Determinants of exercise capacity in patients with coronary artery disease and mild to moderate systolic dysfunction

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1 Europen Hert Journl (1996) 17, eterminnts of exercise cpcity in ptients with coronry rtery disese nd mild to moderte systolic dysfunction Role of hert rte nd distolic filling bnormlities S. S. Lele*,. cfrlnef, S. orrison^, H. Thomson*,. Khfgif nd. renneux* eprtments of'*crdiology fnucler edicine nd ^Thorcic edicine, Royl Brisbne Hospitl nd eprtment of edicine, University of Queelnd, Brisbne, Austrli Bckground To test the hypothesis tht distolic filling bnormlities re n importnt cuse of exercise limittion in some ptients with coronry rtery disese we ssessed the fctors limiting exercise cpcity in group of ptients with coronry rtery disese in whom exercise limittion ws greter thn expected from the degree of resting left ventriculr systolic dysfunction. ethods nd Results We ssessed the reltiohip between exercise cpcity (mximl oxygen coumption) during erect cycle ergometry, hert rte, rdionuclide indices of left ventriculr systolic function (ejection frction) nd distolic filling (pek filling rte, nd time to pek filling) during semi-erect cycle ergometry in 20 ptients (15 mle, five femle) who were ged 42- yers (men 61 yers) nd hd ngiogrphiclly proven coronry rtery disese nd evidence of reversible myocrdil ischemi on thllium scintigrphy. All ptients exhibited mrked exercise limittion (mximl oxygen coumption ml. min ~ '. kg ~ ' men 15-9 ml. kg ~ '. min ~ ', which ws 611 ± 16% of ge nd gender predicted mximum) due to brethlessness or ftigue rther thn ngin, in spite of men ejection frction for the group of 465% (rnge 30-67%). We lso compred the distolic filling chrcteristics of these ptients during exercise with 10 helthy controls (ge 38-66, men 58 yers; eight mle, two femle). Compring distolic filling chrcteristics, pek filling rte ws higher nd time to pek filling shorter both t rest nd pek exercise in controls thn ptients (pek filling rte 3-1 ± 0-5 vs 2-2 ± 0-9 EV.s" 1, >=001 t rest nd 8-3 ± 0-8 vs 5-2 ± 1-9EV. s"', > < on exercise; time to pek filling ±29-8 vs ± 71-7 ms, f<00001 t rest nd 52-8 ±16-2 vs ± 44-8 ms, > <00001 on exercise respectively). On univrite nlysis in the ptients studied, mximl oxygen coumption ws correlted with pek hert rte (r=0-45 Z'=004), pek exercise time to pek filling (r=-0-85 ><00001), pek exercise pek filling rte (r=0-51 >0-019), nd the reltive increse in crdic output i.e. crdic output pekcrdic output rest (r=0-58, >=0-008). There ws no correltion between mximl oxygen coumption nd resting indices of distolic filling (pek filling rte nd time to pek filling) or with resting or pek exercise ejection frction. On multiple regression nlysis, only pek exercise time to pek filling ws significntly relted to mximl oxygen coumption. Conclusion We hve observed strong correltion between exercise cpcity nd indices of exercise left ventriculr distolic filling, nd hve confirmed previous studies showing poor correltion with resting nd exercise indices of systolic function nd resting distolic filling, in ptients with coronry rtery disese. (Eur Hert J 1996; 17: ) Key Words: istolic function, exercise cpcity, rdionuclide ventriculogrphy, coronry rtery disese. Revision submitted 21 ecember 1994, nd ccepted 18 Jnury Correspondence. Prof. ichel P. renneux, eprtment of Crdiology, Royl Brisbne Hospitl, Herston Rod, Brisbne 4029, Queelnd, Austrli X $ Introduction yspnoe is common symptom in ptients with coronry rtery disese nd in mny cses is thought to be due to systolic dysfunction' 11. In some cses of crdic dyspnoe, resting systolic function is norml or only 1996 The Europen Society of Crdiology

2 eterminnts of exercise cpcity in CA nd systolic dysfunction 205 Tble 1 Clinicl chrcteristics nd resting rdionuclide ventriculogrphy dt for the 20 ptients included in the study s Pn tifnt r llcul Age (yers) vjender Coronry ntomy NYHA Clss Rest E (%) Rest PR (EV.s" 1 ) Rest TTP (ms) l ±90 1V 3V 3V 3V 1V 3V 1V 3V 1V I I I I I I I I ± ± ±71 V = vessel disese; E = ejection frction; PR = pek filling rte (end-distolic volumes per second); TTP = totl time to pek filling. mildly to modertely impired nd in such ptients the dyspnoe hs been ssumed to be due either to ischemic left ventriculr systolic dysfunction on exercise or to bnormlities of distolic function. Whilst resting bnormlities of distolic function re common in such ptients, previous studies hve demotrted only wek reltiohip