American Journal of Transplantation 2008; 8: 1769–1774Wiley Periodicals Inc.

C© 2008 The AuthorsJournal compilation C© 2008 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2008.02310.xSpecial Article

Twenty-Year Survivors of Heart Transplantationat Stanford University

T. Deusea,∗, F. Haddadb, M. Phamb, S. Huntb,

H. Valantineb, M. J. Batesa, H. R. Mallidia,

P. E. Oyera, R. C. Robbinsa and B. A. Reitza

aDepartment of Cardiothoracic Surgery and bDepartmentof Cardiothoracic Medicine, Stanford University School ofMedicine, Stanford, CA∗Corresponding author: Tobias Deuse,deuse@stanford.edu

Human heart transplantation started 40 years ago.Medical records of all cardiac transplants performedat Stanford were reviewed. A total of 1446 heart trans-plantations have been performed between January1968 and December 2007 with an increase of 1-yearsurvival from 43.1% to 90.2%. Sixty patients who weretransplanted between 1968 and 1987 were identifiedwho survived at least 20 years. Twenty-year survivorshad a mean age at transplant of 29.4 ± 13.6 years.Rejection-free and infection-free 1-year survivals were14.3% and 18.8%, respectively. At their last follow-up,86.7% of long-term survivors were treated for hyper-tension, 28.3% showed chronic renal dysfunction, 6.7%required hemodialysis, 10% were status postkidneytransplantation, 13.3% were treated for diabetes mel-litus, 36.7% had a history of malignancy and 43.3% hadevidence of allograft vasculopathy. The half-life condi-tional on survival to 20 years was 28.1 years. Elevenpatients received a second heart transplant after11.9 ± 8.0 years. The most common causes of deathwere allograft vasculopathy (56.3%) and nonlym-phoid malignancy (25.0%). Twenty-year survival wasachieved in 12.5% of patients transplanted before 1988.Although still associated with considerable morbidity,long-term survival is expected to occur at much higherrates in the future due to major advances in the fieldover the past decade.

Key words: Heart transplantation, long-term graft sur-vival, morbidity

Received 21 March 2008 and accepted for publication03 May 2008

Introduction

Data from the International Society for Heart and LungTransplantation (ISHLT) database show that the transplanthalf-life for adult and pediatric heart recipients is currently

10 years, with a conditional half-life of 13 years for thosesurviving the first year. Perioperative and 1-year survivalhas dramatically improved over the years due to major im-provements in both diagnosis and treatment of graft dys-function, rejection and infection. However, allograft vas-culopathy, late graft failure and malignancies, amongstother causes, continue to decrease survival after the firstyear at an apparently linear rate of approximately 3.4%per year and preclude routine long-term success of hearttransplantation (1).

Stanford University is looking back on 4 decades of hearttransplantation since the first human cardiac transplant op-eration at Stanford was performed on January 6, 1968(2) and it is the only center with a continuously activeheart transplant program ever since (3). We here reportthe characteristics of long-term survivors beyond 20 yearsafter heart transplantation, of which many are among thelongest living heart transplant recipients ever.

Materials and Methods

Patients

The Stanford Transplant Database and medical records of all cardiac trans-plants performed at Stanford University Medical Center from 1968 to 1987were reviewed. Pediatric and adult patients were included.

Operative technique

Donor hearts were arrested using simple topical hypothermia (4) or werepreserved with cold hyperkalemic crystalloid Stanford cardioplegic solu-tion and stored in cold saline solution during transportation. Implantationwas performed according to the biatrial technique developed by Lower andShumway (5).

Immunosuppression

From 1968 to December 1980, patients received azathioprine (1–3 mg/kg),prednisone (1 mg/kg) and polyclonal rabbit antithymocyte globulin (RATG)(Stanford). Thereafter, cyclosporine (CsA) was introduced and became themainstay of immunosuppressive therapy. Polyclonal RATG or polyclonalhorse antithymocyte globulin (ATGAM, Upjohn Co, Kalamazoo, MI) wasused for induction therapy until June 1987 and was then replaced by themonoclonal antibody OKT3 (Ortho Pharmaceutical Corp, Raritan, NJ). Withthe evolution of newer immunosuppressive agents, patient regimens weremodified during follow-up visits and switched to tacrolimus, mycophenolatemofetil (MMF) or sirolimus, as appropriate. Routine cytomegalovirus (CMV)prophylaxis with gancyclovir, diltiazem and lipid-lowering agents were notused in this early patient population.

