Cardiorespiratory Responses of Cardiac Transplant Patients to Graded, Symptom-limited Exercise

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1 CARDIAC TRANSPLANT EXERCISE RESPONSESvin et l. 55 forerm exercise in norml subjects nd ptients with congestive hert filure. Circultion 5: 137, Goldberg S, Mnn T, Grossmn W: Nitrte therpy of hert filure in vlvulr hert disese. Am J Med 65: 161, Clrk DG, McAnulty JH, Rhimtool SH: Results of vlve replcement in ortic incompetence with left ventriculr dysfunction. Circultion 61: 411, Kennedy JW, Doces J, Stewrd DK: Left ventriculr function before nd following ortic vlve replcement. Circultion 56: 944, Pntely G, Morton M, Rhimtool SH: Effects of suessful, uncomplicted vlve replcement on ventriculr hypertrophy, volume, nd performnce in ortic stenosis nd in ortic incompetence. J Thorc Crdiovsc Surg 75: 383, 1978 Crdiorespirtory Responses of Crdic Trnsplnt Ptients to Grded, Symptom-limited Exercise WILLIAM M. SAVIN, M.A., WILLIAM L. HASKELL, PH.D., JOHN S. AND EDWARD B. STINSON, M.D. SCHROEDER, M.D., SUMMARY The electrocrdiogrphic nd ventiltory responses of 15 denervted hert ptients who hd undergone crdic trnsplnttion nd 14 ge-mtched, normlly innervted men were compred to ssess the pttern of response to grded tredmill exercise. A 5-minute postexercise venous lctte smple ws lso obtined. Respirtory exchnge rtio nd ventiltion (VE) were higher in denervted ptients thn in normls during submximl exercise. Pek vlues (normls vs denervted) for hert rte (172 vs 159 betsmin), blood pressure (189 vs 167 mm Hg), oxygen uptke (37 vs 25 mlkgmin), oxygen pulse (.22 vs.16 mlkgbet) nd work time (26.2 vs 18. minutes) were higher in normls thn in crdic trnsplnt recipients. Pek ventiltory equivlent (2.14 vs mlkg) nd lctte vlues were higher for trnsplnts thn for norml subjects, but there were no significnt intergroup differences in pek VE or in the respirtory exchnge rtio. In crdic trnsplnt recipients, work time correlted inversely with mesure of rejection history (r = -.59, p <.1). The response of crdic trnsplnt recipients to tredmill work differs from tht of norml men nd reflects diminished bility to meet the oxygen demnds of the exercising periphery. NUMEROUS INVESTIGATORS hve reported the effects of chronic denervtion on the exercise response of lbortory nimls1-5 nd men.6 12 During dynmic exercise, the denervted dog hs crdic output nd oxygen consumption responses similr to those before denervtion,' though the cpcity for mximl exercise is slightly diminished.2 In the norml dog, crdic output during exercise is incresed lrgely through elevtion of hert rte, while in the denervted dog, n equivlent increse in crdic output is chieved through grdul nd ttenuted increse in hert rte nd n increse in stroke volume subsequent to n incresed venous return.'3 This bility to increse hert rte grdully persists in the denervted, drenlectomized dog,' bringing to mind Blinks's report of positive chronotropic effect of incresed right tril pressure (i.e., venous return).'4 Supine exercise studies in humn crdic trnsplnt recipients hve shown pttern of response similr to tht seen during submximl exercise in nimls. Cr- From the Division of Crdiology nd the Deprtment of Crdiovsculr Surgery, Stnford University Medicl Center, Plo Alto, Cliforni. Supported by NIH Crdic Trnsplnt Grnt HL Address for correspondence: Willim M. Svin, 73 Welch Rod, Suite B, Plo Alto, Cliforni Received September 12, 1979; revision epted Jnury 5, 198. Circultion 62, No. 1, 198. dic output is incresed during exercise by n initil elevtion of stroke volume followed by grdul rise in hert rte.6 7, 9, 1 Clrke et l.1 reported tht during dynmic exercise in the denervted humn, crdic output increses, first by stroke volume ugmenttion due to the Strling mechnism nd lter by enhncement of contrctility by circulting ctecholmines. In the innervted hert these two mechnisms our simultneously. Reports of diminished crdic output response for given level of work ompnied by n elevted rteriovenous oxygen difference suggest tht mximl oxygen uptke nd