between objective mesures of exercise cpcity nd resting distolic filling indices, nd resting nd exercise left ventriculr ejection frction' 2 ' 31. We studied group of ptients with estblished coronry rtery disese nd evidence of reversible myocrdil ischemi but without limiting ngin, who hd mrkedly reduced exercise cpcity. Their dyspnoe or ftigue ppered cliniclly disproportionte to the reduction in their left ventriculr ejection frction. A priori distolic dysfunction is likely to be importnt in such ptients. We evluted the reltive roles of exercise-induced systolic nd distolic dysfunction nd hert rte in limiting exercise cpcity in order to test the hypothesis tht bnormlities of exercise distolic rilling re n importnt determinnt of exercise cpcity in such ptients. ethods Ptients The study popultion ws selected from 42 coecutive ptients ttending the crdiology clinic of the Royl Brisbne Hospitl, with previous myocrdil infrction nd ngiogrphiclly proven coronry rtery disese, in whom exercise cpcity ws mrkedly limited by dyspnoe or ftigue (New York Hert Assocition Clss lib or I) rther thn ngin. Ptients were coidered eligible for the study if their resting left ventriculr ejection frction by rdionuclide ventriculogrphy ws ^30%, the underlying crdic rhythm ws sinus nd there ws objective evidence of reversible myocrdil ischemi (reversible perfusion defects on exercise or dipyridmole thllium scintigrphy). Ptients with history of pulmonry disese or bnorml spirometry, history of current or prior hyperteion or echocrdiogrphic evidence of left ventriculr hypertrophy were excluded. Twenty ptients (15 mle, five femle) stisfied the bove entry criteri nd were enrolled for the study. The study ptients were ged 42- (men 61) yers nd hd body surfce re of 1-84 ±0-1 m 2. The men resting left ventriculr ejection frction ws 46-5% (rnge 30-67%). Twelve ptients were in New York Hert Assocition clss lib nd eight in clss I. The clinicl nd resting rdionuclide ventriculogrphy dt for ll ptients re shown in Tble 1. Ten helthy controls (eight mle, two femle, ge 38-66, men 58 yers nd body surfce re of 1-87 ±0-1 m 2 ) with no history to suggest crdic disese, no risk fctors for coronry rtery disese, norml crdiovsculr exmintion nd negtive resting nd exercise electrocrdiogrms were lso studied in order to compre distolic filling chrcteristics t rest nd during exercise with the 20 ptients.

3 206 S. S. Lele et l. Study protocol All ptients nd controls were studied in the fsting stte. Eleven ptients were on regulr tretment with bet-blockers nd four on clcium chnnel blockers, but both gents were withdrwn for t lest 7 dys prior to the study. Ptients were studied on ngiotein converting enzyme inhibitors (nine ptients) ndor diuretics (four ptients) provided the dose hd not been ltered in the preceding 6 weeks. Six of the 20 ptients studied were on regulr digoxin therpy nd none ws tking regulr nitrtes. All ptients nd norml controls gve informed written coent. The protocol ws pproved by the Royl Brisbne Hospitl ethics committee. Exercise testing nd respirtory gs nlysis Objective ssessment of exercise cpcity in the 20 ptients ws undertken during mximl symptomlimited erect cycle exercise testing. Subjects brethed through low-resistnce one-wy vlve (H Rudolph) nd ipired ventiltion ws mesured with clibrted gs meter (orgn Ventiltion onitor). Expired oxygen nd crbon dioxide concentrtio were mesured distl to 9 1 mixing chmber with n Applied Electrochemistry S3-A oxygen nlyser nd C3 infr-red crbon dioxide nlyser respectively. Ech nlyser ws clibrted before nd fter the experiment with t lest three reference gses checked by the Lloyd-Hldne method. Hert rte ws mesured electrocrdiogrphiclly. The ECG trcing nd outputs from the ventiltion meter nd gs nlysers were recorded on Gould TA 2000 chrt recorder. Ventiltion ws clculted from the chrt recording nd expressed t body temperture nd pressure sturted (BTPS). Oxygen coumption nd crbon dioxide output were clculted using stndrd formule nd expressed t stndrd temperture nd pressure dry (STP)' 41. At the commencement of ech study, 5 min rest period ws used to provide bseline mesurements. A protocol of progressive exercise ws undertken on n electroniclly brked cycle ergometer, the initil worklod ws set t 25 Wtts incresing by 12-5 Wtts every 3 min until symptom-limited mximum. esurements were mde ech minute throughout exercise. The term mximl oxygen coumption ws used to denote the oxygen coumption mesured over the lst minute of the test. ximum predicted