28 5
Long-term Follow-up afte r Orthotopic Heart Transplantation B. Heublein, A. Hauerich", and H. G. Borst' Division of Card iology. Med ical Cen ter • Division of Th or acic a nd Card iovasc ula r Surgery . Su rgical Cente r, Ha nnove r Medical School. Ha nnove r . FRG
While infection and ac ute rejection contin ue to be the most freque nt cau se of ea rly posto per at ive mor tality, chron ic rejection including bot h corona ry vasculopathy and un specific myoca rdia l allograft failur e and side effects ofi mmunosuppressive therapy determ ine late surv ival a nd quali ty of life. Some data arc presented of a syst em ati c progr am for lo ng-term follow-u p of ca rdiac tr an splant recipients with particula r
emphasis on coronary vasculopathy and modern concepts in rejection detection and control. Infections remain a notabl e so urce of morbid ity and mortalit y. The impo rta nce of cont in ued efforts to preven t infection even in the Cyclos po ri n era ha s to be emphasized. Tr icuspid insufficiency is influe nce d by the mismat ch of recipient a nd don or heart size. Intra operative ada ption of the recipient pe rica rdium to the size of the donor heart redu ces th e magn itud e . Unspecific graft failu re has been observed to occur at a n incidence of 8 % th ree yea rs aft er tra ns planta tion. Three types of rejection can be disting uished after heart replacem ent. the hyperacut e rejection as a ra re complicat ion precip itated by prefor med recipient a nt ibo dies to do no r an tigen s. the acute rejectio n as a major risk facto r for survival in the posto perati ve first yea r, a nd , finally, the chronic reje ction which is a n important facto r for long-ter m surv ival and q uality of life . Conside ring the detection a nd classificati on of the ac ute rej ec tion , a se miqua ntificatio n is advantag eous because of its ther ap eutic relevance . The chro nic rejection is cha rac te rized by vascu lar abnormalities . interstitial cha nges. a nd myocardia l alterations. Ofthese , the va scular compo nent is th e most lmporta nt clinicall y. The incide nce of this coro na ry vasc ulopathy , ta king all forms visibl e angio gra phica lly, is a bout 30- 40 % of surviving pati en ts three years a fter transp lantation . A correlation exists bet ween th e frequen cy of ac ute rejection s a nd th e incide nce of coro na ry vas culopathy. This find ing implies an immu nological type of mecha nism pre cipitating the initi al coronary artery inj ury. The correlation betwee n hyperli pidemi a an d the progress of such vas culopathy sup port tha t syne rg istic factors a re necessa ry for the ultimate developm en t of allogra ft vasc ulopa thy. Corticostero id d osage a nd Cyclos pori nc level do not contribute to the developme nt ofvasculopa thy. STvsogme nt depressions we re mon itored after ca rdiac tra nspla ntat ion . Th ere was a relat ion between this find ing and differe nt grades of th e myoca rd ial rejection a ctivity. Atrial- and ventricular arrh ythmias a re unsp ecific marker s of myocardial rejection. Their incidenc e decreased duri ng lat e follow-up. Non-s ustai ned ventricula r runs frequ entl y occ ur du ring th e acu te ph a se of myoca rdial rejection. Sinus node dysfun ction a nd sino -atrial cond uction disturbances a re pr oblems in th e ea rly postop erative ph as e. In 90 % the survivi ng pati ents develope a pe rmane nt incompl ete or complete right-bundle branch block. in 13 %
completed by a left anter ior hem iblock. Side effects of the immunosup press ion drug regimen a re import an t facto rs for the long-term surv ival and qualit y ofl ife. Furt her studies a re necessa ry in ord er to optimize the immu nos upp res sion with respect to loweri ng side effects a nd to ac hieve ind uced immu neto lerance .
