Exercise Stress Echocardiography of the Pulmonary Circulation. Limits of Normal and Sex Differences

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1 CHEST Exercise Stress Echocrdiogrphy of the Pulmonry Circultion Limits of Norml nd Sex Differences Pol Argiento, MD ; Reecc R. Vnderpool, PhD ; Mssimilino Mulè, MD ; Mri Giovnn Russo, MD ; Michele D Alto, MD ; Edurdo Bossone, MD ; Nomi C. Chesler, PhD ; nd Roert Neije, MD Originl Reserch PULMONARY VASCULAR DISEASE Bckground: Exercise stress echocrdiogrphy hs not een recommended in the dignostic workup of pulmonry hypertension ecuse of insufficient certinty out fesiility nd limits of norml. Methods: Doppler echocrdiogrphy pulmonry hemodynmic mesurements were performed t progressively incresed worklod in 56 helthy mle nd 57 helthy femle volunteers ged 19 to 63 yers. Men pulmonry rtery pressure (mpap) ws estimted from the mximl tricuspid regurgittion jet velocity. Crdic index ws clculted from the left ventriculr outflow velocity-time integrl. Pulmonry vsculr distensiility index, the percentge chnge of vessel dimeter per mm Hg of mpap, ws clculted from multipoint mpap-crdic output (CO) plots. Results: Pek exercise t W ws ssocited with n mpap of 33 7 mm Hg nd CO of 18 5 L/min. The slope of mpap-co reltionships ws mm Hg/L/min, nd the distensiility coefficient ( ) ws 1.3% 1.0%/mm Hg. Mximl worklod nd crdic index were higher in men thn in women ( P,.05), ut mpap-crdic index reltionships were not different. However, women hd higher (1.6% 1.3%/mm Hg vs 1.1% 0.6%/mm Hg, P,.05). The verge mpap-crdic index slope ws higher nd lower in sujects 50 yers old. Upper limits of norml of mpap t exercise were 34 mm Hg t CO, 10 L/min, 45 mm Hg t CO, 20 L/min, nd 52 mm Hg t CO, 30 L/min. These vlues re in keeping with previously reported invsive mesurements. Conclusions: Exercise stress echocrdiogrphy of the pulmonry circultion is fesile nd llows for flow-corrected definition of upper limits of norml. Women hve more distensile pulmonry circultion. CHEST 2012; 142(5): Arevitions: 5 distensiility coefficient; CO 5 crdic output; LAP 5 left tril pressure; mpap 5 men pulmonry rtery pressure; PAP 5 pulmonry rtery pressure; PVR 5 pulmonry vsculr resistnce; spap 5 systolic pulmonry rtery pressure Pulmonry hypertension hs een defined previously s men pulmonry rtery pressure (mpap). 25 mm Hg t rest nd. 30 mm Hg dur ing exercise. 1,2 Exercise mesurements were withdrwn from the hemodynmic definition of pulmonry hypertension t n expert consensus conference held in 2008 in Dn Point. 3 This decision ws sed minly on n nlysis of the reported invsive pulmonry hemodynmic studies in helthy sujects t exercise reveling uncertinty out the exct upper limits of norml. 4 In the mentime, exercise-induced pulmonry rteril hypertension ws vlidted s clinicl entity. 5 Thus, roust definition of the limits of norml of 1158 the pulmonry circultion t exercise would e of gret relevnce. However, for ethicl nd prcticl resons, it is unlikely tht lrge numer of rightsided hert ctheteriztions in helthy sujects will e reported in the ner future. Therefore, there is currently interest in noninvsive exercise stress echocrdiogrphy of the pulmonry circultion. 6 We previously reported preliminry study on the fesiility of noninvsive echo-doppler mesurements of the norml pulmonry circultion t rest nd t exercise. 7 From multipoint mpap-flow coordintes in 25 helthy dults, we recovered pulmonry vsculr resistnce (PVR) nd distensiility clcultions Originl Reserch

