N N EM Y R 99 J AO VU A RB E 1 9 2 0 0 0 Vo l u m e 4 , I s s u e 9 3 1 ™Cardiac transplantationB Y G I L B E RT H . M U D G E , J R . , M . D . A Teaching Hospital of HARVARD MEDICAL SCHOOL Cardiac transplantation is an important therapeutic modality for the treatment of the mor- Cardiovascular Division (Clinical)bidity and reduced survival associated with end-stage congestive heart failure. Cardiac trans- Elliott Antman, MD Donald S. Baim, MDplant has evolved and matured and is often used as a gold standard to compare novel medical Joshua Beckman, MD Charles M. Blatt, MDand surgical therapies for advanced heart failure. This issue of Cardiology Rounds will provide Eugene Braunwald, MDan update on current national standards and present some aspects of cardiac transplantation Christopher Cannon, MD Michael Chin, MD, PhDmanagement used at Brigham and Women’s Hospital. Although cardiac transplantation has Mark Creager, MD Victor Dzau, MDemerged as a sub-subspecialist career path, this discussion of the unique clinical challenges Elazer Edelman, MD, PhD Andrew Eisenhauer, MDencountered with this particular patient population is directed to the general cardiologist. Kristin Ellison, MD Laurence Epstein, MD James Fang, MDGeneral characteristics Jonas Galper, MD, PhD Peter Ganz, MD J. Michael Gaziano, MD The ﬁnite number of donors in any geographic area limits the overall size of any cardiac trans- Marie Gerhard-Hermen, MDplantation program. Because of such limited single center volume, virtually all large transplant centers Robert Giugliano, MD Samuel Z. Goldhaber, MDhave had to form collaborative relationships to accumulate sufﬁcient patient populations for clinical Thomas B. Graboys, MD Howard Hartley, MDinvestigative protocols, to establish national outcome standards, and to provide more meaningful Mukesh Jain, MD John Jarcho, MDinsight into demographic information of this patient population. There are three such databases in the Paula Johnson, MD Wendy Johnson, MDUnited States: Ralph Kelly, MD James Kirshenbaum, MD • UNOS (United Network of Organ Sharing) provides national oversight to the transplantation/ Gideon Koren, MDorgan donation process. The major role of UNOS is in developing the optimal and fairest allocation of Richard Kuntz, MD Michael J. Landzberg, MDthe precious resource. Richard Lee, MD James Liao, MD • The Registry of the International Society of Heart and Lung Transplantation records outcomes Peter Libby, MD (Division Chief) Leonard Lilly, MDand general clinical characters for all programs. Bernard Lown, MD Thomas Michel, MD, PhD • The Cardiac Transplant Registry Database (CTRD) compiles demographic treatment and Karen Moulton, MD Gilbert Mudge, MDoutcome data from high volume programs. Patrick O’Gara, MD Oglesby Paul, MD By constructing collective outcome data, these organizations have established international and Marc A. Pfeffer, MD, PhD (Editor)national standards and expectations. The number of yearly cardiac transplantations performed world- Jorge Plutzky, MD Jeffrey Popma, MDwide peaked at 4068 procedures in 1995 and declined to 2961 in 1998, primarily because of limited Shmuel Ravid, MD Paul Ridker, MDdonor availability.1 Approximately 2300 transplantations will be done each year in the United States. Thomas Rocco, MD Campbell Rogers, MDSuch decline has occurred despite broadening the acceptance age of donors, increased public educa- Maria Rupnick, MD, PhD Arthur Sasahara, MDtion, and other measures to expand donor availability. Concurrent with this diminished pool, the need Jay Schneider, MD Christine Seidman, MDhas expanded. Currently, approximately twice as many potential recipients will be listed as will be Andrew Selwyn, MDtransplanted. This simple inequity translates to more patients on waiting lists and continuing pressure Daniel Simon, MD Laurence Sloss, MDas transplant cardiologists to re-evaluate each patient’s priority status. Scott Solomon, MD Lynne Stevenson, MD In the early years of cardiac transplantation, approximately 60% of all transplants were done for William Stevenson, MD Peter Stone, MDdilated cardiomyopathy, the balance for ischemic heart disease. At the present time, however, approx- Michael Sweeney, MD Nancy Sweitzer MD, PhDimately 45% of patients are transplanted for non-ischemic cardiomyopathy, 45% for ischemic car- Frederick Welt, MDdiomyopathy, with approximately 3.5% for valvular heart disease, 2.5 % for retransplantation, 2% for Brigham and Women’s Hospital 75 Francis Streetcongenital heart disease, and another 2% for other conditions,1 such as sarcoid, hypertrophic car- Boston, Massachusetts 02115 Fax: (617) 732-5291diomyopathy, amyloid, Chagas, chemotherapeutic, and other myopathies. Cardiovascular Division Website: www.heartdoc.org The editorial content of Cardiology Rounds is determined solely by the Cardiovascular Division of Brigham and Women’s Hospital. This publication is made possible by an educational grant.