exercise tolernce fter trnsplnttion my be restricted.9 To document the crdiorespirtory response nd exercise cpcity of crdic trnsplnt recipients during symptom-limited tredmill exercise, the following study ws performed. Methods Subjects To ssess the effect of crdic trnsplnttion upon exercise cpcity, 15 crdic trnsplnt recipients (12 men nd three women) nd 14 norml men performed grded, symptom-limited tredmill exercise. The trnsplnt recipients were ptients returning to Stnford for their nnul evlution, while the controls were volunteers, similr in ge to the crdic trnsplnt ptients, who were symptomtic for cr-

2 56 diovsculr nd respirtory disese. To obtin norml subjects with ctivity hbits similr to the trnsplnts, we solicited men who considered themselves physiclly ctive but who were not vigorously trining. Testing Procedure All subjects performed 3-minute work lods on the tredmill, strting t 2.5% grde nd 2 mph nd progressing to 2.5% grde nd 3 mph t the next stge; the grde ws incresed by 2.5% every 3 minutes therefter. Throughout exercise the subject's expired ir ws routed from low-resistnce Dniel's vlve through 5-foot length of respirtory tubing pst Fleisch pneumotch hed interfced to Vertek VR 4 pneumotchometer, into Plexigls mixing chmber. Gs ws continuously smpled from the mixing chmber into 2-liter nesthesi bgs, s described by Wilmore nd Costill.15 One-minute liquots were dried nd then nlyzed for 2 (Beckmn OM- 11) nd CO2 (Godrt Cpnogrph), llowing clcultion of oxygen uptke (V2), ventiltion (VE), respirtory exchnge rtio (RER), ventiltory equivlent for oxygen (VEV2) nd oxygen pulse. A 12-led ECG ws monitored t rest, before exercise, throughout the exercise period, nd for t lest 7 minutes of recovery. Blood pressure ws mesured by sphygmomnometer before exercise nd t the end of ech work lod. One milliliter of blood ws obtined from the ntecubitl vein 5 minutes fter exercise for lctte nlysis by modifiction of the method of Hohorst.'6 The work tests for n dditionl 13 crdic trnsplnt recipients done without mesurement of VO2 were included in the grphic presenttion of hert rte recovery. Subjects were told to continue exercising s long s possible nd give "mximl" effort. Sttisticl Anlysis Unless otherwise noted, ll sttisticl comprisons were done using the unpired t test; p <.5 ws considered significnt. Results Subject Chrcteristics The chrcteristics of trnsplnt recipients, trnsplnt donors nd norml controls re listed in tble 1. Trnsplnt recipients were tested n verge of 39 months fter trnsplnttion (rnge months). Six hd been dignosed s hving coronry rtery disese before trnsplnttion, while the other nine hd crdiomyopthies. All ptients re still living; one hs been retrnsplnted s result of recurrent coronry rtery disese. The men ge of recipients ws higher thn tht of donors (p <.1), but body msses did not differ significntly (.5 < p <.1). Trnsplnt recipients nd norml controls did not differ in men ge, height or mss. Electrocrdiogrphic Results Results of the exercise ECGs were unremrkble. Two-thirds of the trnsplnt recipients nd no controls CIRCULATION VOL 62, No 1, JULY 198 TABLE 1. Subject Chrcteristics Age Height Body mss (yers) (cm) (kg) Trnsplnt recipients (3-54) ( ) ( ) (n = 15) Trnsplnt donors (15-39) - ( ) Norml 45.4 = = ,4-1 5 controls (35-55) ( ) ( ) (n= 14) Vlues re men SD, with the rnge in prentheses. hd sinus tchycrdi t rest. No trnsplnts nd two norml subjects exhibited sinus dysrhythmi nd brdycrdi. Six norml subjects nd four trnsplnt recipients hd dysrhythmis during exercise nd recovery. No one in either group hd signs of ischemi or hypertrophy on the ECG, though one ptient hd mrked ST-segment elevtion during recovery from n exercise thllium scn the dy fter his tredmill test reported here. The ST chnges were interpreted to hve resulted from coronry spsm; the ptient ws subsequently retrnsplnted fter being resuscitted fter crdic rrest severl months lter. Pttern of Response to Exercise Stress Figure IA shows tht men hert rte incresed from 72 to 172 betsmin in normls nd from 17 to 162 betsmin in trnsplnt