Results of Radionuclide Assessment of Cardiac Function Following Transplantation of the Heart

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1 Results of Rdionuclide Assessment of Crdic Function Following Trnsplnttion of the Hert Dvid C. McGiffin, M.B., B.S., F.R.A.C.S., Robert B. :Krp, M.D., Joseph R. Logic, M.D., Welby N. Tuxe, M.D., nd Ricrdo Cebllos, M.D. ABSTRACT Rdionuclide ssessment of ejection frction ws determined erly nd lte postopertively following crdic trnsplnttion in 16 ptients. In 11 ptients, ejection frction ws determined within 48 hours of n endocrdil biopsy. There ws no reltionship between the severity of histologiclly evident rejection nd the ejection frction (Person correltion coefficient [rl = -.11; p =.47). In 2 ptients, severe grft fibrosis developed with consequent diminution in ejection frction. There ws no reltionship between severity nd durtion of rejection or the mount of immunosuppression required to tret cute rejection nd the development of grft fibrosis. The men resting ejection frction in 7 ptients in follow-up rnging from 6 to 21 months fter trnsplnttion ws.59 f.6 (stndrd devition), nd the men exercise ejection frction in 6 of these ptients ws.72 f.8. Rdionuclidedetermined ejection frction is not predictive of rejection erly fter opertion. During short-term lte follow-up, systolic left ventriculr function t rest nd exercise hs been retined t norml levels. Erly noninvsive detection of rejection following crdic trnsplnttion remins problem, nd informtion on ejection performnce of the hert fter trnsplnttion is scrce. Consequently, we used rdionuclide ngiogrphy (multiple gted cquisition [MUGA] scn) prospectively in series of 16 ptients undergoing crdic trnsplnttion to determine whether the procedure hd ny vlue in detecting rejection noninvsively. We lso sought to document left ventriculr systolic function t rest nd on exercise postopertively. Mteril nd Methods The records of the first 16 ptients undergoing consecutive hert trnsplnttion procedures t the University of Albm in Birminghm form the bsis of this report. Tble 1 gives the ges of ll ptients, the cuses of the 6 deths, nd length of follow-up for the survivors. There hve been no lte deths, nd ll 1 survivors re in New York Hert Assocition Functionl Clss I. From the Deprtments of Surgery, Nucler Medicine, nd Pthology, University of Albm in Birminghm, Birminghm, AL. Accepted for publiction Oct 28, Address reprint requests to Dr. Krp, Professor of Surgery, University of Albm Medicl Center, University Sttion, Birminghm, AL No MUGA scns were performed on Ptient 1 in the hospitl, nd scns were performed only occsionlly in the hospitl on Ptients 2'3, nd 4. Subsequent ptients hd scns performed in the hospitl every week, ech within 48 hours of endocrdi1 biopsy. All ptients surviving to dischrge from the hospitl hd MUGA scns done every two months of follow-up. For ech study, the ptient ws given n intrvenous injection of stnnous pyrophosphte followed within 3 minutes by 17 to 22 mci of technetium 99m pertechnette for in vivo lbeling of red blood cells [l]. With pproximtely 1 minutes llowed for rdiotrcer equilibriion, semisupine multigted imges of the blood pool were cquired in the "best septl" seprtion, left nterior oblique view (35 to 5 degrees), t rest. The dt were cquired for 6 minutes using n Ohio Nucler 15 mobile cmer equipped with high-sensitivity collimtor, nd were trnsmitted on-line to n Informtek Simis I11 computer system. Once the resting dt were cquired, ech ptient begn exercising ginst progressively incresing worklods of 15 kilopounds per minute for 3-minute intervls until ftigue occurred. Electrocrdiogrphic monitoring ws performed continuously throughout the exercise period, s ws recording,of the hert rte nd blood pressure. A specil computer progrm ws developed to cquire scintigrphic dt for only the second nd third minute of ech exercise period. Ejection frctions t rest nd t pek levels of exercise were determined from the difference between bckground-corrected end-distolic counts minus endsystolic counts, divided by the end-distolic