Len gzett ergebntsse na ch orthotop er Ile rztra nspl a nta tio n w ahrond Infektl onen und d ie akute Abst oBun g Morbiditat und Mort alita t im ersten Jah r nach der Herztran splan ta tion m TX) besttm men . si nd Obe rle be ns ra te un d Leben squ alitat im weit eren Verl auf ube rwie gend von de n Foigen de r chro nisc he n Hejektion (kor cn are Vaskulcp athi e . un sp eziflsch e myokardiale Insuffizienz) und von den Nebe nwi rkunge n der lm munsuppression a bha nglg. Es werden Fakto ren vorg estellt und mit einer kr itischc n Wertung die gegenwa rttgen Moglichke ite n ihrer effektiven Beein flussu ng verbund en , d ie fur den Langzeitvcrla uf von beso nderer Bedeu tung sind. Das bre ite Spekt rum von potent icllen Infcktionen verlangt a uch in de r Cyclosporin-Ara cine rat ion ale Pravent ic n. Die Perlka rd ra ffung vers pr icht cine dcutltche Hedu ktion der pro gn ostisch ungGnst igcn Trik usp idalinsuffizienz. Die in etwa 8 % na ch 3 Ja hr e n a uftre ten dc unspezifische myoka rdiale Insuffizienz kan n nu r durch He-Transpla ntati on behandelt werden. Eine dilTercn zierte The ra pie der a kute n AbstoBung stellt neu e Anford erungen an deren Diagn os tik (Sem iquantifizierbarkelt]. Die chronisc he Abst oBung dominiert als ko rona re Va sku lopathic (KVPI, die na ch 3 Ja hre n etwa 30 % der Ubor lebcnden befallt und so die Lan gzeitGberl eb en srat e nach I1TX bestimm t. Eine ursachliche Beziehung zwische n de r Inzid en z, der a kute n Abst oliun g und der Hyperli pldarn le ist wah rs cheinl ich , bcson ders d ie Progress ion ein er vorhanden en KVI) zeigt ci ne Bcziehung zur Schw ere der Hyperllpid ami e. Kein Zusa mme nha ng wu rd e zwisc he n de r KVP und der Steroid- oder Cyclospo rinMedikation gefu nden. Su pra - und ventrikulare Ektopie n sind auch auBerha lb der AbstoB ung sp hase n za hlre ich. Wa h rend der akute n Abst oBung wird die Zuna hme des Auftre te ns vent rikula re r Salven a uffallig. SA-B1ock icr ungen (I.-III. Grades) sind ein Problem der frlihe n postopera tiven Pha se . 90 % der Patienten zeige n im wcitc rcn Verl au f eine n inkomp lett en oder kom plctten Hechtssche nkelblock. in 13% kombi niert mit ei nem linksan terior e n Ifem iblock oh ne die Konseq ue nz ei ne r prop hylak tischen Schrittmacherim plantation. Das umfangliche Spektrum von Nebe nwirkungcn der gege nwa rtlgen Imm unsuppression unt ers tutzt die Suche na ch medtkamcntosen und a nderen Alternat iven . Key words Heart tr an sp lan ta tion - Coro na ry vasculopathy - Imm un osup pres sive th erap y - Acute a nd chronic rejection
Head at the 19111 Ann ual Meetin g of the German Society for Tho racic a nd Ca rdiovasc ula r Surgery, Bad Na uhel m. February 22-24. 1990 Thorae . cardiov asc. Surgeon 38 (1990) 285 -290 © Georg Thie me Verlag Stuttgart - New York
Received for Publi ca tion : Aprile., I lJlJO
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Summary
Thome. eardiovase . Surgeon 38 (1990)
Introdu ction Ca rdiac transplantation (HTX) h as evo lved as an acce pte d tr eatm ent mod a lity for certa in pati ents with end-s ta ge h eart disease. Improved surviva l afte r HTX has heen ach ieved by better selection of transplant candidat es , advances in myocardial preservation techniques, improved rejection detection, and the introduction of new immunosuppressive agents . While infection and acute rejection contin ue to be th e most fre que nt cause of ea rly postope rati ve mortality, ch ronic rejection both including coronary vas culopathy and unsp ecific myocardial a llograft failure a nd side effects of immunosuppres sive therapy determin e late survival and qua lity of life. Important factors of long-term survival are depi cted in Ta ble I. Thus, furt her knowledge is req uired to avoid these complications and to improve the long-term resul ts afte r HTX. Th is pa pe r describes some dat a of a sys te ma tic pro gra m for lon g-term follow-up of ca rdiac transplant recipients at Hann over Medi ca l School acquire d since 19 85 with particular emphasis on coron ary vasc ulopathy and modern concepts in detection and control of rejection .