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CsA target levels were 150–250 ng/mL within the first 12 weeks after trans-plantation and 100–150 ng/mL thereafter. After 5 years, target CsA concen-trations of approximately 100 ng/mL were used (6).

Follow-up

Patients have been closely followed by the Stanford posttransplant cardi-ologists together with the patients’ primary care physicians. Graft functionand rejection was monitored by endomyocardial biopsy (EMB) since 1972(7) and echocardiography since 1987 (8). Right and left heart catheteriza-tion, coronary angiography, and more recently, intravascular coronary ultra-sonography (IVUS) was additionally used to assess hemodynamic parame-ters and allograft vasculopathy. No long-term surviving patient was lost tofollow-up. The incidence of death, rejection requiring steroid pulse therapy,infection, allograft vasculopathy, lymphoid and nonlymphoid malignancy hasbeen recorded in most (>90%) of the patients.

Statistical analysis

Results are shown as mean ± standard deviation. Survival analysis wasperformed using the Kaplan–Meier method. Independent t-test and v 2-test was utilized to compare numeric and categorical variables betweentwo groups, respectively. Statistical significance was defined as a p value<0.05.

Results

Survival after heart transplantation

Between January 1968 and December 2007, a total of 1446heart transplantations have been performed at StanfordUniversity. Cumulative survival after heart transplantationcontinuously improved with every successive 5-year period(Figure 1). Until December 1987, 524 heart transplantationshave been performed in 479 patients of which 43 patientsreceived a second and two patients a third graft. Sixty pa-tients survived 20 years or more and are summarized in thisarticle. Survival of these 60 patients who survived a min-imum of 20 years is shown in Figure 1B. The conditionalhalf-life in this patient population was 28.1 years. The 16

Figure 1: (A) This part shows the cumulative survival of all heart transplant recipients at Stanford University over the 40-year

period, broken down into 5-year intervals. The cumulative survival continuously improved with every successive 5-year period. (B)This part presents the survival after heart transplantation conditional on survival to 20 years. The conditional half-life in this population of60 patients was 27.1 years. The improvements of the 1-, 5-, 10- and 20-year survivals over the 40-year period are depicted in (C).

deaths in these long-term survivors were related to allo-graft vasculopathy (n = 9), nonlymphoid malignancy (n =4), infection (n = 1), lymphoma (n = 1) and multiorgan fail-ure with infection and dialysis after severe kidney allograftrejection (n = 1).

Patient demographics of long-term survivors

The diagnoses leading to heart transplantation in the 60long-term survivors are shown in Figure 2A. Forty-eightpatients were male and 12 female. The mean BMI was22.2 ± 10.7. The mean age at transplant was 29.4 ± 13.6years and the age distribution is depicted in Figure 2B.Twelve patients (20%) had previous heart surgery and twopatients (3.3%) had previous thoracotomy. The mean wait-ing time to transplant was 32 ± 36 days. Eleven patientsreceived a second heart transplant 11.9 ± 8.0 years af-ter their initial transplant. The 45 adult long-term survivorswere significantly younger (35.0 ± 10.5 years) than the 391patients receiving their heart transplant during the sametime period and living less than 20 years, who were 43.1± 9.5 years of age (p < 0.001). Among adult long-termsurvivors, the underlying disease was significantly moreoften cardiomyopathy and significantly less frequent coro-nary artery disease compared to non-long-term survivors(p = 0.046).