Survival following transplantation Approximately 38% of these neoplasms will be a traditional post-transplant lymphoproliferative disease, a B-cell lym- There has been a difference in survival in the four differ- phoma. Other post-transplant malignancies include lung andent eras of immunosuppression. The early clinical experience colonic cancers, as well as skin neoplasm. Malignantbetween 1980 and 1985 was associated with lower survival melanoma is relatively infrequent in this group.rates than those achieved between 1986 to 1990. Improvementwas also noted in the years between 1991 and 1998. But in the Cardiac rejectionpast 9 years, there has been no detectable difference in sur- There are three forms of cardiac rejection that are clini-vival characteristics (1991-1994 and 1995-1998). This under- cally recognized:scores an obvious clinical point, that immunosuppressive • Acute cellular rejection is diagnosed by endomyocardialprotocols have been generally standardized to triple immuno- biopsy, with lymphocytic inﬁltrate and myocyte necrosis.suppressive therapy that includes prednisone, cyclosporine or There is a standardized grading system to these histologicaltacrolimus, and azathioprine or mycophenolate mofetil; that changes, and therapeutic response is guided by both histologyimmunosuppressive protocols for rejections are similar; and and clinical presentation.that longevity standards have been set very high and are con- • A chronic rejection process is often manifest by thesistently achieved across the nation. development of allograft coronary artery disease. Patients will The current overall national standards for one- and ﬁve- develop a progressive and diffuse arteriopathy, usually mani-year survival are 79% and 63%, respectively.1 These data, fest by the development of new regional wall motion abnor-taken from the Registry of the International Society of Heart malities; angina is not a usual clinical presentation because ofand Lung Transplantation, suggest that median survival is the denervated heart.approximately 8.8 years when one takes into account early • Finally, an occasional patient will present with advancedpost-operative mortality. For those surviving the ﬁrst year of graft failure, no coronary disease, and absent histologicaltransplantation, subsequent projected median survival changes. The etiology of such rejection remains controversial,increases to 11.5 years.1 After the ﬁrst year, the average annual but is termed “acute humoral” or “acute vascular” rejection.mortality rate is about 4%. Cardiac transplantation atRisk factors for poor outcome following cardiac Brigham and Women’s Hospitaltransplantation The overall results of cardiac transplantation at Brigham and There are a number of recipient risk factors for cardiac Women’s Hospital are shown in Figure 1. These compare favor-transplantation that have consistently demonstrated an adverse ably to the national standards. The one-year survival is 85.5%;prognosis after transplantation. These variables include the three-year survival is 80.5%. Figure 1 also demonstratesneed for mechanical support with left ventricular assist improved survival with newer immunosuppressive protocolsdevices, respiratory ventilator support at the time of trans- paralleling national outcomes data. The incidence of post-trans-plant, retransplantation, and most importantly, increasing plant morbidities at BWH is similar to national standards.recipient age.1 There is some evidence that suggests that Despite similar outcomes, same selection techniques forfemale recipients and the initial diagnosis of CAD become donor and recipient, and virtually identical immunosuppres-additional risk factors for reduced long-term success. Donor sive regimens when compared to other large programs, therisk factors that have been consistently identiﬁed include incidence of both rejection and infectious complications fol-longer