recipients. Normls hd n exponentil rte-recovery curve (r2 for exponentil fit ws.82) nd trnsplnt recipients hd more grdul, liner diminution in hert rte (fig. 2). Trnsplnt recipients ventilted more for given level of oxygen uptke thn did controls (fig. 1B). RER ws higher for trnsplnt recipients thn for controls throughout exercise, while the oxygen pulse ws lower in trnsplnt recipients thn in controls (fig. 1). Figure 3 shows tht trnsplnt recipients tend to consume less oxygen for given work lod thn normls who ttin the sme pek speed nd grde on the tredmill. The rte t which trnsplnt recipients nd controls found themselves unble to finish suessive work lods ws similr, though the ptients from the trnsplnt group strted stopping erlier thn controls (fig. 4). Pek Vlues Men pek exercise vlues for the 15 trnsplnt recipients nd 14 controls re listed in tble 2. Controls hd higher pek hert rte, systolic blood pressure, rte-pressure product, V2, oxygen pulse nd work time. Trnsplnt recipients did not differ significntly from controls in VE or RER, while VEVO2 nd postexercise lctte were significntly higher in trnsplnt recipients. Controls nd trnsplnt recipients stopped exercising for similr resons: Ftigue limited exercise in over 5% of ech

3 CARDIAC TRANSPLANT EXERCISE RESPONSESvin et l ~ (A) _ 16 _ - 4) _ - w W.:x tr LU I :X C,1 m I9 8 6' 1.1 (C) _ 1. _ 1.9 I _.8 _ * TRANSPLANTS.7 CONTROLS r-.e R LJ _v E LU V2 (Lmin STPD) FIGURE 1. (A) Hert rte, (B) ventiltion (JVE), (C) respirtory exchnge rtio nd (D) oxygen pulse plotted ginst oxygen uptke (VO,) t pproximtely 3%, 6%, 9% nd 1% of pek work lod for crdic trnsplnt recipients nd norml men. Vlues re men ± SEM. group. Other resons for test cesstion included leg discomfort in six, throt discomfort in three, dyspne in one, dizziness in one nd hert rte bove 2 betsmin. Discussion In this study we compted the crdiorespirtory responses of crdic trnsplnt ptients nd norml controls. Trnsplnt recipients nd controls were well mtched with respect to ge, height nd mss, nd n ttempt ws mde to select norml subjects with, Q I 1 Ht}... wv I I _ 12 _ 1 X X 1 A T * TRANSPLANTS O CONTROLS A MAX MINUTES OF RECOVERY FIGURE 2. Men hert rte (± SEM) is shown t pek exercise nd the first 7 minutes of recovery for crdic trnsplnt recipients nd controls. routine ctivity levels similr to those of trnsplnt recipients. Contrry to experience with lbortory nimls fter denervtion,'17 18 previous workers hve filed to document reinnervtion in humn crdic trnsplnt recipients Ptients in the present study did not exhibit evidence of reinnervtion. While normls showed significnt men increse in hert rte of 12 betsmin (p <.1, pired t test) when compring the erect with the supine posture, trnsplnt recipients hd no rise in men hert rte. The high resting hert rte nd diminished chronotropic reserve in the trnsplnt ptients is chrcteristic of the denervted stte. The lck of ischemi nd reltively norml rte of rrhythmis seen in trnsplnt recipients t rest s well s during exercise nd recovery provide confirmtion tht these ptients were well controlled regrding rejection t the time of the study.19 The hert rte response of crdic trnsplnts to grded exercise (fig. 1) is similr to tht in dogs when compred with norml nimls,13 though there ws much greter disprity in mximl hert rtes of denervted nd innervted dogs thn in humns. The trnsplnted humn hert hs n impired chronotropic bility to respond to sudden increses in work, becuse it must rely solely upon intrinsic rte regultion nd circulting ctecholmines. Smll work increments were selected in this study to llow grdul ommodtion to incresing exercise levels. Thus, when compring the similr slopes of hert rte increse vs work lod exhibited by normls nd trnsplnt ptients in our study with the dissimilr slopes in dogs shown by Donld nd Shepherd,'3 one my postulte tht the work increments were low enough to llow for substntil nonneurl rte ugmenttion. One my suppose tht the inotropic stte of the hert ws enhnced by circulting ctecholmines s well, bsed upon the reports of McLughlin et l." regrding mximl supine exercise in crdic trnsplnt recipients. The