Donor characteristics and transplant operation

The donors had a mean age of 21.7 ± 8.0 years, rangingfrom 0.4 to 44 years of age. The most common causes ofdeath were motor vehicle or motorcycle accidents (55%),gun-shot wounds (17%), bike accidents (7%), head trauma(7%), anoxia (5%), cerebrovascular accident (3%) and oth-ers (6%). The gender match was male → male (n = 41),female → male (n = 7), male → female (n = 6) andfemale → female (n = 6). The mean cardiopulmonary by-pass time was 113 ± 48 min, the mean ischemic time for

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Twenty-Year Survivors of Heart Transplantation

Figure 2: The diagnoses (A) and age groups (B) of the 60 long-term survivors after heart transplantation are presented.

the graft was 138 ± 74 min, and the mean hospital staywas 35.7 ± 17.1 days. No significant difference was foundfor donor age comparing adult long-term survivors (22.8 ±7.1 years) and non-long-term survivors (24.2 ± 7.5 years;p = 0.21). Also, the percentages of female donors for malerecipients were not significantly different between adultlong-term survivors (11.1%) and non-long-term survivors(14.8%; p = 0.66).

HLA matching

Only HLA-A and HLA-B loci were typed before 1990,and thus, a maximum of four matches were possible. In14 cases, HLA matching had either not been performed

Figure 3: Shown is the rejection-free overall survival and the

rejection-free 1-year survival (inset) for the 60 long-term sur-

vivors who lived more than 20 years after heart transplanta-

tion.

or was not reported. Sixteen patients had no HLA match,21 patients had one match and nine patients had twomatches. There were no patients with three or four HLAmatches.

Rejection

Rejection-free 1-year and overall survival are depicted inFigure 3. In total, the patients experienced a mean of3.6 ± 2.7 rejection episodes requiring hospitalization andtreatment.

Infection

The most common infections within the first 90 days aftertransplant were viral (46.7%), usually oral herpes simplexvirus (HSV) infections (24.4%) and CMV infections (17.8%).Bacterial infections (44.4%) most frequently affected theurinary tract, the lung or the bowel. Fungal infections wererare (6.7%). Later infections could be attributed to a similarextent to viral (49.1%) and bacterial pathogens (39.6%).Infection-free 1-year and overall survival are shown inFigure 4.

Morbidity at last follow-up

Hypertension requiring medical treatment was present in52 patients (86.7%). Chronic renal dysfunction with a base-line plasma creatinine level ≥1.5 mg/dl was found in 17long-term survivors (28.3%), another four patients (6.7%)required hemodialysis and six patients (10%) were statuspost kidney transplantation. Only eight (13.3%) patientswere treated for diabetes mellitus. Bradycardia and heartblock was treated with pacer implantation in eight (13.3%)patients.

Most recent immunosuppressive regimen

The immunosuppressive therapy after 20 years was un-available in eight patients (13.3%). In four of 11 patients

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Figure 4: The infection-free overall survival and the infection-

free 1-year survival (inset) for the long-term survivors is pre-

sented.

of the pre-CsA era with reported follow-ups, a calcineurininhibitor (CsA in three cases and tacrolimus in one) wasadded to the regimen over the years, whereas, seven pa-tients remained on azathioprine and prednisone.

Seven (17.1%) of 41 patients of the CsA era were switchedto tacrolimus for CsA-side effects or rejection and 34 pa-tients (82.9%) remained on CsA. No patient was switchedfrom a CsA-based to a calcineurin inhibitor-free regi-men. Azathioprine was still used in 13 patients. MMFand sirolimus were used as second immunosuppressiveagents in 17 and 5 patients, respectively, mainly if allograftvasculopathy was present. Twenty-eight patients (68.3%)remained on low-dose steroids of less than 5 mg/day, mostof these because of prolonged complaints of generalized,possibly Addisonian, weakness after complete withdrawalof corticosteroids that resolved when small doses werereintroduced.

Malignancy

Twenty-two patients (36.7%) developed some kind of ma-lignancy over the years. The most common type was skincancer (n = 15), which was diagnosed a mean of 7.8 ±7.6 years after transplantation and was the cause of deathin one patient after 20.5 years. The second most commonmalignancy was lymphoma (n = 3). All three patients werediagnosed early (2.0 ± 2.9 years after transplant) and onepatient died of lymphoma after 21.5 years. One of the twopatients diagnosed with posttransplant colorectal cancerdied after 22.4 years. Prostate and parotid cancer werethe cause of death after 20.2 and 22.4 years in one patienteach.