hert rte ws clculted using the formule' 5 ': 220-ge(yers)=mx predicted hert rte (mles) 210-ge(yers) = mx predicted hert rte (femles) Age nd gender-predicted mximl oxygen coumption ws clculted using the formule' 6 ' 71 : en: ximl Oxygen Coumption (ml. kg" 1. min "')=60-(gex 0-55). Women: ximl Oxygen Coumption (ml. kg" 1. min"')=48-(gex 0-37). Equilibrium rdionuclide ventriculogrphy Twenty four hours fter the erect exercise studies, left ventriculr ejection frction nd distolic filling were ssessed by equilibrium R-wve gted blood pool scintigrphy (GBPS) using stndrd technique, t rest nd during grded semi-erect exercise on cycle ergometer. Ten minutes fter the intrvenous injection of pproximtely 1-7 mg stnnous pyrophosphte, 5 ml of blood ws drwn into heprinized syringe nd incubted for 20 min with 925 Bq (25 mci) of Tc-99m pertechnette before re-injection. Studies were cquired on smll field-of-view gmm cmer (GE300A, GE edicl Systems, ilwukee, WI, U.S.A.) fitted with low-energy, generl-purpose, prllel-hole collimtor nd interfced to dedicted mini-computer (xelt, Sieme, es Plines, IL, U.S.A.). With the ptient on the cycle ergometer, the detector ws djusted for the left nterior oblique view with the best ventriculr seprtion, nd of cudl tilt. A 15% tolernce window ws set bout the ptient's hert rte, nd ech R-R intervl divided into 28 equl frmes t rest nd during exercise. A cotnt number of frmes per R-R intervl eured cotnt temporl resolution during distole t ll levels of hert rte. t from ech bet were cquired into memory buffer in 64 x 64 'word' mtrix nd if ccepted were reformtted using 23 forwrd, 13 bckwrd gting. our minutes of dt were cquired t rest, nd t ech incrementl level of exercise fter 30 s period for stbiliztion of hert rte t the commencement of ech stge. The initil worklod ws set t 25 Wtts, incresing by 12-5 Wtt increments. Exercise ws terminted due to ptient ftigue, brethlessness, rrhythmi, hert rte >200 bets per minute, or hypoteion (systolic blood pressure<bseline). None of the ptients developed ngin during the exercise protocol. The rest nd exercise gted blood pool sc were nlysed by single opertor unwre of the ptient's history or exercise performnce. The composite cycle derived from ech stge ws sptilly nd temporlly filtered. Left ventriculr counts in ech frme were determined by semi-utomted edge-detection lgorithm. Left ventriculr ejection frction (%) ws clculted from the bckground-corrected left ventriculr ctivity-time curve. Stroke counts were clculted s the product of bckground-corrected end-distolic counts (corrected for number of cycles ccepted nd cycle durtion) nd left ventriculr ejection frction. Pek left ventriculr filling rte in terms of end distolic volumes per second (EV.s"') nd time to pek filling in milliseconds (ms) fter end-systole were clculted from the second derivtive of the distolic ctivity-time curve. The reltive increse in crdic output from rest to pek exercise ws clculted using the formul: Reltive increse in crdic output = (Stroke counts x Hert rte) t pek exercise (Stroke counts x Hert rte) t rest

4 eterminnts of exercise cpcity in CA nd systolic dysfunction 207 Tble 2 Hemodynmic vribles during erect cycle exercise performed to ssess the exercise cpcity by VO 2 mx rllctlls Rest HR (bets. min ~ ') Pek HR (bets. min~') Rest BP (mmhg) Pek BP (rrunhg) VO 2 mx (ml. kg" ' min~ ') l en ± S ± ± % ± ± 111 HR = hert rte; BP=men blood pressure; VO 2 = mximl oxygen coumption This ssumes no chnge in left ventriculr vlvulr incompetence during exercise. None of the ptients hd evidence of resting mitrl or ortic regurgittion. The vlidity of these rdionuclide mesures of distolic filling t high hert rtes hs been previously estblished Sttisticl nlysis Results re expressed s men vlues ± 1 S. Sttisticl nlysis ws performed using the pired nd unpired t-test nd by simple nd multiple regression where pproprite. Results Exercise testing with respirtory gs nlysis All ptients performed mximl symptom-limited exercise nd in ll but one cse respirtory exchnge rtio ws 5:1-05 t pek exercise. In one cse, respirtory exchnge rtio t pek exercise ws 102 but this ptient stisfied one of the stndrd criteri for nerobic threshold' 10 ' nd ws therefore included in the study. Exercise ws terminted due to brethlessness in 12 nd ftigue in eight ptients. ximl oxygen coumption rnged from ml. kg~'. min ~ ' (men 15-9 ±4-4) nd ws 61 1 ± 16% of ge- nd sexpredicted mximum. Hert rte incresed from 78-2 ± 7-4 bets. min~ ' t rest to ±21-5 bets. min~' t ±4-8 pek