4 58 CIRCULATION VOL 62, No 1, JULY g.E E, N~ * MIN _-} 24 MIN (5.78) (5.5),, (7.1) (6.57) (3.14),, 1- (9.62) - 33 MN (5.4)- WORK TIME (MIN) 1,= FIGURE 3. Oxygen uptke (Vo2) is shown during the third minute of ech tredmill work lod for crdic trnsplnt recipients (solid dots) nd controls (open dots) ble to complete mximum of 21, 24, 3 nd 33 minutes of the protocol. (During the first 3 minutes of exercise, subjects wlked t 2 mph up 2.5% grde. The second stge ws 3 mph nd 2.5% grde. The grde ws incresed by 2.5% for ech subsequent 3- minute work lod.) Pek lctte vlues (pmolml) re shown in prentheses. -1 = -~~~~~~ exponentil decline of hert rte in normls fter exercise compred with the liner decline of trnsplnted donor hert rte (fig. 2) prompted us to wonder whether the rpid phse of hert rte decrese fter exercise in normls is due to sympthetic withdrwl or to enhnced prsympthetic tone. Venipuncture for lctte nlysis ws performed between minutes 5 nd 6 of recovery, when hert rte incresed suddenly in norml subjects but not in trnsplnt recipients. The difference in ventiltory response to exercise in denervted ptients nd normls is not ttributble to difference in sttes of trining. When plotted (fig. 5), dt from Sltin et l.2 show "norml" ventiltory response to submximl exercise fter both bed rest nd trining. Our trnsplnt recipients hd elevtions in VE t submximl nd pek exercise. The ventiltory dt presented indicte n erlier onset of nerobiosis in the trnsplnt recipients thn < 1 _i O 8 z F 6 LU O 4 z Ui u 2 c ESTIMATED METS TIME (min) FIGURE 4. The percentges of crdic trnsplnt recipients nd controls ble to complete ech suessive work lod re shown with the estimted energy requirement (mets) nd test durtion tht correspond to ech work lod. in normls. VE, RER, nd VEVO2 were higher for trnsplnt ptients throughout exercise, reflecting incresed CO2 production during submximl work, while lower VO2 t higher levels of work, s well s diminished oxygen pulse throughout exercise, points TABLE 2. Pek Vlues Norml Trnsplnt controls recipients p Hert rte (betsmin) <.2 Systolic pressure (mm Hg) <.5 Rte-pressure product (bets min X mm Hg X 1-2) <.2 YE (1min, BTPS) NS V2 (mlkgmin, STPD) ==6 <.1 RER NS Oxygen pulse (mlkgbet) <.1 YEVO2 (lmlkg) <.1 Lctte vlue 5 minutes fter exercise (,umolml) <.1 Work time (min) <.1 Vlues re men SD. Abbrevitions: VE = ventiltion; V2 = oxygen uptke; RER = respirtory exchnge rtio; VEV2 = ventiltory equivlent for oxygen; BPTS = body temperture nd pressure, sturted with wter vpor; STPD = O C, 76 mm Hg, dry.

5 CARDIAC TRANSPLANT EXERCISE RESPONSESvin et l. 59. m.e W _- 2 _ nv V2 (Lmin STPD) FIGURE 5. Men dt from Sltin et l.2 Filled tringles with solid line represent control exercise test, open tringles represent response fter 2 dys of bed rest, nd filled tringles with dshed line represent response fter dys of trining fter bed rest. VO2 = oxygen uptke; VE = ventiltion. B TPS = body temperture nd pressure, sturted with wter vpor; STPD = C, 76 mm Hg, dry. to decresed 2 delivery to the exercising periphery. If the volitionl ftigue for which most subjects stopped ws the result of buildup of nerobic metbolic end products, then the different work times in trnsplnt recipients nd controls correlte well with their ventiltory dt. The trend towrd erlier ftigue in trnsplnts (fig. 3) would be expected in light of their elevted RER nd 'E vlues t these exercise levels. The fct tht trnsplnts nd controls did not differ in their pek VE or RER vlues, nd the fct tht trnsplnts hd significntly higher pek lctte level despite diminished work time when compred with normls, is further evidence for n indequte 2 supply to the exercising periphery throughout exercise. In contrst to the present findings in humns, Donld nd Shepherd13 found no deteriortion in mximl work cpcity, crdic output or mximl VO2 in dogs fter denervtion, though crdic output ws lrgely incresed by stroke volume ugmenttion in denervted dogs nd crdioelertion in norml dogs. Studies done on dogs2l 22 soon