Allograft vasculopathy

Of the 43 patients with coronary angiography available forreview, allograft vasculopathy was absent angiographicallyin 17 patients, was mild in four patients and advanced in22. Nine of the 16 deaths in this patient population werecaused by allograft vasculopathy. Seventeen (28.3%) of thelong-term survivors did not undergo coronary angiographyand/or intravascular ultrasound for vasculopathy workup forat least 10 years because of lack of clinical suspicion ormarginal renal function.

Discussion

The era of human heart transplantation now spans a pe-riod of 4 decades, over which newly gained immuno-logic knowledge and the implementation of more selectiveimmunosuppressive strategies have made clinical hearttransplantation an established ‘curative’ treatment for endstage heart disease, and the work is still in progress.

Management of heart transplant patients before 1988

During the early phase of the program at Stanford, immuno-suppressive regimens included azathioprine and steroids,drugs that were already in use for kidney transplantationat that time (9). However, reliable diagnostic tools for cel-lular rejection were unavailable, which made the dosingof immunosuppression a challenge. The inevitable over-and underimmunosuppression led to relatively high inci-dences of death from infection and rejection (10). The firstheart transplant recipient at Stanford lived for 15 days anddied of bacterial pneumonia and sepsis (11). A total of 19more heart transplant procedures were performed in 18patients within the following 2 years. A total of 29 seriousand 5 minor infectious episodes occurred in these patients,four eventuating in death (12). The first recipients that livedlonger than 1, 3 or 5 years after transplant were patient no.4, 7 and 14 and the 19th patient already lived more than 21years and was the first long-term survivor.

Major advances in the field of heart transplantation oc-curred in the 1970s. The implementation of EMB in July1972 established an objective method for studying cardiachistopathology and diagnosing cellular rejection in living pa-tients (7). The 45th transplant recipient was the first toundergo EMB and histology confirmed the clinical suspi-cion of severe acute rejection. EMB was applied routinelythereafter. A major step forward in providing an increasednumber of donors was the introduction of distant heartprocurement, which was first performed in 1973 for the62nd heart transplant recipient and became routine in mid-1977 (13). Equine antithymocyte globulin, available since1970, was replaced by the more potent RATG in 1973,starting with the 65th Stanford transplant recipient (14).Introduction of RATG significantly reduced hospital stay,decreased the frequency of rejection and improved 1-yearsurvival from 41% to 66% (14). The 75th patient was thefirst pediatric heart transplant at Stanford. He received his

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transplant in August 1974 and lived for more than 11 years(15). Brain death was legally defined in California in 1974and minimized legal problems with organ procurement(13). A total of 219 heart transplants in 200 patients hadbeen performed before the first patient received a CsA-based immunosuppression in December 1980. Fifteen pa-tients (7.5%) transplanted in the pre-CsA era became long-term survivors and lived for more than 20 years. The 1-yearsurvival for patients transplanted within the first 2 years af-ter introduction of CsA significantly improved from 62.5%to 81.6% compared to patients who received their trans-planted up to 2 years earlier. The monoclonal anti-CD3 anti-body OKT3 was initiated in mid-1987 in the 450th recipientand significantly reduced hospital stay and rejection ratesin the following year (16).

Predictors and patient characteristics of long-term

survivors

The overall adult patient population between 1968 and1987 was significantly different from our current patientsin terms of age. Whereas the 2007 ISHLT report presenteda mean recipient age of 50.7 ± 12.5 years between 2004and 2006 (1), the early patients at Stanford were younger(42.2 ± 9.9 years). The donors were also younger in thefirst 2 decades (24.1 ± 7.4 years) compared to today(33.5 ± 13.0 years) (1). However, the diagnoses leadingto heart transplantation now and then were similar, withCAD and cardiomyopathy each accounting for 40–45% (1).

Age and diagnosis have been identified by the ISHLT as riskfactors for mortality within 15 years (1). Accordingly, theadult 20-year survivors at our institution were significantlyyounger and more frequently transplanted for cardiomy-opathy than recipients that died within 20 years. However,donor age and the percentage of female donors for malerecipients, although found to be further risk factors (1),were equally distributed among long-term and non-long-term survivors in this study. Importantly, the risk stratifica-tion reported by the ISHLT includes only patients who weretransplanted after 1987 and may therefore not be accuratefor previous eras.