exercise nd ws 79-6 ± 11-3% of ge- nd sexpredicted mximum. The mximum hert rte chieved rnged from 59 bets. min ~ ' below mximum predicted to 7 bets. min ~' bove mximum predicted (men hert rte deficit 31-8 ± 17-6 bets. min" 1 ). Systolic blood pressure incresed from ±5-2 to 156 ± 12-9 mmhg. The results of erect exercise testing re summrized in Tble 2. Rdionuclide ventriculogrphy All ptients nd 10 norml controls performed symptom-limited semi-erect exercise. en exercise durtion ws 88 ± 2-4 min in ptients nd 16-0 ±40 min in controls. Hert rte ws similr t rest in controls nd ptients (-3 ± 110 vs 78-2 ± 14-1 bets, min "', P) but ws higher t pek exercise in controls compred to ptients (136-6 ±8-7 vs ±21-5 bets. min " ', P=0-04, respectively). Systolic blood pressure ws similr t rest in both controls nd ptients (125-5 ± 5-2 vs 122 ± 8-4 mmhg P ) but t pek exercise ws higher in the controls thn in the ptients (188 ±9-4 vs 156± 12-9 mmhg, ) =003). Ejection frction ws higher both t rest nd t pek exercise in the controls thn in the ptients (60-8 ±6-2 vs 46-5 ±11-4%, >=0001 nd 750±6-5 vs 46-2± 12-8% P<00001 respectively). Pek filling rte ws higher both t rest nd t pek exercise in controls compred with the ptients (31 ±0-5 vs 2-2 ±0-9 EV. s~\ ^=001 nd 8-3 ± 0-8 vs 5-2± 1-9 EV. s" 1, ^OOOOl respectively). Totl time to pek filling ws shorter both t rest nd t pek

5 208 S. S. Lele et l. Tble 3 Hemodynnuc nd rdionuclide vribles t rest nd t pek semi-erect exercise in the 10 controls nd the 20 ptients studied Normls Ptients P Hert rte rest Hert rte pek Ejection frction rest Ejection frction pek Pek filling rte rest Pek filling rte pek Time to pek filling rest Time to pek filling pek % chnge in EC -3 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± < < <00001 EC = end distolic counts. exercise in controls compred with the ptients (115-2 ±29-8 vs ± 71-7 ms, P<00001 nd 52-8 ± 16 2 vs ± 44-8 ms, ><0O001). There ws reltiohip between the chnge in time to pek filling during exercise nd the chnge in hert rte in controls, (r=0-78, > =0007) wheres no such reltiohip ws present in ptients (r = 0-ll, P ). These results re summrized in Tble 3 nd ig. 4. Reltiohip of exercise cpcity to resting nd exercise indices of systolic nd distolic function in the 20 ptients with ischemic hert disese On univrite nlysis, mximl oxygen coumption ws correlted with pek hert rte ttined during both erect nd semi-erect exercise (r=0-49 >=002 nd r=0-45 >=0-04 respectively), with the reltive increse in crdic output (i.e. crdic output pekcrdic output rest; r=0-58 > =0008) nd with indices of exercise distolic filling (r = 0-51 ><0-019 vs pek filling rte; r= > <0-001 vs time to pek filling). There ws no significnt correltion with resting time to pek filling or pek filling rte, resting or pek exercise ejection frction. Ejection frction incresed in 12 ptients nd fell in eight ptients but the mximl oxygen coumption ws not significntly different in these two groups (14-8 ±51 vs 171 ± 2-9 ml. kg" '. min~', P respectively). Pek exercise pek filling rte ws wekly relted to pek exercise hert rte (r=0-5 > =002) but pek exercise time to pek filling ws not (r=0-42 P=006). ultiple regression nlysis ws performed using ll univrite vribles ffecting exercise cpcity with P<0-\. On this nlysis, only pek exercise time to pek filling ws significntly relted to mximl oxygen coumption ( > <00001) i.e. when time to pek filling ws included s vrible, hert rte nd pek filling rte cesed to be significnt determinnts of exercise cpcity. Compring those ptients whose mximl oxygen coumption ws below the men for the group nd those bove the men for the group, pek exercise hert rte ws lower r = p< Pek exercise time to pek filling (m) igure 1 Reltiohip between pek exercise time to pek filling nd exercise cpcity (VO 2 mx) in the 20 ptients studied. (113-9 ±14-8 vs ±23-2 bets, min" 1, >=0006), pek exercise time to pek filling ws higher (176 ± 35-3 vs 109 ± 25-5 ms, > =00001) nd pek exercise pek filling rte ws lower (4-2 ± 1-4 vs 60 ± 1-9 EV. s~ ', > =004) in the former. ximl oxygen coumption ws lower in ptients whose pek hert rte ws <80% of predicted thn those with pek hert rte >80% of predicted (140±4-2 vs 18-2 ± 3-5 ml. kg" '. min" 1 ) =003). The results re summrized in Tble 4 nd igs iscussion Exercise limittion is common feture in ptients with coronry rtery disese. Exercise is often limited by ngin but in mny cses brethlessness or ftigue is the limiting symptom 11]. Although resting left ventriculr systolic dysfunction is commonly present in such ptients, previous studies hve demotrted