ischemic time of the donated organ, an increasing lowing cardiac transplantation at BWH is signiﬁcantly lessdonor’s age, and donor’s gender; a female heart transplanted than projected by analysis of CTRD data. This is summarizedinto a female recipient may perhaps have an adverse long- in Figure 2. The overall incidence of rejection is one-half thatterm prognosis.1 of national standards. With less treated rejection and hence less immunosuppression, it follows that there will be fewerPost-transplantation morbidity infectious complications. We suspect that the primary expla- Major morbidities following cardiac transplantation nation for the lower reduced rate of rejection and subsequentinclude infection, hypertension, and renal dysfunction, all infection complications relates to the expertise of our pathol-often the consequence of immunosuppressive therapies. ogy colleagues in differentiating between ischemic injury andHypertension often requires multiple pharmacologic thera- acute cellular rejection. Such differentiation is often subtle,pies, and renal dysfunction is clinically signiﬁcant in approxi- and many times missed by less experienced pathologists.mately 25% of patients, with 2 to 5% of patients ultimately Believing that much of the early histologic changes are relatedrequiring dialysis. Hyperlipidemia and glucose intolerance are more to ischemic injury rather than to acute cellular rejection,signiﬁcant medical problems that require ongoing medical the program at BWH has been generally reluctant to providecare.1 “over immunosuppression” to its patient population. Survival Post-transplant malignancies represent a signiﬁcant has not been compromised by this more conservativeongoing risk to all patients following heart transplantation. approach, and long-term morbidity seems the same. However,
Figure 1: Survival following cardiac transplantation in two Figure 2: Comparison of incidence of rejection and infec- different eras of immunosuppression. tious complications between BWH program and 1– national standards. 0.9 – Kaplan-Meier survival of heart transplant 2– Rejection and infection Survival distribution function patients in BWH January 1990-December 1998 0.8 – 0.7 – n = 293 1.5 – Cumulative episodes p < 0.0001 0.6 – 0.5 – p < 0.005 p < 0.0001 0.4 – 1– p < 0.0001 0.3 – n = 103 0.2 – Treatment 1984-1989 p < 0.0001 Treatment 1990-1999 Rejection (CTRD) 0.5 – 0.1 – Infection (CTRD) Rejection (BWH) 0– Infection (BWH) 0 2 4 6 8 10 12 14 16 18 Survival post transplant (years) 0– 0 1 2 3 4 5 6 7 8 9 Years after transplantthis conservative approach to biopsy interpretation andimmunosuppression seems justiﬁed, with fewer infectious common with prior pregnancy, multiple transfusions, or priorcomplications encountered. This variance in the incidence transplantation.of rejection also implies that other transplantation programs In the new era of left ventricular assist devices (LVAD),may “over-immunosuppress” their patients in the early HLA sensitization may emerge as a signiﬁcant clinicalyears following surgery, predisposing them to infectious dilemma.6 Because LVAD patients often require multiple bloodcomplications. transfusions that will include platelets as well as plasma, these patients often develop high PRA activities while subsequentlyClinical dilemmas of heart transplantation awaiting transplantation. Moreover, LVADs may generateHLA matching cross-reactive antibodies to HLA molecules by activation of Matching for the HLA locus is well-established in the inﬂammatory response.6 Fifteen per cent of patients whocadaver renal transplantation and serves as one means of allo- required LVAD prior to transplantation at BWH neededcating kidney donations. In the heart transplant population, prospective cross-matching because of high PRA, compared tothree or more HLA mismatches is associated with more rejec- only 2% of the patients who did not require such support; 2 oftion, the primary beneﬁt to an HLA match may be at the A the patients with LVADs were nearly 100% sensitized. Theand DR loci.2, 3 However, as opposed to renal transplantation, dilemma is obvious; growing numbers of patients with anprospective HLA crossmatching continues to be impossible in LVAD will generate a large group of sensitized patients thatthe heart transplant community, primarily because of the very will have more limited opportunities for ﬁnding suitablelimited donor supply, the acuity of the