fter crdic trnsplnttion hve shown reltively fixed stroke volume with pcing; however, the norml inverse reltionship between hert rte nd stroke volume hs been observed lter in the postopertive course of trnsplnted dogs22 23 nd in mn.24 Stinson et l.9 11 found tht lthough crdic trnsplnt ptients exhibit norml increment of crdic output per unit of externl work during supine exercise, the bsolute vlue of their crdic output is below norml t rest nd throughout submximl exercise, while rterio- A 'S I venous oxygen differences re bove norml t ny given work level. Our dt re consistent with the pttern of elevted rteriovenous oxygen difference nd diminished crdic output reported by Stinson et l. In ttempting to resolve the differences between response of denervted nimls nd humn crdic trnsplnt ptients to exercise, one must consider the effects of grft rejection nd interference from immunosuppressive or other medictions. At Stnford, dignosis of rejection is bsed upon myocrdil biopsy results, summted QRS voltge chnges, nd chnges in clinicl crdic sttus. Rejection episodes my be designted s mild, moderte or severe, bsed on the clinicl evlution of crdic function.'9 Though our ptients were not experiencing dignosed rejection t the time of their exercise test, we were ble to exmine the rejection history of 22 trnsplnt ptients who hd performed ftigue-limited tredmills in our lb on the stndrd protocol. Using work time s single indictor of exercise cpcity, we exmined the reltionship between rejection history nd exercise performnce. Men work times were ssocited with zero to six episodes of erly, lte nd combined erly nd lte rejection. (Erly indictes rejection onset less thn 9 dys fter surgery; lte mens onset more thn 9 dys fter surgery.) To weight the severity of erly rejection episodes, n rbitrry vlue of one ws given to mild, two to moderte, nd three to severe rejection episodes, nd the totls were designted n "rbitrry erly rejection score." There is generl, though not significnt, trend towrd decrese in work time s the number of erly, lte, nd totl rejection episodes increses. A trend is lso seen with incresing mgnitude of rbitrry erly rejection score. Figure 6 shows the liner regression of work time vs rbitrry erly rejection score. It ppers tht there is signifi- - _ 2 _ 36 INDIVIDUAL DATA POINTS 3 MEAN WORK TIMES \ A~~~~ r =-.59, p<.1 I I II ARBITRARY EARLY REJECTION SCORE FIGURE 6. Regression of work time on rbitrry erly rejection score.

6 6 CIRCULATION VOL 62, No 1, JULY 198 cnt reltionship between rejection history nd work performnce, though other fctors, such s degree of physicl trining nd mediction side effects, re lso importnt. Potentil mediction interference with exercise performnce flls under two ctegories. First, one must consider the effects of potentil muscle wekness, muscle mss loss, osteoporosis nd steroid myopthy tht cn ompny prednisone dministrtion. Loss of muscle mss hs been problem in this ptient group nd could provide prtil explntion for the decrese in work time reltive to the control group. Were it not for the ltered crdic output nd rteriovenous oxygen difference responses reported by Stinson et l.,9 s well s the evidence of excessive nerobic work in the present study, steroid-induced ltertions of peripherl muscle could explin the differences in work cpcity of trnsplnt recipients compred with normls. Second, the oxygen-crrying cpcity of the blood could be compromised by the dministrtion of the hemtopoietic drugs zthioprine nd cyclophosphmide. This does not pper to be significnt fctor in the present study group; 87% of our trnsplnt ptients hd norml hemtocrits nd 8% hd norml hemoglobin vlues25 t the time of their exercise test. Liner correltions between both hemoglobin level nd work time nd hemtocrit nd work time were performed, nd no reltionship ws found. Conclusions The response of crdic trnsplnt ptients to grded, symptom-limited tredmill exercise is chrcterized by decresed chronotropic reserve, ltered ventiltory pttern, decresed work time nd elevted postexercise lctte level. Our dt point to