2 tht were in good greement with those of previously reported invsive studies. We, therefore, now extend these mesurements to lrger numer of helthy men nd women to define limits of norml nd therey offer potentilly useful test for the screening of people who re symptomtic or mildly symptomtic with diseses ssocited with pulmonry hypertension. Mterils nd Methods One hundred twenty-four volunteers (62 women nd 62 men) ged yers (rnge, yers) with height nd weight of cm nd kg, respectively (ody surfce re, ) gve n informed consent to the study, which ws pproved y the ethicl committee of the Ersme University Hospitl (No. P2011/101; Ref. Eudrct/CCB: B , Brussels, Belgium). The sujects were nonsmokers nd were free of ny crdiovsculr or lung disese. None hd fmily history of pulmonry hypertension. All were physiclly ctive, ut none trined for. 5 h per week, nd, thus, were not considered thletes. Bseline clinicl exmintion nd ECG were norml. Eleven volunteers were excluded ecuse of echocrdiogrphy of insufficient qulity. Thus, complete sets of mesurements were otined in 57 women nd 56 men. Forty-two women were tking orl contrceptives. A stndrd echocrdiogrphic exmintion ws performed t rest nd during exercise s reported previously. 7 The worklod ws incresed y 20 to 30 W every 2 min until the mximl worklod tolerted ecuse of dyspne nd/or leg pin. Echocrdiogrphic mesurements were tken during the lst minute of ech worklod. Doppler echocrdiogrphy ws performed with Vivid 7 ultrsound system (GE Helthcre) on semirecument cycle ergometer (model 900 EL; Ergoline). The exercise tle ws tilted lterlly y 20 to 30 to the left. Crdic output (CO) ws estimted from the left ventriculr outflow trct cross-sectionl re nd pulsed Doppler velocity-time integrl mesurements. 8 Systolic pulmonry rtery pressure (spap) ws estimted from trns-tricuspid grdient clculted from the mximl velocity (V) of continuous Doppler tricuspid regurgittion s 4 3 V mm Hg ssigned to right tril pressure. 9 mpap ws clculted s spap Left tril pressure (LAP) ws estimted from Mnuscript received Jnury 10, 2012; revision ccepted Mrch 31, Affilitions: From the Deprtment of Crdiology (Drs Argiento, Russo, nd D Alto), Second University of Nples, Nples, Itly; the Clinicl Division of Crdiology (Dr Mulè), Ferrrotto Hospitl, University of Ctni, Ctni, Itly; the Deprtment of Crdic Surgery (Dr Bossone), IRCCS Policlinico Sn Donto, Sn Donto Milnese, Miln, Itly; the Deprtment of Biomedicl Engineering (Dr Chesler), University of Wisconsin-Mdison, Mdison, WI; nd the Deprtment of Physiology (Drs Vnderpool nd Neije), Fculty of Medicine, Free University of Brussels, Brussels, Belgium. Drs Argiento nd Vnderpool contriuted eqully to this rticle. Funding/Support: This work ws supported y the Ntionl Institutes of Helth [1R01HL to NCC], the Funds for Crdic Surgery [to R. N.], the Fonds de l Recherche Scientifique Médicle [ to R. N.], nd the Bureu for Interntionl Reltions nd Coopertion [to R. R. V.]. Correspondence to: Roert Neije, MD, Deprtment of Physiology, Fculty of Medicine, Free University of Brussels, Ersme Cmpus CP 604, 808 Lennik Rd, 1070 Brussels, Belgium; e-mil: rneije@ul.c.e 2012 Americn College of Chest Physicins. Reproduction of this rticle is prohiited without written permission from the Americn College of Chest Physicins. See online for more detils. DOI: /chest the rtio of Doppler mitrl E flow-velocity wve nd tissue Doppler mitrl nnulus flow E 9 erly distolic velocity (ie, LAP E/E 9 ). 11 The echocrdiogrphic recordings were stored on opticl disks nd red in duplicte y linded oservers (P. A., M. D., nd M. M.). We previously reported introserver vriilities for spap nd CO estimtes of 4.3% nd 4.0% t rest nd 8.2% nd 7.7% t mximl exercise, respectively, nd interoserver vriilities of spap nd CO estimtes of 1.9% nd 4.9% t rest nd 7.9% nd 13.9% t mximl exercise, respectively. 