recipient’s illness, and donors despite their dependence on the LVAD for survival.limited geographic distribution for organs imposed by current Therapeutic modalities to reduce pretransplant PRAtissue preservation techniques. levels remain speculative.7 Some studies have utilized preop- The panel reactive antibody screen (PRA) is used to erative immunosuppression, including cyclophosphamide ordetermine humoral sensitization to a common panel of HLA steroids, as a means of lowering PRA activity. Other investi-antigens. Such PRA screening, conducted prior to listing for gators have incorporated low dose total body lymphoid radia-transplantation and during the waiting period, begins to deﬁne tion, plasmapheresis, or gamma globulin. The long-termthe immunologic status of the recipient. For example, a poten- outcomes with such approaches are unknown.tial recipient with a PRA greater than 25% is an individualwho has been sensitized to greater than 25% of HLA antigens Nuances of immunosuppressive therapyin a randomly selected population. This individual will need a It is beyond the scope of this limited review to providecross-match with any identiﬁed donor before transplantation all the clinical nuances of immunosuppressive therapy.can be performed. Positive cross-matches are to be avoided, as However, there are several important clinical considerationsthey are associated with a high likelihood for acute rejection. regarding induction and maintenance therapy that areThe presence of a retrospective positive cross-match is a pre- deserving of mention.dictor for hyperacute rejection, although such a rejection Induction therapy: The choices of induction therapy inprocess is not always related to PRA activity.4,5 Perhaps most the year 2000 include steroid therapy, OKT3 antibodyimportantly, patients who develop new anti-donor HLA anti- directed against the CD3 T-cell complex, the use of an antithy-bodies after transplantation are patients who are predisposed mocyte (polyclonal), antilymphocyte serum, or an Interleukin-to hyperacute rejection and may require intensive immuno- 2 receptor antibody. Solumedrol induction therapy is standard,suppressive therapy. A high degree of PRA sensitization is and the rationale for the addition of other induction therapy is
that both the number of rejections and complications of Figure 3: Comparison of survival of patients with-immunosuppressive therapy will be reduced. But such drawn from steroid immunosuppression to those on conventional triple drug therapy.additional induction therapy has many drawbacks thathave to be balanced in any ﬁnal decision. Kaplan-Meier survival The use of OKT3 monoclonal therapy is associated 1– n = 23with a cytokine release syndrome, manifested by fever, Survival distribution function 0.9 – p = 0.02chills, and non-cardiogenic pulmonary edema that may 0.8 –appear very early following its administration. This 0.7 – n = 270requires pretreatment with high-dose steroids, as well as 0.6 –antihistamines. In addition, induction therapy with OKT3 0.5 –monoclonal therapy may induce antimurine antibodies 0.4 –that precludes or limits the use of OKT3 for severe rejec- 0.3 –tions in the future. Finally, the incidence of post-trans- 0.2 – Steroid-free patientsplant lymphoproliferative disease may be higher in 0.1 – Treatment 1990-1999patients who receive OKT3 induction therapy,8 the inci- 0– 0 2 4 6 8 10 12dence of acute “vascular” rejection may be higher, and Survival post transplant (years)the incidence of signiﬁcant CMV infection is certainlyenhanced. Because of this, induction therapy with OKT3 agents, and unknown effect on allograft coronaryis usually only considered in patients who have signiﬁ- artery disease.cant contraindications to conventional immunosuppres- For patients deemed at low risk for rejection,sive therapy; renal dysfunction that limits the ability to approximately one-half should be successfully weanedstart cyclosporine is perhaps the single most important from daily prednisone therapy. It is interesting to noteindication for a brief course of OKT3 induction therapy.9 that the subsequent survival of such selected patients Experience with IL2 receptor antibodies and mono- may be superior to patients who require triple therapy.11clonal therapy directed against various T-cell ligands are The survival of patients at BWH with and withoutmuch more limited in the heart transplant population, but steroids is shown in