limited supply of oxygen to the exercising periphery, probbly s result of the crdic output limittion noted by Stinson et l.9 It ppers tht there is some reltionship between functionl cpcity nd rejection history supporting the possibility tht crdic output is limited in trnsplnt ptients s result of residul myocrdil injury subsequent to rejection. Acknowledgments We cknowledge the cpble ssistnce of Ctherine Fotopolos nd Dr. Pul Thompson. We lso express our pprecition to Fred Fuller for nlyzing the blood smples nd to Edelen Stevens for prepring the mnuscript. References 1. Donld DE, Shepherd JT: Response to exercise in dogs with crdic denervtion. Am J Physiol 25: 393, Donld DE, Milburn SE, Shepherd JT: Effect of crdic denervtion on the mximl cpcity for exercise in the rcing greyhound. J Appl Physiol 19: 849, Donld DE, Shepherd JT: Initil crdiovsculr djustment to exercise in dogs with chronic crdic denervtion. Am J Physiol 27: 1325, Dggett SM, Willmn VL, Cooper T, Hnlon CR: Work cpcity nd efficiency of the utotrnsplnted hert. Circultion 35 (suppl I): 1-96, Donld DE: Myocrdil performnce fter excision of the extrinsic crdic nerves in the dog. Circ Res 34: 417, Lechmn RD, Lethermn LL, Rochelle DG, Cooley DA, Hllmn GL, Bloodwell RD, Nor JJ: Physiologic behvior of the trnsplnted hert in six humn recipients. Am J Crdiol 23: 123, Shver JA, Leon DF, Gry S, Leonrd JJ, Bhnson HT: Hemodynmic observtions fter crdic trnsplnttion. N Engl J Med 281: 822, Cmpeu L, Pospisil L, Grondin P, Dyrd I, Lepge G: Crdic ctheteriztion findings t rest nd fter exercise in ptients following crdic trnsplnttion. Am J Crdiol 25: 523, Stinson EB, Griepp RB, Schroeder JS, Dong E, Shumwy NE: Hemodynmic observtions one nd two yers fter crdic trnsplnttion in mn. Circultion 45: 1183, Clrke DA, Schroeder JS, Griepp RB, Stinson EB, Dong E, Shumwy NE: Crdic trnsplnttion in mn: review of first three yer's experience. Am J Med 54: 563, McLughlin PR, Kleimn JH, Mrtin RP, Doherty PW, Reitz B, Stinson E, Dughters GT, Ingels NB, Aldermn EL: The effect of exercise nd tril pcing on left ventriculr volume nd contrctility in ptients with innervted nd denervted herts. Circultion 58: 476, Schroeder JS, Rider AK, Stinson EB, Shumwy NE: Crdic trnsplnttion: review of seven yer's experience. Trnsplnt Proc 8: 5, Donld DE, Shepherd JT: Sustined cpcity for exercise in dogs fter complete crdic denervtion. Am J Crdiol 14: 853, Blinks JR: Positive chronotropic effect of incresing right tril pressure in the isolted mmmlin hert. Am J Physiol 186: 299, Wilmore JH, Costill DL: Semiutomted systems pproch to the ssessment of oxygen uptke during exercise. J Appl Physiol 36: 618, Hohorst HJ: Enzymtische Bestimmung von L(+)- Milchsure. Biochem Z 328: 59, Peiss CN, Cooper T, Willmn VL, Rndll WD: Circultory responses to electricl nd reflex ctivtion of the nervous system fter crdic denervtion. Circ Res 19: 153, Kontos HA, Thmes MD, Lower RR: Responses to electricl nd reflex utonomic stimultion in dogs with crdic trnsplnttion before nd fter reinnervtion. i Thorc Crdiovsc Surg 59: 382, Griepp RB, Stinson EB, Dong E, Clrk DA, Shumwy NE: Acute rejection of the llogrfted humn hert. Ann Thorc Surg 12: 113, Sltin B, Blomqvist G, Mitchell JH, Johnson RL, Wildenthl K, Chpmn CB: Response to exercise fter bed rest nd fter trining. Circultion 38: 1, Chrtrnd D, Angell WW, Dong E, Shumwy NE: Atril pcing in the postopertive mngement of crdic homotrnsplnttion. Ann Thorc Surg 8: 152, Mttil S, Ingels NB, Dughters GT, Adler SC, Wexler L, Dong E: The effects of tril pcing on the synergy nd hemodynmics of the orthotopiclly trnsplnted cnine hert. Circultion 48: 386, Chrtrnd D, Dong E, Shumwy NE: Hemodynmics of the orthotopic homotrnsplnted hert. Surg Forum 19: 238, Ingels NB, Rii DR, Dughters GT, Aldermn EL, Stinson EB: Effects of hert rte ugmenttion on left ventriculr volumes nd crdic output of the trnsplnted humn hert. Circultion 56 (suppl II): 11-32, Altmn PL, Dittmer DS (eds): Biologicl Hndbooks: Respirtion nd Circultion. Bethesd, Federtion of Americn Societies for Experimentl Biology, 1971, pp