7 PVR ws clculted s (mpap 2 LAP)/CO. Multipoint mpap-co nd mpap-indexed CO (crdic index) plots were tested for linerity, nd liner regressions were clculted for pooled mle nd femle mesurements fter Poon djustment for individul vriility. 12 Ech multipoint mpap-co plot ws lso fitted to the eqution : LAP 5 R0( CO) 1 mpap where R 0 is the totl PVR t rest, to clculte distensiility index in percentge chnge in dimeter per mm Hg increse in trnsmurl pressure. 13 To investigte the effect of exercise on the distensiility index, specific distensiility coefficient ( ) index ws clculted t rest ( -rest) s well s t pek exercise ( -pek). Results re presented s men SD. The sttisticl nlysis consisted of lest-squres liner regression clcultions nd Student t tests fter checking for normlity of distriutions using the D Agostino skewness test. Nonnorml distriutions were found in clcultions of nd slopes of pressure-flow curves, so Wilcoxon rnk sum test ws performed. P,.05 ws considered significnt. Limits of norml on slopes of mpap-co nd mpap-crdic index were defined s men 2 2 SD to men 1 2 SD. Prediction nds (S-pred) were clculted sed on qudrtic fit of the pooled pressure-flow dt in MATLAB (The MthWorks, Inc), using the eqution: x x Spred x s 1 2 n xi x Sttisticl nlysis ws performed using R (R-project.org, version ). Results Good-qulity signls were ville t ll levels of exercise in ll sujects. Becuse 11 sujects hd een excluded t n initil echocrdiogrphic evlution, this corresponds to n 87% recovery rte of complete exercise stress echocrdiogrphy of the pulmonry circultion in helthy dults. Pressure-Flow Reltionships nd Limits of Norml As shown in Tle 1, pek exercise t n verge of 175 W (men 1 women) ws ccompnied y closeto-fourfold increse in CO nd douling of mpap. Exercise incresed LAP y n verge of 2 mm Hg nd did not ffect PVR. Ech mpap-co plot ws well 1 journl.pulictions.chestnet.org CHEST / 142 / 5 / NOVEMBER

3 Tle 1 Hemodynmic Mesurements t Rest nd t Pek Exercise in 56 Mle nd 57 Femle Sujects Men Women Mesurement Rest Pek Exercise Rest Pek Exercise mpap, mm Hg LAP, mm Hg CO, L/min Crdic index, L/min/m PVR, Woods units c d d PVRi, Woods units c /m , %/mm Hg Dt re presented s men SD. The verge ge in oth the mle nd femle group ws similr, with 11 women nd 14 men 50 yers old. CO 5 crdic output; LAP 5 left tril pressure; mpap 5 men pulmonry rtery pressure; PVR 5 pulmonry vsculr resistnce; PVRi 5 indexed pulmonry vsculr resistnce; 5 distensiility coefficient. P,.001 compred with men. P,.01 compred with men. c Or mm Hg/min/L. d P,.05 compred with men. descried y liner pproximtion, with ver ge correltion coefficients of 0.92 nd n SD of The verge slope of mpap-co ws mm Hg/L/min. After Poon djustment, the verge slope of line est fit to pooled dt ws 1.46 mm Hg/L/min nd the intercept 8 mm Hg. The mpap-co reltionships were ctully slightly curviliner nd, ccordingly, lso well fitted y the distensiility eqution. The ver ge distensiility coefficient ws 1.3% 1.0%/mm Hg ut it decresed y pproximtely 50% from rest to mximl exercise. The limits of norml of the slopes of multipoint mpap-co reltionships clculted s men 2 2 SD to men 1 2 SD were 0.5 to 2.5 mm Hg/L/min. Limits of norml of prediction nds for mpap-co reltionships re shown in Figure 1. This presenttion shows tht the upper limit of norml of mpap would e 34 mm Hg t CO elow 10 L/min, 40 mm Hg t CO of 15 L/min, 45 mm Hg t CO of 20 L/min, nd 52 mm Hg t CO of 30 L/min. CO ws expectedly correlted to worklod. However, s illustrted in Figure 2, there ws wide rnge of CO for ny given level of worklod. Sex Differences Comprisons etween mle nd femle sujects re presented in Tles 1 nd 2. The men nd women were of similr verge ge, nd the women hd lower ody surfce re. Resting mpap ws the sme, ut oth CO nd crdic index were higher in men, wheres PVR, not indexed PVR, ws higher in women (Tle 1). The upper limit of norml of resting mpap clculted s men mpap 1 2 SD ws 21 mm Hg in Figure 1. A, Men pulmonry rtery pressure (mpap)-crdic output (CO) reltionships t rest nd t progressively incresed worklods. The prediction nd is shown y the shded re. mpaps t CO vlues of 10, 20, nd 30 L/min re shown y the stippled lines. B, Poon-djusted liner fit of the dt points to recover norml slope of 1.46 mm Hg/L/min Originl Reserch