Figure 3. Individuals who have beenthe initial results are promising.10 successfully weaned from steroids may be an “immuno- Chronic rejection therapy: There are general clini- logically” preferred patient population, predisposed tocal characteristics that deﬁne the recipient population fewer rejection episodes and hence, a better survival. Thepredisposed to higher risk for acute cellular rejection. improved survival in these patients may have less to doThese characteristics include the younger patient, the with their immunosuppressive regimen (ie, less steroid-multiparous female, patients with active myocarditis, related morbidities) and more to do with their own intrin-individuals with positive cross-match, and the rare sic ability to accept a transplanted organ.patient following retransplantation. With each individual Cyclosporine: Cyclosporine remains an importantrecipient, immunosuppressive regimens are tailored to immunosuppressive agent in virtually all patients follow-their needs. The predisposition to acute rejection, the ing heart translation. The mechanisms of action ofpatient’s serial endomyocardial biopsy, response to cyclosporine are multiple and complicated. Much clini-therapy, and the morbidity of such therapy, are all taken cal data suggests that cyclosporine primarily reduces theinto account in developing an individual long-term main- severity of rejection episodes rather than preventing thetenance program. rejection process. Patients who reject on cyclosporine Corticosteroids: The administration of solume- therapy usually have early histologic changes that are notdrol therapy at the time of surgery remains the cor- associated with hemodynamic compromise. Thesenerstone of initial immunosuppression following changes can usually be addressed with modest changesheart transplantation, and is tapered rapidly over the in immunosuppressive regimens. The primary toxicity ofsubsequent six months to low maintenance dose, cyclosporine includes nephrotoxicity, neurotoxicity, gin-prednisone 0.1 mg/kg. In the past 5 years, many gival hyperplasia, and hirsutism.centers have developed protocols to wean patients Azathioprine: Azathioprine is the third componentfrom corticosteroid administration completely. Justi- to conventional triple immunosuppressive therapy. Byfication for this includes avoidance of steroid- inhibiting DNA synthesis, it suppresses activated T andinduced morbidities, hypertension, diabetes, osteo- B cells. It is usually adjusted to reduce the white count toporosis, obesity and infectious complications that are 3000-5000 cells/mm.3 Hepatotoxicity is rarely encoun-the most common side effects. Disadvantages of a tered with its judicious use.steroid-free regimen might include more risk of Mycophenolate mofetil: Mycophenolate mofetilrejections, the need for more biopsies, meticulous inhibits guanine synthesis, with subsequent depletion ofcompliance with the remaining immunosuppressive guanine molecules. Since proliferating lymphocytes are
fully dependent upon such synthesis, mycophenolate Allograft coronary artery diseasemofetil is a speciﬁc lymphocyte inhibitor. A recent, large,randomized study reports that mycophenolate mofetil Allograft coronary artery disease remains one of thecan be substituted for azathioprine, with reduced rejec- major dilemmas following cardiac transplantation. Thistion rates, perhaps improved survival, but a slightly diffuse arteriopathy represents the major morbidity tohigher incidence of a CMV infectious complications.12 over 35% of patients following heart transplantation. ItsBecause of this, mycophenolate mofetil is currently used clinical presentation is often subtle, for high-grade prox-as a replacement drug for azathioprine in patients who imal obstructive disease is often not visualized on con-are intolerant of azathioprine or have persistent rejection. ventional arteriograms until it is far advanced. Rarely, Tacrolimus: Tacrolimus likewise inhibits T-cell pro- occlusive arterial damage may be visualized on endomy-liferation and suppresses the antibody response to T-cell ocardial biopsy. Scintographic studies are usually of littlemediated antigens. There is some clinical evidence to incremental help given the global nature of the arterialsuggest that it is superior to cyclosporine in the pediatric process and the absence of regional variation to coronarypopulation, with fewer long-term side effects in this