6 eterminnts of exercise cpcity in CA nd systolic dysfunction Controls c o -J3 O, I o O r = P = ^_, i 's ts. i ; ' O S T = 0.78 P = Pek exercise Pek filling rte (EV ) igure 2 Reltiohip between exercise cpcity (VO 2 mx) nd pek exercise pek filling in the 20 ptients studied. 30 r = 0.58 p = Pek increse in crdic output igure 3 Reltiohip between reltive increse in crdic output nd exercise cpcity (VO 2 mx) in the 20 ptients studied. poor reltiohip between resting ejection frction nd exercise cpcity Whilst ischemi-medited left ventriculr systolic dysfunction occurring on exercise is theoreticlly n explntion for exercise limittion, previous studies hve lso demotrted lck of correltion between exercise cpcity nd ejection frction t pek exercise lthough one must recognize tht ejection frction is n indirect nd imperfect mesure of systolic function. Previous studies hve lso shown poor reltiohip between resting distolic filling indices nd exercise cpcity in ptients with ischemic hert disese 12 " 31. The importnt new findings of this study re tht in this group of ptients with ischemic hert disese, exercise cpcity is strongly relted to 10 ' i J, 40 1 i S 120 g J2 100 So S 80 o Ptients L r = 0.1 p = Chnge in time to pek filling (rest-pek) ms igure 4 Reltiohip between chnge in totl time to pek filling nd chnge in hert rte in the 10 controls nd the 20 ptients. mesure of distolic filling (time to pek filling) t pek exercise, nd there ws significnt reltiohip between exercise cpcity nd the reltive increment in crdic output during exercise. Hert rte ws significnt but wek determinnt of exercise cpcity on univrite nlysis but not on multiple regression nlysis. istolic dysfunction nd exercise cpcity istolic dysfunction my be reltively 'fixed', for exmple due to myocrdil fibrosis ndor myocyte hypertrophy 1 " 1, my be due to pericrdil cotrint 1 ' 2 ' 131 or my be ischemi medited' 14 ' 151. Isovolumic relxtion is mrkedly slowed by ischemi' 161 probbly becuse reduced cyclic AP retrds re-uptke of cytosolic clcium into the srcoplsmic reticulum. Indeed, the isovolumic phse of distole is more energy dependent Eur Hert J, Vol. 17, ebrury 19%

7 210 S. S. Lele et l. Tble 4 Reltiohip between exercise cpcity (VO 2 mx) nd indices of systolic nd distolic function t rest nd on exercise Pek HR (erect) Chnge in HR Rest E Pek E Chnge in E Rest PR Pek PR Chnge in PR Rest TTP Pek TTP Chnge in TTP Reltive chnge in stroke counts Reltive increse in crdic output r P < HR = hert rte; E = ejection frction (%); PR = pek filling rte; TTP = totl time to pek filling (ms). thn systole 1171 nd in ptients with demnd ischemi, bnormlities of distolic function usully occur erlier in the ischemic process thn bnormlities of systolic function' 18 '. Whilst in norml subjects exercise is ssocited with downwrd shift in the distolic component of the left ventriculr pressure volume reltiohip implying bet receptor-medited improvement in distolic function' 19 ', in ptients with ischemic hert disese 1201 nd dilted crdiomyopthy 1211 there is prdoxicl upwrd shift in the distolic component of the left ventriculr pressure volume reltiohip on exercise implying impired distolic function. In norml subjects, pek filling rte incresed nd time to pek filling shortened on exercise presumbly s coequence of both prelod chnges nd bet-receptor medited improvement in distolic function. Our observtion of n ssocition between mximl oxygen coumption nd pek exercise pek filling rte nd time to pek filling in the ptients my reflect n ssocition between distolic filling prmeters nd hert rte, but we believe this is probbly not so becuse: first, on multiple regression nlysis, hert rte cesed to be determinnt of exercise cpcity, wheres pek exercise time to pek filling remined significnt determinnt. Second, whilst in normls there ws reltiohip between chnge in hert rte during exercise nd chnge in time to pek filling, in the ptients there ws loss of this norml inverse liner reltiohip between hert rte nd time to pek filling. Our dt suggest, therefore, tht distolic filling prmeters filed to improve in prllel with the increse in hert rte. The observtion of strong reltiohip with exercise distolic filling indices in the bsence of reltiohip with resting distolic indices, suggests tht 'fixed' chnges in the crdic muscle, such s fibrosis or myocyte hypertrophy, my not be the sole fctor, nd reversible fctors such s ischemi or pericrdil cotrint my be importnt. Ischemi-medited