The 20-year survivors reported today have been trans-planted before 1987 and 15 of these patients were eventransplanted in the pre-CsA era. These patients were notscreened for antibody sensitization preoperatively and re-ceived immunosuppression with azathioprine and steroidsonly and these had to be dosed according to the clinical pic-ture given the lack of immune assays or drug levels. Theydid not get CMV prophylaxis with ganciclovir (introducedin 1989 (17)), nor diltiazem (used since 1990 (18)) or lipid-lowering agents to reduce allograft vasculopathy (startedin 1993 (19)), nor fungal prophylaxis with inhaled ampho-tericin B during inpatient stays (introduced mid-1993 (20).Hence, the infection-free 1-year survival rates of all hearttransplant patients at Stanford in the pre-CsA and CsA eras,until 1987, were as low as 16% and 21%, respectively (21).The rejection-free 1-year survival rates during these periods

were 11% and 10% (21). Among the patients who becamelong-term survivors, only 18.3% did not get an infectionand only 13.3% did not have a rejection episode within thefirst year after transplantation. The long-term success inthese patients would therefore not have been obvious inthe early posttransplantat period.

An increasing number of HLA mismatches between donorand recipient has been shown to impair recipient survival(22). However, although HLA typing was only incompletelyreported in this series, our data show that the number ofHLA matches in our long-term survivors were not higherthan average (1).

Morbidity

Long-term survival is accompanied by long-term exposureto immunosuppressants and associated with considerablemorbidity. Hypertension is among the most common sideeffects of calcineurin inhibitors (23). Hypertension is re-ported in 98.5% of CsA-treated patients in the ISHLTdatabase (1) and 83.8% of heart transplant recipients atStanford (24) after 10 years. The rate of hypertension in 20-year survivors in this report is 86.6%, and thus, similar tothe 10-year data at our institution. This lack of increase maybe because this report also includes patients who wereon a calcineurin inhibitor-free regimen with azathioprin andsteroids, which is associated with a lower rate of drug-related hypertension (25). The rate for chronic renal dys-function in our long-term survivors after 20 years (45.0%) ishigher than that reported by the ISHLT for 10-year survivors(38.7%) (1). Although less stringent immunosuppressionis used after 5–10 years, an ongoing nephrotoxic effectmust be assumed. Interestingly, all patients in this studywho were on hemodialysis or status post kidney trans-plantation at their last follow-up were in the de novo CsAtreatment group and no patient was from the pre-CsA era.Malignancies account for significant morbidity and mortal-ity in long-term heart transplant survivors, and they seemto be more frequent than in other solid organ transplantrecipients (26). Since the mean age at transplant is rising,more malignancies may be expected in older patients inthe future. However, evidence for anticancer effects ofmammalian Target of Rapamycin (mTOR) inhibitors raisethe possibility for new therapeutic strategies for the pre-vention and treatment of malignancies in clinical practice(27).

Pediatric patients

Fifteen (34.9%) of the 43 pediatric transplant recipients be-fore 1988 became long-term survivors >20 years and 12of these patients are still alive. These outcome data areencouraging and reflect the current ISHLT estimates forpediatric 20-year survival of 36.9% (28). Although allograftvasculopathy has been reported to be less prevalent in pe-diatric patients (29), we did not find a relevant differencebetween long-term survivors who were ≤18 years (fivepatients with severe and one with mild vasculopathy of

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15 pediatric transplants) compared to >18 years of age attransplant (17 patients with severe and 3 with mild vascu-lopathy of 45 adult transplants).

Conclusion

Entering the fifth decade of heart transplantation, oursingle-center outcome data show that survival rates haveimproved with every successive 5-year interval and thatthe slopes for 5-, 10- and 20-year survival over time con-tinue to improve. Due to significantly improved immuno-suppressive regimens and infectious prophylaxis and othertreatment options in the past decade, the long-term sur-vival rates are expected to rise in the future as the patientstransplanted in the 2000s reach their 10- or 20-year anniver-saries. Current research is dedicated to better understandthe molecular and immunologic mechanisms of host-graft-adaption which may offer better predictors of long-termsurvival and help to individualize treatment regimens.

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