counts. If the pek exercise ejection frction vlue did not increse by seven ejection frction units, ech previous exercise intervl ejection frction ws clculted to determine the chnges throughout the exercise test. The norml vlue for resting ejection frction in this institution is.5 or greter, nd norml exercise response is regrded s n increment of.5 or greter. However, when the resting ejection frction is.7 or greter, this vlue is regrded s norml for both rest nd exercise [2]. Postopertively ll ptients received conventionl immunosuppression consisting of prednisone, zthioprine, nd rbbit ntihumn thymocyte globulin (RATG). Ptients 1 nd 11 lso received severl doses of equine ntithymocyte globulin. Prednisone nd zthioprine were continued on long-term bsis. Acute rejection ws determined by mens of histologicl ex- 382

2 383 McGiffin et l: Rdionuclide Assessment of Crdic Function fter Trnsplnttion Tble 1. Clinicl Dt on 16 Crdic Trnsplnt Recipients Age t Ptient Trnsplnt Time to Deth No. (yr) Cuse of Deth or Follow-up Multisystem filure following retrnsplnttion Disseminted spergdlosis 21 mo 17 mo 15 mo 16 mo 6d 3 d 1 mo 1 mo 8% mo 2 mo 54d 6 mo 4 mo 47 d 2 mo 3 wk mintion of percutneous endocrdil biopsy specimen from the right ventricle using stndrd techniques [3]. The seventy of the rejection process ws grded using the criteri of Billinghm [4]. ws treted with pulsed doses of methylprednisolone, or temporry reinstitution of RATG, or both. Fig I. Reltionship between ejection frctions recorded within 48 hours of n endocrdi1 biopsy nd degrees of rejection with incresing severity. Vlues shown re men & stndrd devition. Results The reltionship of the rdionuclide-determined ejection frction to biopsy-determined cute rejection is shown in Figure 1. There were two bnorml ejection frction vlues. One ptient hd n ejection frction of.33 with moderte histologicl rejection, nd nother ptient hd n ejection frction of.34 with mild histologicl rejection. No reltionship ws found between the histologicl degree of rejection of incresing severity (none, miniml, mild, moderte, nd severe) nd the men ejection frction. Using the individul ejection frction vlues nd ssuming tht ech pir of redings (ejection frction nd severity of rejection) ws independent, we clculted the Person correltion coefficient (r) to be -.11 (p =.47). Among the 1 erly survivors, 2 ptients (Nos. 8 nd 1) hd bnorml ejection frctions. Both hd the ppernce of severe diffuse myocrdil fibrosis following the resolution of erly cute rejection. The fibrosis ws chrcterized by seprtion of myocrdil fibers by mture collgen nd the presence of interstitil fibroblsts (Figs 2, 3). Ptient 8 hd histologicl evidence of grft fibrosis erly in the postopertive course tht persisted in ll subsequent biopsy specimens. By 4% months fter trnsplnttion her resting ejection frction ws.34, nd t 9 months from trnsplnttion her ejection frction ws unchnged. She is in New York Hert Assocition Clss I but requires diuretic for fluid retention. In Ptient 1, the ejection frction decresed to.22 six weeks fter trnsplnttion, producing low crdic output syndrome with secondry orgn dysfunction. Consequently, retrnsplnttion ws crried out, but the ptient died of multisystem filure nd disseminted spergillosis. There is no difference in the histologicl degree of rejection or mount of immunosuppressive therpy between those ptients in whom myocrdil fibrosis subsequently did or did not develop (Figs 4, 5). Tble 2 shows resting nd exercise ejection frctions recorded t the ltest follow-up in 7 ptients who hve survived 6 months or longer, excluding the surviving None Miniml &lij Moderte Severe -.8 E IA m.4 3 o I. f.65k.1 Degree of Rejection : I *.61k.19

3 384 The Annls of Thorcic Surgery Vol 37 No 5 My 1984 Fig 2. Photomicrogrph of endocrdil biopsy specimen from ptient with severe grft fibrosis (Ptient 8). Mture collgen nd fibroblsts re interspersed between the myocrdil fibers. ( x 25; trichrome stin.) Fig 3. Photomicrogrph of endocrdil biopsy specimen from Ptient 8. Myocrdil fibers re preserved but re seprted by collgen. ( x 64; trichrome stin.)