B. Heublein. A. Ilaverich. II. G. Borst
nsiti vity a nd subseque nt alte ra tion of th e response of the tra ns pla nted hea rt to corres ponding drugs (4, 28 ), a nd the de velopm ent of syste mic hypertension in a subgro up of patients . Norma lization of eleva ted pu lmonary a rte rial pressures after transplantation occurs rapidly and remains sta ble in th e late r postope ra tive cou rse (Fig. 1). Neverthe -
400
300
~
1, u
• 200 e
~ « '" ~ 100
_c n
o Table 1 Factors influencing the long-term surviva l and quality of life afte r orthotopic heart transplantation -
infections rejection rhythm disturbances hemodynamic disorders malignancies si de effects of drug therapy compliance of patients intensityof med ical care
Infections Infection rem ains a notable source of morbidity an d mo rtality in cardiac transplant recipi ents . Causative agents show a predominance of opport unistic path ogens. Bacterial (gram negative), vira l (he rpes, cyto megalovirus ), fungal (aspergillus, ca nd ida , no cardia , crypt ococcus ), and protozoal (pneumocystis, toxoplasma) infections require effective prophylaxis , intensive and complete diagnostic measures , close surveillance, and an aggressive treatm ent combine d with decreased mainten ance of immunosuppression at a level ju st toler ab le for graft survival, Th e prim ary ta rget organ for postoperative infections is the lung. Effective preve ntion of infection should include pro phylactic administration of aciclovir (a ga inst herp es), trim ethop rim/ su lfam etho xazole (aga inst pne um ocysti sl . an d CMV-hy pe rim munoglobuline during treatme nt for episod es of acute rejection (9 , 21, 22). Gene ra lly, th e im po rtance of cont in ue d efforts to prevent infection eve n in the cyclos porine era has to he em phasize d.
Ilem odynam ic disord ers Ilemo dynamic disorders include the donor's right ventricular reaction to the abnormal recipient pulmona ry circulation a nd its dynam ics in th e follow -up (dilatation a nd tricus pid regurgitati on) (2), a n imp aired diasto lic ve ntr icular performance (25), th e delayed heart-rate resp on se of a denervated hea rt (20), th e pres yn a ptic type of adren e rgic su pe rse -
96
o
94
61
20
2
3 years
Fig, 1 Normalisation of pulmonary arterialpressure (PAR) attertransplantation
less . right ventricular enlargemen t persists. As we have shown in th e past , the grade of tricuspid regu rgitatio n , wh ich ca n be frequ ently obs erved , is influen ced by the mism at ch of recipient a nd don or hea rt size. Intraop erati ve ad a ption of th e recip ien t peri cardium to the size of th e donor heart distin ctly reduces th e magnitud e of tri cuspid insufficien cy. Permanent low glob a l ejectio n fra ction , im paired fractio na l sho rten ing, elevat ed filling pr essure , mitral insufficien cy, and corresp onding clinical disorders of left- and right-heart failure represent the hem odynami c results of severe corona ry vasculopathy (CVP) or unsp ecific graft failure . Th e latter disorder ha s been obs erved to occur at an incidence of 8 % in our patients three yea rs after HTX. Allogra ft r ej ection Sim ila r to im mu nologic allograft failure following transplant ati on of other orga ns suc h as kid ney a nd live r, three types of rejection can be disti ngui sh ed aft er heart rep lacem ent. Hyp eracut e rejection develops alm ost immediate ly a fter transp lanta tion and is pr ecipitated by pr eformed recipient antibodies to don or a ntige ns . Fortunately, hyperacut e rejection rep resents a rare complication in heart transplantation. A cute rej ection, by contrast, occurs frequ ently a nd re peatedly in heart tr an sp lant re cipi ents a nd is a major risk factor for su rvival in th e po stoperati ve first yea r. Lon g-term surv ival is limit ed by a third type of rejectio n, which is referred to as chronic or vasc ular rejec tion . Cur re ntly, right vent ricula r endomyocardia l biop sy (EMB) represen ts th e mo st relia ble technique for detection of ac ute rejection. Noninvasive methods have been shown to reduce th e rate of EMB perform ed , but th e EMB by an ex pe rience d path ologist still represents th e method of choice (3, 14) . In our ex perience a detailed morphologic