4 In the women, decresed s function of ge ( %/mm Hg/y, R ), down to vlues indiscernile from men t 50 yers (Tle 2). Age Differences Twenty-five sujects, 11 women nd 14 men, were 50 yers old. Their chrcteristics nd hemodynmic mesurements, compred with those of sujects, 50 yers old, re presented in Tles 3 nd 4. Older sujects hd slightly higher mpap nd LAP t rest, lower mximl worklod nd crdic index, steeper slopes of mpap-co or mpap-crdic index plots, nd trend to lower. PVR ws not differ ent. Steeper slopes of Poon-djusted mpap-crdic index reltionships in older sujects re illustrted in Figure 4. Discussion Figure 2. CO vs worklod reltionships t exercise. There is wide rnge of CO vlues t ny given worklod. See Figure 1 legend for expnsion of revition. oth men nd women. At pek exercise, men chieved higher mximl worklod, CO, crdic index, nd mpap, wheres PVR or indexed PVR were not different. There ws slight increse in LAP, y n verge of 2 mm Hg, t mximl exercise, which ws not different in women nd in men. The upper limits of norml of mpap t exercise were 48 mm Hg in men nd 45 mm Hg in women. mpap-co or mpap-crdic index reltionships were not different etween men nd women (Tle 2). This ws confirmed y the slopes of the liner fit to the Poon-djusted mpap-co nd mpap-crdic index dt ( Fig 3 ). As lso shown in Tle 1, sex hd no mesurle effect on t rest, ut t pek exercise ws significntly less in men. Tle 2 Chrcteristics of 56 Mle nd 57 Femle Sujects Vrile Men Women Age, y BSA, m mpap-co, mm Hg/L/min mpap-crdic index, mm Hg/L/min/m Poon mpap-co, mm Hg/L/min , %/mm Hg , 50 y y Mximl worklod, W Dt re presented s men SD unless indicted otherwise. BSA 5 ody surfce re. See Tle 1 for expnsion of other revitions. P,.001 compred with men. P,.01 compred with men. The results show tht the upper limits of norml for mpap t stress echocrdiogrphy depend on the chieved mximl CO. The previously used cut-off vlue of 30 mm Hg for the dignosis of exerciseinduced pulmonry hypertension is ccurte for CO elow 8 to 10 L/min. Higher upper limits of norml for exercise mpap, up to 50 mm Hg, re to e considered for higher COs chieved y fit helthy sujects. The results lso show, we elieve for the first time, tht there re no sex differences in PVR, ut there is higher pulmonry vsculr distensiility in women, 50 yers old. Limited dt on smll sugroup of sujects 50 yers old revel expected steeper pulmonry vsculr pressure-flow reltionships nd decresed distensiility. Exercise stress echocrdiogrphic mesurements of the pulmonry circultion re usully reported s single spap estimtes with or without mention of the chieved worklod. This pproch hs indicted higher prevlence of higher-thn-norml exercise spap in the reltives of ptients with pulmonry rteril hypertension s compred with control sujects. 14 In these studies, the upper limit of norml of spap t exercise ws estimted to e round 40 mm Hg. However, the sme upper limit of norml hs een determined for resting ging nd overweight sujects 15 or resting young dult thletes. 16 This could e explined y ltered left ventriculr distolic function with ging nd oesity 15 nd y incresed stroke volume s result of trining. 16 It hs long een elieved tht pulmonry rtery pressure (PAP) does not increse much with exercise, so tht n mpap. 30 mm Hg (corresponding to n spap of 47 mm Hg 10 ) t exercise would definitely e dignostic of pulmonry vsculr disese. 2 However, mpap increses t high levels of exercise, up to vlues of round 40 to 50 mm Hg s reported in invsive 4,17 s well s noninvsive studies. 7,18 In the journl.pulictions.chestnet.org CHEST / 142 / 5 / NOVEMBER

