocardiogr ;23(3): Chemla D, Castelain V, Humbert M, et al. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest ;126(4): Jeon DS, Luo H, Iwami T, et al. The usefulness of a 10% air-10% blood-80% saline mixture for contrast echocardiography: Doppler measurement of pulmonary artery systolic pressure. J Am Coll Cardiol ;39(1): Linehan JH, Haworth ST, Nelin LD, Krenz GS, Dawson CA. A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves. J Appl Physiol (1985) ;73(3): Poon CS. Analysis of linear and mildly nonlinear relationships using pooled subject data. J Appl Physiol (1985) ;64(2): Castelain V, Chemla D, Humbert M, et al. Pulmonary artery pressure-flow relations after prostacyclin in primary pulmonary hypertension. Am J Respir Crit Care Med ;165(3): Provencher S, Hervé P, Sitbon O, Humbert M, Simonneau G, Chemla D. Changes in exercise haemodynamics during treatment in pulmonary arterial hypertension. Eur Respir J ;32(2): Langer SZ. Presence and physiological role of presynaptic inhibitory alpha 2-adrenoreceptors in guinea pig atria. Nature ;294(5842): Murray PA, Lodato RF, Michael JR. Neural antagonists modulate pulmonary vascular pressure-flow plots in conscious dogs. J Appl Physiol (1985) ;60(6): Naeije R, Lejeune P, Leeman M, Melot C, Closset J. Pulmonary vascular responses to surgical chemodenervation and chemical sympathectomy in dogs. J Appl Physiol (1985) ;66(1): Stickland MK, Welsh RC, Petersen SR, et al. Does fitness level modulate the cardiovascular hemodynamic response to exercise? J Appl Physiol (1985) ;100(6): Jewitt D, Birkhead J, Mitchell A, Dollery C. Clinical cardiovascular pharmacology of dobutamine. A selective inotropic catecholamine. Lancet ;2(7877): Parker JD, Landzberg JS, Bittl JA, Mirsky I, Colucci WS. Effects of betaadrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle. Circulation ;84(3): el-said ES, Roelandt JR, Fioretti PM, et al. Abnormal left ventricular early diastolic filling during dobutamine stress Doppler echocardiography is a sensitive indicator of significant coronary artery disease. J Am Coll Cardiol ;24(7): Nakajima Y, Kane GC, McCully RB, Ommen SR, Pellikka PA. Left ventricular diastolic filling pressures during dobutamine stress echocardiography: relationship to symptoms and ischemia. J Am Soc Echocardiogr ; 22 ( 8 ): Kafi SA, Mélot C, Vachiéry JL, Brimioulle S, Naeije R. Partitioning of pulmonary vascular resistance in primary pulmonary hypertension. J Am Coll Cardiol ;31(6): Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med ;179(2): Pavelescu A, Vanderpool R, Vachiéry JL, Grunig E, Naeije R. Echocardiography of pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. Eur Respir J ;40(5): Reeves JT, Dempsey JA, Grover RF. Pulmonary circulation during exercise. In: Weir EK, Reeves JT, eds. Pulmonary Vascular Physiology and Physiopathology. New York, NY : Marcel Dekker ; 1989 : Original Research [ 146 # 4 CHEST OCTOBER 2014 ]