4 385 McGiffin et l: Rdionuclide Assessment of Crdic Function fter Trnsplnttion I Fibrosis I No Fibrosis Degree of Rejection In mild ) '5 7 moderte m 6 severe % 5 1 n,, $ 4 n 5 3 * 2 I Ptient Number Fig 4. There ws no difference in degree of rejection between biopsy specimens from ptients in whom grft fibrosis subsequently developed nd those in whom it did not develop (nlysis excludes ptients who died during tretment of cute rejection)..e (3 c l 8-2, x 7- E, f.- 6- c 2 5- b 21 2L 4 4 ll 5 z z Fibrosis No Fibrosis Fibrosis No hbrosis Fig 5. Similr mounts of prednisolone nd rt ntihumn thymocyte globulin were given to ptients with grft fibrosis nd those in whom this condition did not develop (nlysis excludes ptients who died during tretment of cute rejection). Results oft tests compring group mens for both drugs were not significnt (p <.2). c ptient with severe grft fibrosis. Six ptients hd norml resting ejection frction; 1 (Ptient 7) hd slightly bnorml ejection frction. Exercise response ws norml in 5 ptients nd bnorml in 1 (Ptient ); this vrible could not be determined for 1 ptient (No. 2) becuse of inbility to use the exercise bicycle. Comment Currently, the most relible nd most sensitive indictor of cute rejection of the trnsplnted hert is by mens of the histologicl chnges evident in percutneous endocrdil biopsy specimens. However, noninvsive method of dignosing erly cute rejection is lcking. Rdionuclide ssessment of ejection frction ws used to monitor systolic left ventriculr function postopertively in 16 hert trnsplnt ptients to determine if the technique could give some clue to the presence of cute rejection. Unfortuntely, no predictive vlue cn be plced on this method for erly dignosis of rejection. Furthermore, the dt indicte tht there ws no difference in the men ejection frction ssocited with vrying degrees of severity of rejection. This is not surprising, since clinicl signs of hemodynmic deteriortion do not pper erly in the rejection process [5]. In ddition, mesurement of crdic output postopertively is not sensitive index of the presence of rejection [6]. Finlly, lbortory evidence hs demonstrted tht in cnine hert recipients, stroke volume nd crdic output do not fll until the rejection process is quite dvnced [7]. In 2 ptients in this series, decresing ejection frction corresponded to the development of severe grft fibrosis. The reson s to why myocrdil fibrosis developed in these 2 ptients is not pprent. There ppers to be no reltionship between the development of grft fibrosis nd the severity nd durtion of cute rejection, or the mount of dditionl immunosuppression required to tret cute rejection. In our ptients, resting left ventriculr ejection frctions determined 6 to 21 months following trnsplnt- Tble 2. Lute RestinR nd Exercise Ejection Frctions in Ptients Surviving 6 Months or Lonxer Ptient No. Ejection Frction Exercise Wll Motion Resting Exercise Stge Abnormlities None 2.62 b None None None Smll re of sept1 hypokinesis None None Men?.59?.6.72 *.8 stndrd devition "Excluding the surviving ptient with severe grft fibrosis (No. 8). bptient ws unble to exercise becuse of vsculr necrosis of the femorl hed.