5 Figure 3. Poon-djusted mpap s function of crdic index t rest nd t progressively incresed worklods in helthy sujects. Sex hd no effect on the slopes of the reltionships. A, Men. B, Women. CI 5 crdic index. See Figure 1 legend for expnsion of other revition. present study on helthy young to middle-ged dults of vrile fitness, the upper limit of norml of mpap t exercise ws 52 mm Hg. Becuse mpap-co reltionships re close to liner, 17 these oservtions underscore the need to express mximl exercise mpap mesurements s function of CO. An lterntive option is to normlize mpap for worklod. However, even though there is n oligtory reltionship etween CO nd musculr work, the present results show tht ny given level of worklod is ssocited with wide rnge of flows. Becuse it is flow, rther thn worklod, tht determines pulmonry vsculr pressures, expressing the pulmonry vsculr response to exercise s mpap-co reltionships is preferle. Echocrdiogrphic estimtes of pulmonry vsculr pressures nd CO re dvntgeous ecuse they re noninvsive nd flexile ut hve to rely on series of ssumptions in the clcultions of vsculr pressures nd volume flows. Qulity control studies hve reported disppointingly poor greement etween spap estimted from the mximl velocity of tricuspid regurgittion nd invsive mesurements t right-sided hert ctheteriztion. 19 CO clculted from the left ventriculr outflow trct dimension nd velocity-time integrl tends to e underestimted, minly ecuse of the underestimtion of left ventriculr out flow trct dimensions. 8 However, lthough this is not proof, it my e noted tht in the present study the Doppler echocrdiogrphic mesurements of mpap nd CO were in good greement with previous invsive studies t ny given level of worklod. 4,17 They even llowed for the clcultion of expected distensiility coefficients in the rnge of 1% to 2%/mm Hg, 13 which would not occur y chnce or in the presence of too-lrge Tle 3 Hemodynmic Mesurements t Rest nd t Pek Exercise of 25 Sujects 50 Yers Old Compred With 88 Sujects, 50 Yers Old, 50 y 50 y Chrcteristic Rest Pek Exercise Rest Pek Exercise mpap, mm Hg LAP, mm Hg CO, L/min c Crdic index, L/min/m PVR, Woods units d PVRi, Woods units d /m , %/mm Hg See Tle 1 for expnsion of revitions. P,.001 compred with sujects, 50 yers old. P,.05 compred with sujects, 50 yers old. c P,.01 compred with sujects, 50 yers old. d Or mm Hg/min/L Originl Reserch

6 Tle 4 Chrcteristics of 25 Sujects 50 Yers Old Compred With 88 Sujects, 50 Yers Old Vrile Age, 50 y 50 y Age, y BSA, m mpap-co, mm Hg/L/min mpap-crdic index, mm Hg/L/min/m 2 Intercept , %/mm Hg Mximl worklod, W See Tles 1 nd 2 for expnsion of revitions. P,.001 compred with sujects, 50 yers old. P,.05 compred with sujects, 50 yers old. errors on mesurements. The wekest me surement from methodologic point of view in the present study would proly e LAP estimted from n E/E 9 rtio, which could explin why LAP did not increse t the highest level of exercise, s expected. 17 Previous vlidtion studies of E/E 9 to esti mte LAP or wedged PAP reported excessively high crdic indexes 11 nd n sence of liner reltionship etween E/E 9 nd wedged PAP t exercise. 20 However, wedged PAP hs lso een shown to correlte poorly with left ventriculr end-distolic pressures, 21 so invsively mesured wedged PAP might not e n optiml gold stndrd for noninvsive estimtes of LAP. Furthermore, mpap-co reltionships t exercise show little chnge in LAP up to CO round 20 L/min, ut steep increse t higher CO, which is delyed to even higher CO in the most fit sujects. 