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286
Lone-term Follow-up After Orthotopic Il eart Transplantation
Incide nce ofcoro nary vasculopa t hy
The incidence ofCVP in our cardiac transplant recipients as assessed by yea rly coronary angiograms is depi cted in Fig. 2. Uretzku (24), Oliuar i (18), and Gao (8) rep orted sim ilar data for th eir patien ts even though differ en t dru g regimens were applied. Thu s, whe n ta king all form s visible an giogr aphically, about 30- 40% of surviving patients will develop CVP th ree yea rs after HTX. In addition, one has to take into cons ideration the low sensitivity of coronary an giography in th e detection ofCVP after HTX because of its diffuse natu re, especially in the beginni ng. Moreover, first manifestati on will be drop-out of third- an dlor fourth-orde r br an ch es which may be difficult to det ect by angiography (6, 19).
Types ojCV? Three types of CVP have been class ified by Gao (6). Type A consists of focal ecce ntric luminal narrowing or (generally discrete) obstruction involving the proxima l epicardial ves se ls. Type B demonstrates normal proximal vesse ls with diffuse narrowing of medium -sized and distal vess els, including s udden cut-off or smo oth cylindrical tap ering of the arteries involved , Type C is cha rac te rized by irregular and diffuse dis ease of the coronary artery system , The d istribution of un e-, two- or three -vessel disease in our patient group is shown in Fig. 3, In th e first year followin g HTX the num ber of vesse ls involved is distributed evenly, After two years, by contrast, a clear shift to three vesse l disease is present. When compared to coronary artery disease in the non-transplant ed heart, CVP does involve peripheral vessels in a higher percentage of cases an d the developm ent of collatera ls in ca rdiac allogra fts rema ins poor.
287
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7 1.4
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50
25 n (total)
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143 16
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Freedom fromcoronaryvasculopathy (CVPj after heart transplantation
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CVP and acute rejection
We, like Uretzky (24) an d Winters (27) were a ble to demonstrate a statistically significant correlation between the frequen cy of acute rejection s and the inciden ce ofCVP (Fig. 4). In a previous study, we we re able to define a 'rejection potenti al' which includes the total nu mber and seve rity of rejec tion episodes over time. It also takes into cons ideration the dynamics of development and reso lution of histologic findi ng between two episodes of acute rejection (13). Whe n compa ring this rejection potential with the inciden ce of CVP, the sa me study groups showed no significant differences after the first and the seco nd posttransplantation yea r (3,65 ± 0,72 an d 3,35 ± 0. 53 points, respectively). These findings imp ly an (expected ) immunological type of mechanism precip itating the initial coronary artery injury, but also ind icate tha t synergistic factors are necessary for th e ultimate development of allograft vasc ulopat hy. This clinical observation is also su pporte d by data deri ved from anima l studies of A lonso (I ). One of these additiona l risk factors may be hyperlipidemia, wh ich is com mo nly obse rve d after HTX.