5 386 The Annls of Thorcic Surgery Vol 37 No 5 My 1984 tion were norml, with the exception of slightly subnorml vlue in 1 ptient. Thus, systolic function, t lest, is well preserved, provided severe grft fibrosis is not present. The exercise ejection frction dt lso confirm tht the systolic function of the trnsplnted left ventricle is cpble of responding to the requirements of exercise. This is in keeping with crdic ctheteriztion dt obtined one yer following trnsplnttion nd demonstrting incresed crdic output in response to exercise (81. Our ptients were treted with conventionl immunosuppression. In group of crdic trnsplnt recipients treted with cyclosporin-a, left ventriculr ejection frction ws found to be norml t rest ( ). However, ejection frction did not increse with exercise (.65 f O.l), lthough the resting ejection frction ws quite high [9]. The men long-term resting ejection frction in the present series is lso high, but the men exercise ejection frction does increse. The lck of n increse in ejection frction fter exercise in the cyclosporin-treted ptients my be due either to the fct tht resting ejection frction ws high, or it perhps my be secondry to the mild fibrosis noted in ptients requiring cyclosporin [9]. In summry, rdionuclide ngiogrphy does not detect erly rejection. However, substntil diminution of ejection frction in the postopertive period my herld the onset of grft fibrosis, which requires histologicl confirmtion. Short-term follow-up indictes preservtion of left ventriculr systolic function t rest nd norml exercise response. It remins to be demonstrted whether norml or nerly norml left ventriculr systolic function nd exercise response will persist with longer follow-up. References 1. Pve1 DG, Zimmer AM, Ptterson VH: In vivo lbelling of red blood cells with -"'Tc: new pproch to blood pool visuliztion. J Nucl Med 18:35, Berger HS, Zret BC: Nucler crdiology. N Engl J Med 35:855, Cves PK, Stinson EB, Billinghm ME, Shumwy NE: Seril trnsvenous biopsy of the trnsplnted humn hert: improved mngement of cute rejection episodes. Lncet 1:821, Billinghm ME: Dignosis of crdic rejection by endocrdil biopsy. Hert Trnsplnt 1:25, Bumgrtner WA, Rietz BA, Oyer PE, et l: Crdic homotrnsplnttion. Curr Probl Surg 1613, C,tinson EB, Cves PK, Griepp RB, et l: Hemodynmic observtions in the erly period fter humn hert trnsplnttion. J Thorc Crdiovsc Surg 69:264, Stinson EB, Griepp RB, Bieber CP, Shumwy NE: Hemodynmic observtions fter orthotopic trnsplnttion of the cnine hert. J Thorc Crdiovsc Surg 6334, Schroeder JS: Hernodynmic performnce of the humn trnsplnted hert. Trnsplnt Proc 11:34, Devineni R, McKenzie N, Kostuk WJ, et l: Cyclosporine in crdic trnsplnttion: observtions on immunologic monitoring, crdic histology nd crdic function. Hert Trnsplnt 2219, 1983 Notice from the Southern Thorcic Surgicl Assocition The Thirty-first Annul Meeting of the Southern Thorcic Surgicl Assocition will be held t the Mrriott's Hilton Hed Resort, Hilton Hed Islnd, SC, Nov 1-3, There will be $1 registrtion fee for nonmember physicins except for guest spekers, uthors nd couthors on the progrm, nd residents. There will be $25 registrtion fee for ttendees of the Postgrdute Course on Thursdy, Nov 1. Members wishing to prticipte in the scientific progrm should submit bstrcts in triplicte, by My 15, 1984, to Frederick L. Grover, M.D., University of Texs Helth Science Center, 773 Floyd Curl Dr, Sn Antonio, TX Abstrcts should be double-spced on one side of one sheet of pper, with 1-inch left mrgin, nd limited to 2 words. All slides used during the presenttion must be 35 mm. Mnuscripts of ccepted ppers must be submitted to The Annls of Thorcic Surgey prior to the 1984 meeting or to the Secretry-Tresurer t the opening of the Scientific Session. Applictions for membership should be completed by September 1, 1984, nd forwrded to Lmn Gry, Jr., M.D., Deprtment of Surgery, University of Louisville, 55 S Jckson St, Louisville, KY 427. Hivey W. Bender, Jr., M.D. Secret y-tresurer