22 Thus, only mild increse in LAP y n verge of 2 mm Hg from rest to mximl exercise in the present study is not unexpected. It my e dded tht LAP is prt of the distensiility clcultions, which yielded the expected rnge of vlues.13 Becuse pulmonry vsculr pressures re flow dependent, 17 we defined the resistive properties of the pulmonry circultion y multipoint mpap-co or mpap-crdic index reltionships. This pproch hs een shown repetedly to llow for improved definition of PVR. 23 We confirmed previously reported high levels of liner correltions etween mpap nd flow t exercise, so these reltionships could resonly e descried y liner pproximtions. 17 Previously clculted men slopes of mpap-co were of 1 mm Hg/L/min in young dults, incresing to 2.5 mm Hg/L/min in dvnced ge. The verge slopes of mpap-co reltionships in the present study on middle-ged dults stilized t 1.5 mm Hg/L/min nd, thus, were in keeping with these previous estimtes from invsive mesurements. However, ecuse pulmonry resistive vessels re distensile, multipoint mpap-co plots re ctully slightly curvilin er. 13 I t is possile to clculte distensiility coeffi cient ccount ing for the recovered curvilinerity of mpap-co. Using relistic distensiility model of the pulmonry circultion, n vlue of pproximtely 2%/mm Hg hs een clculted previously from invsive mesurements in young dult volunteers. A distensiility of the sme order of mgnitude ws clculted from the present noninvsive determintions, confirming the previous report. 7 It is of interest tht decresed y pproximtely 50% from rest to exercise, in keeping with the notion tht pulmonry Figure 4. Poon-djusted mpap s function of crdic index t rest nd t progressively incresed worklods in helthy sujects. Aging ws ssocited with n incresed slope of the reltionships. A,, 50 yers. B, 50 yers. See Figure 1 nd 3 legends for expnsion of revitions. journl.pulictions.chestnet.org CHEST / 142 / 5 / NOVEMBER

7 vsculr complince decreses long with incresed distending pressures. Previous exhustive reviews of invsive pulmonry hemodynmic studies filed to uncover sex differences. This my e explined y the reltively smll numer of reported individul exercise mesurements nd the limited vrile levels of worklod nd CO, mking isoflow comprisons difficult. 4,17 In the present study, the liner pproximtions of pulmonry vsculr pressure flow reltionships were not different in men nd women. However, when the pressure-flow coordintes were fitted to distensiility model of the pulmonry circultion, it ecme pprent tht women elow the ge of 50 yers present with higher pulmonry vsculr complince. In the present study, ws 45% higher in women thn in men, ut the sex difference disppered in sujects 50 yers old. CO ws lower in women thn in men in the present study, which is in greement with previous invsive mesurements. 4,17 Somewht surprisingly, the difference persisted fter correction for ody size. Recent MRI mesurements confirmed lower CO in women, ut this sex difference ws not ny more significnt when corrected for ody size, with crdic index round 3.0 L/min/m 2 for men nd 2.8 L/min/m 2 for women. 24,25 However, in these studies, ody sizecorrected right ventriculr volume nd mss were lower in women. 24,25 The present results suggest tht this my e due to the lower fterlod of more distensile pulmonry circultion. The exercise stress tests were performed in semirecumnt position. Previous invsive studies reported higher resting PVR in the upright, compred with recument, position, ecuse of grvity-dependent lower venous return leding to pulmonry vsculr derecruitment. However, the difference disppered with exercise, in reltion to incresed pulmonry lood flow nd full vsculr recruitment. Accordingly, multipoint mpap-co reltionships were not ffected y ody position. 