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classification is advantageous because of its therapeutic relevance: semiquantification of myocyte-necro sis (A3a and A3b - Hannover Classificati on [14]) allows for a significant redu ction of add itiona l anti-rejec tion th erap y cons ide ring the natural history of moderate rejection , a nd classification of mild histopathologic cha nges may suggest potential progress into forms of rejection requiring th er ap y. Accordingly, some histopat hologic grades of rejection (A2; A5 b/B2 Ilannover Classification) showed an early convers ion into moderate/s evere rejection in 7 of 10 cases therefore requiring re- EMBwithin 2 wee ks. Chronic rejection represe nts the most obscure type of allograft rejection , both regarding etiology an d potenti al tr eatmen t. This importan t category is charac te rized by vascular abn orma lities (endothelial swe lling with degen erative cha nges , peri vascul ar infiltr ates), inter stitial cha nges (fibrosis with varying exten sion of lymphocytic infiltrat es), and myocardi al alterations (expression of oncoge ns, degener ative cha nges) (14, 25), Of th ese, th e vasc ula r compone nt, coro na ry vasc ulopa thy (CVP) or allogra ft cor onary arte ry disease, is th e most importan t clinically. It also has a conside rable imp act on long-term survival ofca rdiac tran sp lan t recipi ents . In the following sec tion, data about incidence, relation of lipids to acute rejection , morphologic types, an d progr ession ofCVP in relation to lipid levels and, finally, th e inciden ce of temp orary ST-seg me nt depressions in the 24hour electrocardiogram are rep orted .
Thorae . eardiolJusc. Surgeon .18 (1990)
Thorac. cardiovasc . Surgeon 38 (1990)
B. Heublein. A. lI a ve rich, 1I. G. Bors t
20 ~----------------, O with
CVP without
O CVP
15 p
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< 0.05
p
< 0.05
p
< 0.05
IT
v
10
~
E
11
it:
5
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Fig.4
2nd year
cha nges of blood lipid levels as ea rly as two wee ks following the application of CyA. He concluded that CyA-mediated cellular dam age results in defective cholesterol clearance as manifested by atheroge nic lipoprotein profiles, and injury of the coronary endothelium, resu lting in CVI'. Gao (8) and Hess (12), howeve r, could demonstrate, that CyA was not associate d with an incr eased risk of CVI' in the first three years after tran splantation. Our results (Table 3), considering the first two posllra nsp lan tati on yea rs , are in agreement with these findings in that CyA ha s no significant impact on the developm ent ofCVI'.
1st + 2nd year
Correlationbetweenfrequencyof acute rejection and inc idence of CVP
Table 3 Coronary vasculopathy and total mean Cyclosporine A level and amount inthefirst and secondyea rafter cardiactransplantationintwocomparable patient groups(both n = 23)
CVP pas. amount(mg)
level [ng/rnl)
CV!' an d hyp erlipi d emia
To assess the influen ce of serum lipid levels in HTX recipients on CVI', a retrosp ective analysis of two compa ra ble patient groups was performed, examining mean total cholesterol and triglycerids (Table 2). The statistica l ana ly-
l st year 2nd year
374 ± 78 367 ± 103
466 ± 168 452 ± 134
CVP neg. amount (mg)
level (ng/ml)
385 ± 99 373 ± 96
462 ± 148 443 ± 117
CV!' and temporary S T-dep ression Table2 Totalcholesteroland triglyceridelevelsone and twoyearsafter heart transplantation intwo comparab le patient groups (both n = 23)
CVP pas. triglycerides (mmal/ I)
cholesterol (mmal/I)
l st year 2nd year
7.07 ± 1.84 6.74 + 1.81
2.37 ± 1.08 2.52 + 1.1t
CVP neg. triglycerides (mmal/I)
cholesterol (mmal/ I)
6.55 ± 1.11 7.03 + 1.62
1.90 ± 0.65 2.36 + 1.1 7
CVPpos.- angiographically determined coronary vasculopathy CVP neg.- angiographically no signof coronaryvasculopathy