impirment of distolic relxtion seems much more likely thn pericrdil cotrint in this group of ptients since none of them hd significnt crdic enlrgement. The reltive contributio of myocrdil infrction nd reversible ischemi to the exercise distolic filling bnormlities observed is, however, uncertin. How might the observed bnormlities of distolic filling result in diminished exercise cpcity? There is ongoing controversy regrding the mechnisms of brethlessness nd exercise limittion in ptients with hert disese. Proposed mechnisms hve included impired skeletl muscle blood flow on exercise 122 " 251 nd stimultion of juxt-cpillry receptors by high pulmonry cpillry pressures Skeletl muscle blood flow limittion on exercise in ptients with chronic hert filure is thought to be due to n impired crdic output respoe nd to locl vsculr nd functionl chnges in the skeletl muscle 122 " 251. Previous studies in normls nd in ptients with hert disese hve demotrted tht crdic output t pek exercise is strongly relted to exercise cpcity istolic filling bnormlities will limit crdic output ugmenttion on exercise by the rnk-strling mechnism nd will lso increse left ventriculr end-distolic pressure nd hence pulmonry cpillry pressure. Whilst the trpulmonry cpillry-lveolr pressure grdient my theoreticlly be determinnt of exercise cpcity, previous studies hve demotrted no reltiohip between pek exercise pulmonry cpillry wedge pressure nd mximl oxygen coumption nd it seems likely tht distolic filling bnormlities limit exercise cpcity principlly by ffecting stroke volume nd hence crdic output. The fctors determining crdic output ugmenttion during exercise re n increse in hert rte, n increse in contrctility nd chnges in left ventriculr end-distolic volume nd hence stroke volume or the group s whole, ejection frction did not increse on exercise (in some it incresed nd in others it fell). There ws no reltiohip between pek exercise ejection frction nd exercise cpcity nd exercise cpcity did not differ in those in whom ejection frction ws reduced compred with those in whom it ws incresed. Thus the rnk Strling mechnism is likely to be very importnt determinnt of stroke volume nd crdic output on exercise in these ptients. The degree by which left ventriculr end-distolic volume chnges for given chnge in left ventriculr end-distolic pressure is determined by the distolic properties of the ventricle. In ptients with mrkedly impired distolic function, increses in left ventriculr end-distolic pressure result in only smll increses in left ventriculr end-distolic volume nd hence stroke volume. We believe tht this provides rtionl explntion for the importnce of distolic filling in determining exercise cpcity in this group of ptients in whom the norml increse in contrctility seen on exercise is blunted or bolished. In this study, end-distolic volume fell slightly during exercise in ptients with ischemic hert disese coistent with distolic filling bnormlity.

8 eterminnts of exercise cpcity in CA nd systolic dysfunction 211 Hert rte nd exercise cpcity The other determinnt of crdic output is hert rte. ny of these ptients hd significnt limittion of hert rte ugmenttion on exercise nd this ws ssocited with objectively lower exercise cpcity. Although on univrite nlysis hert rte ws wekly ssocited with exercise cpcity it ws not significnt determinnt of exercise cpcity on multivrite nlysis. This my t first sight be surprising but, priori, the influence of exercise hert rte respoe on crdic output ugmenttion is likely to be dependent on the distolic filling ptter of the ventricle. In the presence of restrictive filling bnormlity (in which the mjority of filling occurs in erly distole) hert rte will be the mjor determinnt of crdic output. Conversely in the presence of clssic distolic dysfunction (in which distolic filling is delyed nd slowed) one might expect n increse in hert rte to produce lesser increse in crdic output becuse of reduced time for distolic filling nd therefore, by the rnk Strling mechnisms, lower stroke volume. In the ptients presented in this study, hert rte ppers to be weker determinnt of exercise cpcity thn reported in previous studies in norml subjects 1301, presumbly reflection of the underlying distolic filling bnormlity. Study limittio This study does not demotrte n ssocition between distolic function per se nd exercise cpcity but rther n ssocition between distolic filling nd exercise cpcity. Assessments of distolic function would require simultneous mesurement of pressure nd