17 It is, therefore, unlikely tht ody position would hve ffected the stress echocrdiogrphyderived pulmonry vsculr pressure-flow reltionships. Our study ws not designed to study the effects of ging on the pulmonry circultion. However, in 25 of the 113 sujects ged 50 yers old, the slope of mpap-crdic index ws incresed nd ws decresed, confirming previous estimtions. 4,13,17 The group of sujects 50 yers old ws too smll, with the oldest suject ged 63 yers, to llow for estimtions of limits of norml s function of incresed ging. Nevertheless, it is remrkle tht the present noninvsive mesurements uncovered the expected effects of ging on resistive nd distensiility properties of the pulmonry circultion. There re severl dditionl limittions to the present study. The recovery rte of 87% of sufficient-qulity signls t the echocrdiogrphy of the pulmonry circultion of norml sujects is unusully high nd is proly explined y high levels of previous trining nd the dediction of the investigtors. Lower recovery rtes my e expected in dily clinicl prctice. Furthermore, there ws no vlidtion ginst gold stndrd invsive mesurements. However, this would e ethiclly nd prcticlly very difficult to otin in lrge numer of helthy sujects. Finlly, the study ws performed in single center nd, thus, would require confirmtion in multicentric fshion. In summry, the present results offer flow-corrected upper limits of norml of PAPs t exercise stress echocrdiogrphy tht re in comptile with previous invsive mesurements. The results lso show tht women hve more distensile pulmonry circultion, which is likely estrogen relted. It is hoped tht improved definition of the limits of norml of exercise stress echocrdiogrphy estimtes of pulmonry vsculr pressures nd CO will help mke the method useful for the erly dignosis of pulmonry hypertension. Acknowledgments Author contriutions: Dr Argiento: contriuted to the originl design nd concept of the study, dt cquisition, dt nlysis, nd preprtion nd criticl review of the mnuscript. Dr Vnderpool: contriuted to the nlysis nd interprettion of dt nd preprtion nd criticl review of the mnuscript. Dr Mulè: contriuted to the dt cquisition, dt nlysis, review of echocrdiogrphic imges, nd criticl review of the mnu script. Dr Russo: contriuted to the concept of the study nd criticl review of the mnuscript. Dr D Alto: contriuted to the review of the echocrdiogrphic imges nd criticl review of the mnuscript. Dr Bossone: contriuted to the concept of the study nd criticl review of the mnuscript. Dr Chesler: contriuted to the dt nlysis nd criticl review of the mnuscript. Dr Neije: contriuted to the overll design nd concept of the study, nlysis nd interprettion of dt, nd preprtion nd criticl review of the mnuscript. Finncil /nonfinncil disclosures: The uthors hve reported to CHEST tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my e discussed in this rticle. Role of sponsors : The sponsors hd no role in the design of the study, the collection nd nlysis of the dt, or in the preprtion of the mnuscript. Other contriutions: This work ws performed t the Free University of Brussels, Brussels, Belgium. References 1. Neije R. In defence of exercise stress tests for the dignosis of pulmonry hypertension. Hert ;97(2): Ruin LJ. Primry pulmonry hypertension. N Engl J Med ;336(2): Bdesch DB, Chmpion HC, Snchez MA, et l. Dignosis nd ssessment of pulmonry rteril hypertension. J Am Coll Crdiol ;54(suppl 1 ):S Originl Reserch

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