pop- blood ﬂow. Moreover, in patients who have advancedulation. In the adult population, it is currently utilized in allograft coronary artery disease, systolic function maythose patients who have persistent rejection or have intol- be well-preserved until the ﬁnal stages of advancederable side effects (ie, gingival hyperplasia) to disease; its clinical presentation is often explained bycyclosporine therapy.13, 14 Nephrotoxicity to tacrolimus diastolic abnormalities with symptoms of dyspnea, highcontinues to be an ongoing dilemma, and is comparable right and left heart diastolic ﬁlling pressures, but normalto cyclosporine. systolic function. High dose nitrates are often effective Rapamycin: Rapamycin is a newer immunosuppres- therapy for this population.sive agent of great promise. It inhibits cyclosporine resistant Recent clinical observations suggest that the use ofT-cell and B-cell stimulation. It inhibits B-cell immunoglob- HMG-CoA reductase inhibitors may prevent or delay theulin synthesis, and also inhibits ﬁbroblast growth factors. It evolution of allograft coronary artery disease. Initial studiesis this action that may deﬁne the role of rapamycin in the with pravastatin reported a reduction in both intimal thick-prevention of allograft coronary artery disease. Comparative ness and intimal index as determined by intravascular ultra-clinical studies are currently underway. sound when compared to control patients.17 A more recent Biopsy interpretation: There are many considera- study not only conﬁrms a reduction in intimal thickeningtions in the decision to treat histological rejection. The and index with HMG CoA reductase inhibitors, but alsoclinician must take into account not only the histologic suggests that survival of patients is improved and that thisgrade of rejection, but also how many biopsy samples therapy is associated with less angiographic coronary arteryshowed such rejection, the levels of histologic change disease and a trend towards reduced episodes of histologicthrough each sample, objective changes in cardiac func- rejection.18 These preliminary observations suggest thattion, and responses to prior therapy. HMG-CoA reductase inhibitors have profound and multi- Acute vascular rejection: Perhaps the greatest chal- ple effects following heart transplantation. There arelenge to treating rejection is seen in patients who have several potential explanations for such pharmacologicminimal or absent histologic changes, but unexplained effect, including their impact on LDL, anti-inﬂammatorylow cardiac output, unexplained increase in left ventricu- actions, potentiation of cyclosporine effect by increasinglar wall thickness, new regional wall motion abnormali- levels, and blocking Interleukin 2 synthesis. These prelimi-ties, all occurring in the absence of allograft coronary nary clinical observations are fertile ground for additionalartery disease. This acute rejection process has been translational research between basic investigative protocolstermed “acute vascular rejection,” for traditional histo- and clinical outcomes.logical markers of lymphocytic inﬁltrate and myocytenecrosis are absent. It is hypothesized that this rejection Retransplantationprocess is secondary to antibodies to the donor HLA Heart transplant specialists continue to be reluctantclass II antigens,15 and may be more frequently observed to consider retransplantation in a group of patients whoin patients who have received OKT3 induction therapy.16 redevelop severe heart failure, usually as a consequenceFortunately, such rejection is relatively rare, occurring in of chronic rejection. Such patients have traditionally2-4% of transplant recipients. Treatment of acute vascu- been considered to have a more limited prognosis withlar rejection remains problematic. It may well respond to retransplantation, prone to more rejections, infection, andmonoclonal or polyclonal therapy, plasmapheresis, total a higher incidence of allograft coronary artery disease.body lymphoid radiation, or photopheresis. Randomized, They pose an additional ethical dilemma since they havemulticenter studies assessing the therapeutic efﬁcacy of already been the recipient of a donor organ. Given theeach of these forms of therapy remains difﬁcult to orga- limitations to the number of donated organs, reluctancenize given its rare presentation and rapid clinical decline. to retransplant has been considered reasonable.