sis revealed a tendency towards a positive correlation between lipids an d the initial incidence CVI', but this did not reach statistical significance . This observation is also supported by findings of Gao (7) and Griepp (10). Our da ta do, by contras t, suggest a link between hyperlipid emia (especially hyper triglyceridemia) and the progre ssion of CVI' between the first and second year after HTX (p < 0.01) (Fig. 5). These findings support the hypothesis that CVI' may be primarily immune-mediated , buttbat other factors, such as hyperlipid em ia , may play an important role in pro gress ion of the disease 11 , 11, 17). Corticosteroids exert their own cardiovascular effects and may acce lerate coronary atherosclerosis in the nontrans planted hea rt (5). To assess their influence in CVI', both the mean dose and the total amount of steroids given in individual patient s in both groups throu ghout the entire postoperative interval we re compared. We could not find any signifi ca nt differ ence between the CVI' positive and CVI' negative groups suggesting that corticosteroid dosage alone does not contribute to the development ofCVI'. Cyclosporine ha s been shown to cause endo the lial dam age as well as renal and hepatocellular toxicity (23). Controversial data exist concerning the influence of cyclosporine A (CyA)on the development of hyperlip idemia. While l.ioi (16) reported tha t CyA does not exert an y influence on the lipid profile, the data of Stam ler (23) suggest significant
Path oph ysiological ST-segme nt de press ion (STD) in the ECG of de nervated hearts represent s a special form of silent ischemia. STD may occur as a result of CYP. Therefore, we ana lyzed a group of 77 cardiac tra ns plant recipient s by Holter moni torin g an d compa red the results both with the incidence a nd degree of rejection and the prevalence ofCVI' on a ngiography. No sign ificant differ ence in the incidence of STD in pati ents with CVI' (15.0 %) or without CVI' (8.7 %) was noted. There was, however, a clear relation between STD and differ ent gra des of the myocardi al rejection activity. We the refore postulate that the pr esence of STD after ca rdiac tra ns plantation may be related to a regional release or imbalance of active vasomotoric substances in coincidence with acute myocar dial rejection. Ar r hyt hmias and conduction dist urba nces after IITX In agree ment with data from Litt le (15) our res ults of 24hours Holter monitoring in 77 IITX recipients (mean age 45 ± 19 yea rs , 7 to 1198 days after transplant ation), clearl y dem onstrated atrial and ventricular arrhythmias to be unspecific markers of myocardial rejection . Irrespective of the result of EMBs, the incidence of early postop er ative supraventri cular arrhythmias (302/2 4 h) and ventricular ecto pies (541/ 24 h) decreased durin g late follow-up . The only constant findings were non-su stained ventricular runs frequ ently occur ring during the acute (untreated) phase of myocardial rejection. Thus, in OU f experience , atrial and ventricular arrhythmias are a common feature in patients durin g the initia l posttransp lant period. Conduction disturbances are also commonly observed after JlTX. Sinus node dysfunction, sino-atrial conduction disturban ces or AV-bloc are typical prob lems in the early postoper ative phase. Very often (90% in our patients), the ECG demonstrates a permanent incomplete or complete right -bundle branch block, sometimes (13%) completed by a left ante rior hemiblock. The reasons for this phenom enon are still unclear.
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288
Thome. ca rd iol' Qsc. Surgeo1l38 (1990)
Long-term Follow-up After Orthotopic [teart Transplantation n.s.
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~ ~ ~ ~ ~ ~ 1M ~ ~ ~ ~
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Verani, M. S.. S. E. George, C. A Leon, II. II. Whisennand. G. P. Noon. II. D. S hort lll. M. E. DeBakey, a nd 1. B. Young: Systolic and diastolic ventricular pe rformance at rest and du ring exe rcis e in heart tr an splant recipien ts. J . Heart Tra ns plan t. 7 (988) 145- 151 Winters. G. L , M. R. Constanzo- Nordin. E. J. O'Sullioan . R. Pifarr e. M. A S ilver. M. 1. Zucke r. J. A Robinson. a nd P. J. S canlon: Pred ictors of late acute ortho top ic hea rt tr a ns plan t rejection . Circulation 80111 1(19891106- 110 Yusuj. S.. S. Theodoropoulos . N. Dhalla, C. Matthia s. a nd M. Yacoub: Effect of beta blockad e on dynamic exercise in human hear t tr an spl ant re cipients . Ileart Tran sp lant. IV (1985 1312 -314
B. Heublein. A. llaverich. II. G. Borst
B. Heubl ein. M . D.
Ha nnove r Medical Scho ol Department of Card iology Konsta nty-Gutschow -Su-.B 0 -300 0 Ila nnover 6 1
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290