volume chnges. ogrien et l. hve shown reltiohip between pek filling nd the ctive phse of distolic relxtion (mximum dpdt, r= 0-85) but not with the pssive phse of distolic filling (chmber stiffness, Kd, r= - 008)' 3 ' 1. Other workers hve shown n ssocition between incresed distolic filling during exercise nd decrese in the time cotnt of relxtion (tu) [32]. We do not believe, however, tht this cvet in ny wy negtes the clinicl importnce of our observtion of n ssocition between n index of distolic filling (time to pek filling) chrcteristics nd exercise cpcity. The relible mesurement of distolic filling rtes nd times to pek filling depends upon hving sufficiently high temporl smpling frequency for ech crdic cycle exmined i.e. high temporl resolution. The number of frmes per synthetic crdic cycle is compromise between the requirement for dequte temporl resolution on the one hnd, nd the requirement for sufficient counts per frme for sttisticl precision on the other. Bchrch et l. l9] hve shown tht, for reproducible mesurement of pek filling rte in norml individuls, the frme durtion should not exceed 50 ms t rest or 20 ms with exercise. However, using fixed frme durtion throughout n exercise protocol implies tht, s hert rte increses with exercise, temporl resolution will become corser. In the present study, the frme rte we employed eured tht temporl resolution remined cotnt regrdless of hert rte, while sttisticl precision remined comprble since the shorter frme durtion with incresing hert rtes ws competed for by the greter number of crdic cycles ccumulted during ech 4-min cquisition period. In our ptients, t 28 frmes per cycle, men frme durtion ws 27-4 ms (29-6 ms for controls) t rest, nd 171 ms (15-7 ms for controls) t pek exercise. In this study we did not mesure bsolute volumes. Absolute left ventriculr volumes my be estimted with reference to n externlly-counted peripherl blood smple, but this requires knowledge of ventriculr depth nd the ttenution fctors for ech voxel in the ventriculr region of interest, neither of which cn routinely be ccurtely determined. The lck of bsolute volume mesurements my hve creted two problems: first, the* ssocition between reltive increment in crdic output nd mximl oxygen coumption ws reltively modest (r=0-58 > =0008) nd the ssocition with reltive chnge in stroke volume ws wek (r=0-40 >=007). However, previous studies (including rdionuclide studies) in both normls nd ptients with crdic disese hve shown much stronger ssocition between bsolute pek exercise crdic output nd mximl oxygen coumption. Pek exercise crdic output nd pek exercise stroke volume re the product of resting vlues nd reltive increment during exercise. Thus, bsolute pek exercise crdic output nd stroke volume my hve been more strongly ssocited with exercise cpcity. Second, recent study demotrted smll increses in ""Tc-blood rdioctivity during exercise, prticulrly in younger subjects' 331. This my led to errors in ssessing seril chnges in volumes, crdic output nd pek filling rte during exercise nd hence the uthors suggest the need for blood smpling t rest nd t pek exercise. These reservtio do not detrct, however, from our observtion of strong reltiohip between pek exercise time to pek filling (which would be independent of the bove influence) nd exercise cpcity which is the most importnt messge of this study. It is possible tht one or more of the ten controls my hve hd occult coronry rtery disese in view of their ge (38 to 66 yers) nd tht they were therefore not true controls. We believe, however, tht our exclusion criteri mke significnt myocrdil ischemi in the control group unlikely. Conclusion We observed strong ssocition between exercise distolic filling bnormlities nd exercise cpcity in these ptients. Exercise distolic filling bnormlities my limit exercise cpcity in such ptients by restricting stroke volume ugmenttion nd hence crdic output ugmenttion.

9 212 S. S. Lele et l. References [1] Pntely GA, Bristow J. Ischemic crdioryopthy. Prog Crdiovsc is 14; 27: [2] vies SW, ussell A, Jordn SL, Poole-Wilson P, Lipkin P Abnorml distolic filling ptter in chronic hert filure Reltiohip to exercise cpcity. Eur Hert J 1992; 13: [3] rncios JA, Prk, Levine TB. Lck of correltion between exercise cpcity nd indexes of resting lest ventriculr performnce in hert filure. Am J Crdiol 11; 47: [4] Jones NL. Clinicl exercise testing, 3rd edn. Phildelphi: W. B. Sunders, 18. [5] Spiro SG Exercise testing in clinicl medicine Br J is Chest 1977, 71: 145- [6] rinkwter B, Horvth S, Wells C. Aerobic power of femles, ges J Gerontol 1975; 30: [7] Bruce RA, Kusumi, Hosmer. ximl oxygen intke nd nomogrphic ssessment of functionl erobic impirment in crdiovsculr disese. Am Hert J 1973; 85: [8] Levy WC, Cerqueir, Abrss IB, Schwrtz RS, Strtton JR. Endurnce exercise trining ugments distolic filling t rest nd during exercise in helthy young nd older men. Circultion 1993; 88' [9] Bchrch SI, Green V, Borer JS, Epstein SE. Left ventriculr pek ejection rte, filling rte nd ejection frction-frme requirements t rest nd exercise: concise communiction. JNucled 1979; 20: [10] Lipkin P, Perri J, Poole-Wilson PA. Respirtory gs exchnge in the ssessment of ptients with impired left ventriculr function. Br Hert J 15; 54: [11] Grossmn W. istolic dysfunction nd congestive hert filure. Circultion 1990; 81: I 1-7. [12] Jnicki JS. Influence of the pericrdium nd ventriculr interdependence on left ventriculr distolic nd systolic function in ptients with hert filure. Circultion 1990; 81: I [13] Crroll J, Lng R, Neumn AL, Borow K, Rfter SI. The differentil effects of positive inotropic nd vsodiltor therpy on distolic properties in ptients with congestive crdiomyopthy. Circultion 16; 74: [14] Corroll J, Hess O, Kryenbuehl HP. istolic function during exercise induced ischemi in mn. In: Grossmn W, Lorell BH, eds. istolic Relxtion of the Hert. Boston- rtinus Nijhoff Publishing, Inc, 18: [15] Ssym S. Altered distolic disteibility during ngin pectoris. In: Grossmn W, Lorell BH, eds. istolic Relxtion of the Hert. Boston: rtinus Nijhoff Publishing Inc, 18: [16] Tkeuchi, ujitni K, Kurogne K, Bi HT, Tod C, ukuzke H. Assessment of left ventriculr function in ischemic hert disese. The reltion between pressure decy during the isovolumic relxtion phse nd regionl wll motion bnormlity. Jpn Circ J (Jpn) 14; 48: [17] Lnger GA. Ion fluxes in crdic excittion nd contrction nd their reltion to myocrdil contrctility. Physiol Rev 1968; 48: [18] eldmn, Copels L, Gwthmey JK et l. eficient production of cyclic AP: Phrmcologic evidence of n importnt cuse of contrctile dysfunction in ptients with end-stge hert filure. Circultion 17; 75: [19] Nonogi H, Hess O, Ritter, Kryenbuehl H. istolic properties of the norml left ventricle during supine exercise. Br Hert J 18; 60: [20] Nonogi H, Hess O, Bortone AS, Ritter, Crroll J, Kryenbuehl HP. Left ventriculr pressure-length reltion during exercise-induced ischemi. J Am Coll Crdiol 19; 13: [21] Sto H, Hori, Ozki H et l. Exercise-induced upwrd shift of distolic left ventriculr pressure-volume reltion in ptients with dilted crdiomyopthy Effect of fidrenoreceptor blockde. Circultion 1993; [22] Wilson JR, rtin JL, Schwrtz, errro N. Exercise intolernce in ptients with chronic hert filure' Role of impired nutritive flow to skeletl muscle. Circultion 14; 69: [23] Wilson JR, errro N. Exercise intolernce in ptients with chronic left hert filure. Reltion to oxygen trport nd ventiltory bnormlities. Am J Crdiol 13, 51: [24] Zelis R, lim S. Altertion in vsomotor tone in congestive hert filure. Prog Crdiovsc is 12; 24: [25] Weiner, ink LI, J, Jones RA, Chnce B, Wilson JR Abnorml skeletl muscle bioenergetics during exercise in ptients with hert filure: Role of reduced muscle blood flow. Circultion 16; 73: [26] Pintl AS. echnism of stimultion of type J pulmonry receptors. J Physiol (Lond) 1969; 203: [27] Lipkin P, Cnep AR, Stephe R, Poole-Wilson PA. ctors determining symptoms in hert filure. Br Hert J 16; 55: [28] renneux P, Porter A, Cforio ALP, Odwr H, Counihn PJ, ckenn WJ. eterminnts of exercise cpcity in hypertrophic crdiomyopthy. J Am Coll Crdiol 19; 13: [29] Chitmn B. Exercise stress testing. In: Brunwld E. Hert disese. A textbook of crdiovsculr medicine, Vol I, 4th edn. Phildelphi: W. B. Sunders Compny 1992: [30] Levy WC, Cerqueir, Abrss IB, Schwrtz RS, Strtton JR. Endurnce exercise trining ugments distolic filling t rest nd during exercise in helthy young nd older men. Circultion 1993; 88: [31] ogrien J, Shffer P, Bush C et l. Hemodynmic correltes for timing intervls, ejection rte nd filling rte derived from the rdionuclide ngiogrphic volume curve. Am J Crdiol 14; 53: [32] Cheng Cp, Igrchi Y, Little WC. echnism of ugmented rte of left ventriculr filling during exercise. Circ Res 1992, 70: [33] Levy WC, Cerqueir, Veith R, Strtton JR. ctors influencing seril mesurements of crdic volumes by count-bsed methods: effects of ctecholmines, position, nd exercise on technetium-99m blood rdioctivity concentrtion. J Nucl ed 1992; 33: