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Background: The relationship between pre-transplant body weight and post-transplant outcome has only recently been identified using a single, indirect measure of weight (percent ideal body weight [PIBW]). The literature is equivocal regarding which index is the better indicator of body weight. The purpose of this study was to determine (1) if pre-heart transplant body weight, measured by body mass index (BMI) and PIBW, is associated with post-heart transplant morbidity and mortality and (2) if patient gender, age, and etiology of heart disease affect this association. Methods The sample included 4,515 patients who received a heart transplant from January 1, 1990–December 31, 1995 at 38 institutions participating in the Cardiac Transplant Research Database (CTRD). Patients were divided into groups according to their BMI and PIBW. Data were described using frequencies, measures of central tendency, Pearson correlation coefficients, stratified actuarial analyses and log rank tests for comparisons, and a multivariable risk factor analysis in the hazard domain. Results For all patients ( n = 4,515), being 140% of IBW before heart transplant was a risk factor for increased mortality after heart transplant. The association between pre-heart transplant PIBW and post-heart transplant survival was affected by gender, age, and etiology of heart disease. In males, a higher PIBW was a significant risk factor for death early after transplant ( p = .0003). Although not significant, there was a trend for a higher PIBW being a risk factor for death in females throughout the post transplant period ( p = .07). No differences in cause of death were found for PIBW and BMI. In male and female recipients 140% of IBW. Pre-heart transplant BMI and PIBW were not associated with acute rejection or cardiac allograft arteriopathy after transplant. Conclusions In conclusion, being cachectic or obese preoperatively is associated with decreased survival in all patients after heart transplantation. Being obese preoperatively is associated with increased infection after heart transplant in males and females

Background The utility of long-term endomyocardial biopsy surveillance in heart transplant recipients has been questioned. This study was undertaken to identify risk factors for late rejection and to examine the impact of different biopsy surveillance protocols on outcomes using the registry of the Cardiac Transplant Research Database. Methods The study group consisted of all adult patients who underwent heart transplantation at the 33 centers participating in this investigation between January 1, 1993 and January 1, 2002, survived past the second post-transplant year, and were followed-up by a defined surveillance biopsy protocol. Results During a follow-up that consisted of 24,137 patient-years, 1,626 late rejections occurred. Shorter time since transplant, history of rejection, younger age and African-American ethnicity of the recipient were strong risk factors for late rejection. The practice of surveillance biopsy varied among institutions. Continued surveillance increased the rate of diagnosis of late rejection (RR = 1.3, p = 0.002). There was no reduction in the incidence of hemodynamically compromising rejection and no increase in survival in patients with long-term vs intermediate-term surveillance. Short-term surveillance was associated with an increased incidence of hemodynamically compromising rejection, particularly among high-risk patients, and increased mortality in African-American patients. Conclusions There are no apparent benefits from surveillance biopsy beyond 5 years post-transplant. Surveillance biopsy between 2 and 5 years post-transplant was found to reduce mortality in African-American recipients. Non–African-American recipients at high risk for late rejection will likely benefit from surveillance up to 5 years post-transplant.

Previous studies have shown that skin allograft survival can be augmented by the administration of donor spleen or donor bone marrow in antithymocyte serum (ATS) treated recipients. Because natural killer cells (NK) have been reported to possess immunoregulatory properties, we investigated whether the ability of donor spleen or bone marrow cells to enhance allograft survival was dependent on the presence of donor NK cells.Recipient (C57BL/6 x A/J)F1 strain mice (H2 haplotypes Kb/k, Ab/k, E-/k, Db/d) were treated with ATS on days -1 and +2 relative transplantation of a C3H (H-2k) skin allograft. On day +7, each recipient was randomly assigned to one of the following groups that received i.v. donor C3H cell infusions via the tail vein: 1) 5.0x10(7) wild-type donor spleen cells (SPC); 2) 5.0x10(7) spleen cells from C3H/HeJ-Lystbg-2J/+ mice (commonly called beige mice and have selectively impaired NK cell function); 3) 2.5x10(7) wild-type donor bone marrow cells (BMC); 4) 2.5x10(7)beige C3H bone marrow cells; and 5) no donor cell infusion (ATS controls). In another experiment, each recipient was randomly assigned to one of the following groups that received injections of: 1) 4.75x10(7) spleen cells depleted of NK cells; 2) 2.5x10(6) purified splenic NK cells; 3) a coinfusion of 5.0x10(7) beige spleen cells and 2.5x10(6) purified wild-type splenic NK cells.Recipients infused with wild-type SPC exhibited significant augmentation of allograft survival compared with ATS controls. However, graft survival was reduced in recipients that were infused with spleen cells from beige mice compared with recipients infused with wild-type SPC (median survival time (MST): 38 vs. 92 days, P=0.02). In contrast, infusions of beige BMC augmented allograft survival as well as wild-type BMC (MST: 47 vs. 49 days, P=0.76). Furthermore, the ability of wild-type SPC to augment allograft survival was abrogated by the depletion of NK cells (MST=92 vs. 34 days, respectively, P=0.005). The co-infusion of beige SPC and purified splenic NK cells enhanced allograft survival as well as wild-type SPC (MST=56 days, P=0.65). Finally, recipients infused with purified NK cells did not experience increased graft survival compared to recipients that received no infusion (MST=29 vs. 33 days, respectively, P=0.6).Donor splenic NK cells are necessary, but not sufficient, for the extension of graft survival by infusion of donor splenocytes, suggesting that they may work in concert with another cell-type. In contrast, the extension of graft survival by donor bone marrow does not depend on the presence of donor NK cells.

Studies in animal models and patients have suggested that 31P-magnetic resonance spectroscopy (MRS) may be useful in diagnosing transplant rejection, but such studies often are confounded by the late inclusion of patients after transplantation. The present study examined the utility of 31P-MRS in the diagnosis of acute allograft rejection during the first posttransplant month. Thirteen recent heart transplant recipients underwent 57 resting 31P-MRS studies within 24 hr of a biopsy. Subjects lay supine with a 10-cm surface coil placed over the heart. A 1-dimensionsal chemical shift imaging protocol was used to collect spectral information. Spectra from the heart were weighted for distance from the coil and summed before analysis. ANOVA and Duncan's multiple range test were used to analyze the data comparing phosphocreatine (PCr)/ATP ratios with biopsy scores. Transplant patients had significantly lower myocardial PCr/ATP ratios when compared with a normal control group (1.27 +/- 0.27 versus 1.61 +/- 0.22, p0.001). However, when the patient group was classified by biopsy score, the expected order of score, 0123, was not obtained. Rather, the order was 2013. Although the difference between scores 2 and 3 was significant (1.46 versus 1.14, alpha = 0.05 level), the lower three groups were statistically indistinguishable. In addition, the PCr/ ATP ratios were not predictive of future biopsies. Although significantly lower than normal control subjects, resting myocardial PCr/ATP ratios of transplant subjects are not useful in assessing thelevel of rejection. It is suggested that the measurement may be more predictive in mildly exercised myocardium.

Our previous studies have shown that the ability of donor bone marrow to augment skin graft survival in antithymocyte serum (ATS)-treated recipients is dependent on the presence of functional CD95-ligand (Fas-ligand) molecules on donor cells. Because donor spleen cells can augment graft survival to a similar degree in the same model, we investigated whether the donor spleen cell effect was also dependent on the presence of CD95-ligand on donor cells and CD95 on recipient cells.Mutant mice bearing defects in the expression of CD95 (lpr mutation) and CD95-ligand (gld mutation) were used as recipients and cell donors, respectively. Recipients were injected with rabbit ATS on days -1 and +2, and then were injected with 5x10(7) spleen cells on day +7. Skin graft survival was compared and correlated with the use of mutant mice as recipients and cell donors.The combination of ATS and infusions of wild-type [median survival (MST)=44 days, P=0.0004] and gld (mutant CD95-ligand, MST=37 days, P=0.02) donor spleen cells enhanced C3H graft survival, compared with (C57BL/6 x A)F1 recipients treated with ATS alone (MST=27 days). Furthermore, C57BL/6 lpr (CD95-deficient) strain recipients treated with ATS and donor spleen cells demonstrated enhanced B10.D2(R107) strain skin graft survival (MST=44 days, P=0.003), compared with C57BL/6 lpr recipients treated with ATS alone (MST=31 days). Wild-type C57BL/6 recipients treated in the same manner also exhibited an extension of graft survival (MST=64 days) versus controls treated with ATS alone (MST=31 days).The data demonstrate that the ability of donor spleen cells to augment allograft survival is not dependent on the CD95/CD95-ligand pathway; therefore the deletion of allospecific cells by donor spleen cells may be induced via a pathway other than deletion by donor bone marrow cells.

Peritransplant treatment with antithymocyte serum (ATS) and posttransplantation administration of donor bone marrow or donor splenocytes results in extended skin allograft survival. In this study, we examined the molecular basis of the tolerance promoting effect of donor bone marrow (BMC) cells and splenocytes with emphasis on the role of CD8 expression on the donor cells.(C57BL/6J x A/J)F1 mice were treated on days -1 and +2 with ATS relative to transplantation with C3H/HeJ skin. On day +7, they were infused with CD8+ BMC, CD8- BMC, CD8+ splenocytes, or CD8- splenocyte donor subpopulations isolated by magnetic or fluorescence-based sorting. In additional experiments, B10.D2(R107) mice were treated in the same manner with C57BL/6 skin and BMC or splenocytes from C57BL/6 mice in which the CD8alpha gene had been inactivated.CD8+ donor bone marrow cells induced operational tolerance (defined as graft acceptance in the absence of chronic immunosuppression) in skin graft recipients at a dose that was reduced by 250-fold relative to unfractionated bone marrow cells (1.0x10(5) cells per recipient, median survival time (MST)=41 days vs. 2.5x10(7) cells per recipient, MST=49 days, P=0.40). Similarly, donor bone marrow cells from CD8 knockout mice did not promote graft acceptance (MST=98 days vs. animals not treated with bone marrow cells, MST=70 days, P=0.16). In contrast, the extension of graft survival by donor splenocytes did not require the presence of CD8+ donor cells because splenocytes depleted of CD8+ cells extended graft survival (MST=55 days) as well as unsorted splenocytes (44 days, P=0.2), and splenocytes from CD8 knockout animals (MST=145 days) extended graft survival at least as well as unsorted splenocytes (MST=74 days, P=0.4)These results suggest that the prolongation of graft survival by donor bone marrow is dependent on the presence of the CD8 molecule, whereas prolongation by donor splenocytes is not. Therefore, we suggest that the prolongation of graft survival by these cell types occurs via distinct molecular mechanisms probably mediated by different cell types.

The maximum sinus rate during exertion in humans is inversely related to age. However, the sinus rate at rest is quite variable. The intrinsic heart (IHR) following pharmacologic blockade of autonomic tone with propranolol and atropine has been proposed as a test of sinus node function and is related to age by the linear regression equation: IHR = 118.1 - (0.57 x age). Whether this relationship exists for transplanted hearts for which the donor sinus node is denervated has not been determined.The relationship between the resting heart rate and the age of the donor heart was examined in 103 patients 1 year following orthotopic cardiac transplantation in the absence of rejection or intercurrent illness. Patients receiving beta-blockers, calcium blockers, antiarrhythmic drugs, digitalis, theophylline, or with biopsy evidence of rejection or abnormal coronary arteriograms were excluded from analysis.The recipient age, left ventricular ejection fraction, pulmonary capillary pressure, cardiac index, donor heart ischemic time and cardiopulmonary bypass time did not correlate with the rate of the resting donor sinus node. The resting heart rate was inversely related to age of the donor heart by the linear regression equation: HR = 112.0 - (046 x age).The resting rate of the denervated sinus node is related to donor age with a regression equation that is similar, though slightly slower, than that predicted after pharmacologic autonomic blockade.

Controversy exists regarding donor and recipient factors that promote the development and progression of coronary artery disease after heart transplantation and the likelihood of coronary artery disease causing death or retransplantation.To investigate this issue in a large cohort of patients, we analyzed 5963 postoperative angiograms performed in 2609 of the 3837 patients undergoing heart transplantation at 39 institutions between January 1990 and December 1994. Coronary artery disease was classified as mild, moderate, or severe on the basis of left main involvement, primary vessel stenoses, and branch stenoses. Coronary artery disease was considered severe if left main stenosis was70% or 2 or more primary vessels stenoses were70% or branch stenoses were70% in all 3 systems.By the end of 5 years after heart transplantation, coronary artery disease was present in 42% of the patients, mild in 27%, moderate in 8%, and severe in 7%. Coronary artery disease-related events (death or retransplantation) had an actuarial incidence of 7% at 5 years and occurred in 2 of 3 of the patients with development of angiographically severe coronary artery disease. By multivariable logistic analysis, risk factors for donor coronary artery disease included older donor age (P.0001) and donor hypertension (P=.0002). By multivariable analysis in the hazard function domain, risk factors identified for the earlier onset of allograft coronary artery disease included older donor age (P.0001 ), donor male sex (P=.0006), donor hypertension (P=.07), recipient male sex (P=.02), and recipient black race (P=.01). The actuarial incidence of severe coronary artery disease was 9% at 5 years.Angiographic coronary artery disease is very common after heart transplantation, occurring in approximately 42% of the patients by 5 years. Older donor age, donor hypertension, and male donor or recipient predict earlier onset of angiographic allograft coronary artery disease. Although severe angiographic allograft coronary artery disease occurs in only 7% of the patients at 5 years, its presence is highly predictive of subsequent coronary artery disease-related events or retransplantation.

Pilots who have received a heart transplant may subsequently want to resume flying. This study was undertaken to determine whether a group of heart transplant recipients who had a particularly low risk of sudden unexpected death could be identified from clinical data. An event, "rapid-onset death," was defined incorporating a number of possible causes of death that could result in a heart transplant recipient-pilot losing control of an airplane. The survival of 3676 patients undergoing a first heart transplantation was 85% and 73% at 1 and 5 years, respectively, the hazard function having a high early phase of risk. When time zero was moved to the beginning of the second year after transplantation, the freedom from "rapid-onset death" at posttransplantation year 2 and posttransplantation year 5 was 96.8% and 88%, respectively. For patients who had both a "normal" coronary angiogram and no episodes of acute heart rejection during the first year transplantation, the probability of "rapid onset death" during the second posttransplantation year was 1.4%, and given the same circumstances, during the third posttransplantation year the risk of "rapid-onset death" was 1.6%. This information is potentially useful to the Federal Aviation Administration for policy decisions regarding this issue.

Detailed information regarding the spectrum and predictors of infection after heart transplantation in children is limited because of relatively small numbers of patients at any single institution. We therefore used combined data obtained from the Pediatric Heart Transplant Study Group to gain additional information regarding infectious complications in the pediatric population.To determine the time-related risk of infection and death related to infection in a large pediatric patient population, we analyzed data related to 332 pediatric patients (undergoing heart transplantation between January 1, 1993, and December 31, 1994) from 22 institutions in the Pediatric Heart Transplant Study Group.Among the 332 total patients, 276 infections were identified in 136 patients. Of those patients with development of infection, a single infection episode was reported in 54% of patients, 21% had two infections, and 25% had three or more infections. Of the 276 infections, 164 (60%) were bacterial, 51 (18%) were due to cytomegalovirus, 35 (13%) were other viral (noncytomegalovirus) infections, 19 (7%) were fungal, and 7 (2%) were protozoal. Bacterial infections were more common in infants younger than 6 months of age at time of transplantation, comprising 73% of all infections as compared with 49% in patients older than 6 months of age. The incidence of bacterial infection peaked during the first month after transplantation, with the actuarial likelihood of a bacterial infection among all patients reaching 25% at 2 months. The most common sites of bacterial infection were blood and lung (74% of bacterial infections). Cytomegalovirus accounted for 59% of viral infections, with a peak hazard occurring at 2 months after transplantation. Among all infections, cytomegalovirus was less common in infants younger than 6 months of age (8% of all infections) than in older patients (25%). By multivariate analysis, risk factors for early infection included younger recipient age (p = 0.05), mechanical ventilation at time of transplantation (p = 0.0002), positive donor cytomegalovirus serologic study result with negative recipient result (p = 0.004), and longer donor ischemic time (p = 0.04). The overall mortality rate from infection was 5%, with an actuarial freedom from death related to infection of 92% at 1 year after transplantation. The mortality rate was high in patients with fungal infections (52%), yet was low for those with cytomegalovirus infection (6%). Infections accounted for 27% of the overall mortality rate in infants younger than 6 months of age, compared with 16% for older patients.Although most infections in pediatric heart transplant recipients are successfully treated, infection remains an important cause of posttransplantation morbidity and death, especially in infants. Bacterial infections predominate within the first month after transplantation, whereas the peak hazard for viral infections occurs approximately 2 months after transplantation. Cytomegalovirus infections are common in the pediatric transplant population, but death related to cytomegalovirus is low.

The major limiting factor to successful heart transplantation in infants is the limited supply of donors. To examine the impact of donor limitations on survival after listing, a multiinstitutional study was designed to identify risk factors for death while waiting and for longer interval to transplantation.Between January 1 and December 31, 1993, 118 infants 6 months of age or younger (86 younger than 29 days) were listed for heart transplantation from 21 institutions. The primary diagnosis was hypoplastic left-sided heart syndrome (HLHS) in 70 (59%), other congenital defects in 32 (27%), cardiomyopathy or myocarditis in 13 (11%), and other diagnoses in 3. Among the 48 patients without HLHS, 32 (67%) required inotropic, mechanical, or prostaglandin support, whereas 16 (33%) did not.At 6 months after listing, only 6% remained on the list awaiting transplantation, 59% underwent transplantation. 31% died while waiting, and 4% were removed from the list. The greatest mortality rate before transplantation was among patients with HLHS in whom the actuarial mortality rate if they were unable to receive a transplant was 77% at 6 months, compared with 52% in patients without HLHS and without inotropic or mechanical support (p = 0.05). By multivariable analysis, risk factors for death while waiting included inotropic support (p = 0.02), smaller size (p = 0.0007), and blood type O (p = 0.003). Surgical procedures before listing did not significantly influence pretransplantation mortality rates. The interval from listing to transplantation increased with young age (p = 0.01) in patients without HLHS and smaller size (p = 0.001) and blood group O (p = 0.0006) for patients with HLHS. The effect of blood type O on mortality rates and longer interval to transplantation was due to the distribution of type O donor hearts to non-type O recipients. Palliative operations after listing did not favorably influence survival; nine patients underwent first-stage Norwood while waiting, and six died before transplantation.The mortality rate is unacceptably high among infants awaiting transplantation, particularly in patients with HLHS. Infants receiving intravenous inotropes or mechanical support at listing are at high risk of early death while waiting. The distribution of blood group O donors to non-blood group O recipients results in higher mortality rates among blood group O recipients. Greater emphasis should be placed on medical strategies to improve survival while waiting and on expanding existing graft resources.

Cardiac allograft rejection is largely an inflammatory response that, if allowed to proceed unchecked, will result in hemodynamic compromise or cardiogenic shock. Soluble mediators produced during an inflammatory response could potentially provide information regarding the initiation, progression, and outcome of a rejection episode. To test this hypothesis, we investigated the use of plasma cytokine measurements for interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF alpha) in combination with measurements of soluble vascular cell adhesion molecule-1 (VCAM-1), an adhesion molecule, as a means for the detection of cardiac allograft rejection.Serial enzyme-linked immunosorbent assays were performed on plasma samples collected from 29 patients three times per week during the first 8 weeks after transplantation.IL-6 plasma concentrations increased fivefold in the first week after transplantation (p0.001 vs pretransplantation levels) and thereafter remained at low levels for the next 6 weeks, with a small increase during the 8 weeks after transplantation (p = 0.006). In contrast, TNF-alpha, IL-8, and VCAM-1 levels remained low during the first 6 weeks after transplantation followed by a rise in mean VCAM-1 levels from 841 +/- 38 to 979 +/- 52 ng/ml at week 8. To determine the relationship of levels of each of the four soluble factors with rejection, the mean values obtained during the time interval 1 to 5 days before rejection were compared to mean values obtained during rejection and at other periods of no rejection (baseline). Cytokine levels were not predictive of rejection (no difference in levels 0 to 5 days before rejection versus baseline, p0.3 for IL-6, IL-8, TNF-alpha). However, VCAM-1 levels increased 0 to 5 days before rejection compared with baseline (914 +/- 40 vs 844 +/- 30 ng/ml, p = 0.06).IL-6 levels are increased immediately after heart transplantation. Circulating IL-6, IL-8, and TNF alpha levels do not predict rejection during the first 8 weeks after transplantation. Soluble VCAM-1 increases within 5 days before rejection and may potentially serve as a noninvasive marker for early rejection.

The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy.From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time.Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score.Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

After listing for pediatric heart transplantation, at any point in time one of the following possibilities could have occurred; death, transplantation, removal from the list because of clinical improvement, or continuing to wait. In the setting of those competing outcomes, the Kaplan-Meier estimate portrays the time-relatedness of an event while ignoring the effect of the other possible outcomes. The competing outcomes method, however, depicts the time relatedness of an event while solving for all possible events simultaneously. The competing outcomes method may potentially provide more accurate information regarding the actual proportion of patients experience an outcome after listing.

The growth of the US cardiac transplant waiting list has outpaced the increase in donors, resulting in a widening gap between the number of waiting recipients and available donors. These trends have generated concern that longer waiting times may result in more patients deteriorating to urgent status and that transplanting only patients who are in an advanced state of decompensation will reduce posttransplant survival. Furthermore, the shortage of donors may result in extending the guidelines for donor acceptability to a degree that increases graft failure and posttransplant mortality. We measured these secular trends in the Cardiac Transplant Research Database to provide current data on time-dependent changes in US cardiac transplant practice and survival.At the time of this analysis, the Cardiac Transplant Research Database included all 2749 patients transplanted from January 1, 1990, to June 30, 1994, in the 25 participating transplant centers. During this 4.5-year period, the median waiting time for recipients who received a transplant increased from 2.7 to 3.5 months (P.0001), and the proportion of recipients whose status was urgent at transplantation increased from 41% to 60% (P.0001). Donor ischemic time increased from 150 to 166 minutes (P.0001), and the proportion of donors requiring pressor support increased from 68% to 85% (P.0001). Despite these changes in practice, the 1-year survival rate remained constant at 84% during this 4.5-year interval. There was no significant difference in 1-year survival rate between urgent status patients (83%) and nonurgent status patients (85%) (P = .08).The widening gap between the number of waiting recipients and the number of donors has resulted in a continuing trend toward transplanting urgent status recipients and to a liberalization of donor acceptance criteria. Despite these changes, posttransplant survival has remained constant.

Meaningful analysis of survival and risk factors for death in children who undergo heart transplantation is problematic because of the small number of heart transplantations performed at individual institutions.To more accurately examine survival and risk factors for death in children undergoing heart transplantation, we analyzed 191 patients between 1 and 18 years old who received transplants at 22 centers in the Pediatric Heart Transplant Study between January 1, 1993, and December 31, 1994. Cardiac diagnosis was congenital heart disease in 74 patients (39%), dilated cardiomyopathy in 73 (38%), and other in 44 (23%). Actuarial survival was 93% at 1 month, 82% at 1 year, and 81% at 2 years after transplantation. The major causes of death (n = 31) were rejection (29% of deaths), early graft failure (19%), infection (16%), sudden death (13%), and other causes (23%). By multivariate analysis, risk factors for death were assist devices (P = .02), nonidentical ABO blood types (P = .05), and younger age (P = .10).Contemporary survival for pediatric heart transplant recipientsor = 1 year old is comparable to survival after adult heart transplantation. Risk factors for death are the need for assist devices, nonidentical ABO blood types, and younger age. Rejection is the most common cause of death after pediatric heart transplantation.

By multivariable analysis, risk factors were identified for initial infection of any type, cumulative infections during the first 6 months and fatal infection among 2210 heart transplant recipients at 30 institutions.Of the 1218 infections in 695 patients, bacterial infections were most frequent (47%), followed by viral (42%), fungal (8%), and protozoal (4%). Risk factors for earlier infection included older recipient age (p0.0001), ventilator support at time of transplant (p0.0001), ventricular assist device at time of transplant (p = 0.02), OKT3 induction therapy (p0.0001), donor black race (p = 0.0007), and positive donor cytomegalovirus serology (for cytomegalovirus infection) (p = 0.0007). Cumulative infections during the first 6 months were increased by older recipient age (p0.0001), ventilator support at transplant (p = 0.0004), ventricular assist at transplant (p = 0.009), Black donor (p = 0.03), female donor (p = 0.03), and OKT3 induction therapy (p = 0.005). The actuarial freedom from fatal infection was 96% at 1 year and 95% at 3 years. Risk factors for death from infection included very old (p = 0.002) and very young recipients (p = 0.004), ventilator support at time of transplant (p = 0.004), older donor (p0.0001), and longer donor ischemic time (p = 0.02). The risk of death from infection within the first 3 months exceeded 20% among older recipients (55 years) on ventilator support at time of transplantation who received an older (50 years) donor heart.

Cytokines play a central role in inflammatory responses and in specific immune responses directed toward alloantigens. The pattern and quantity of cytokines produced in graft rejection can yield valuable information regarding the cellular and molecular mechanisms of the antigraft response.We used the polymerase chain reaction to semiquantitatively measure changes in the amount of messenger RNA from the interleukin-1 beta, interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumor necrosis factor-alpha, interferon-gamma, interleukin-1 receptor antagonist, and the interleukin-2 receptor genes in the peripheral blood and endomyocardium of cardiac allograft recipients during the first 8 weeks after transplantation. A total of 328 samples of resting (n = 251) and stimulated (n = 77, stimulated with phytohemagglutinin and lipopolysaccharide for 18 hours) peripheral blood mononuclear cells collected from 16 patients were measured. To measure intragraft cytokine levels, we analyzed 150 endomyocardial biopsy specimens from 19 patients.No elevation in expression was seen before injection, but, after the onset of rejection and concomitant with treatment, there was a decrease in detectable mRNA (p0.05) for the pro-inflammatory monokines interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in resting peripheral blood mononuclear cells, and a decrease for the T-cell derived cytokines interleukin-4 and interleukin-10 in stimulated peripheral blood mononuclear cells. These changes in mRNA expression occurred coincidentally with decreases in the percentage of lymphocytes and monocytes in the peripheral blood after administration of rejection therapy. In endomyocardial biopsy specimens, there were no detectable changes in the quantities of cytokine mRNA specimens for the interferon-gamma, interleukin-6, interleukin-10, interleukin-1ra, and interleukin-1 beta genes before rejection. In general, the levels of these cytokines were near the lower limits of detection by our assay in endomyocardial biopsies, mRNA from the interleukin-2, interleukin-4, tumor necrosis factor-alpha, and interleukin-2R genes were undetectable.We conclude that changes in the expression of cytokine mRNA in both peripheral blood mononuclear cells and endomyocardial biopsy specimens as measured by the semiquantitative polymerase chain reaction method used in this study does not effectively predict rejection. The decline in peripheral blood mononuclear cell cytokine mRNA after rejection treatment is likely due to changes in the proportion of lymphocytes and monocytes in the peripheral blood in concert with a steroid-induced downregulation by cytokine gene transcription.

Seventy-six heart transplants in 73 patients were studied for the formation of lymphocytotoxic panel-reactive antibodies after transplantation. Treatment of patient serum with dithioerythritol was used to discriminate between antibodies of the immunoglobulin M and immunoglobulin G isotypes. Human leukocyte antigen specificities of immunoglobulin G panel reactive antibodies were determined by the pattern of reactivity with the cell panel used in the panel-reactive antibodies determinations. A total of 465 panel-reactive antibodies determinations were made during the first year after transplantation.Mean panel-reactive antibodies values were highest during the first posttransplantation month. Positive dithioerythritol-treated panel-reactive antibodies values were rare after the first month after transplantation. Multivariable analysis indicated that previous pregnancy and positive cytomegalovirus serologic analysis predicted a higher dithioerythritol-treated panel-reactive antibodies within the first 3 months. No decrease in actuarial survival, increase in cumulative rejection episodes, or increase in the incidence of coronary artery disease at 1 year was seen in patients with a standard panel-reactive antibodies greater than 10% or among patients with dithioerythritol-treated panel-reactive antibodies greater than 0%. A significant and major increase in rejection-related death or retransplantation occurred among 11 patients in whom donor human leukocyte antigen specific antibodies of the immunoglobulin G isotype were detected during the first posttransplantation year (p = 0.02). Two of the 11 patients died of refractory rejection and 3 and 6 months after transplantation, whereas one patient underwent retransplantation for refractory rejection at 13 months and subsequently died.(1) Posttransplantation serial standard panel-reactive antibodies or dithioerythritol-treated panel-reactive antibodies are not predictive of rejection-related mortality unless the specificity is determined to be antidonor HLA; (2) routine dithioerythritol-treated panel-reactive antibodies studies are advisable during the first month after transplantation, and, if positive (10%), antidonor human leukocyte antigen specificity should be determined; (3) detection of recipient immunoglobulin G anti-donor human leukocyte antigen antibodies after heart transplantation identifies a group at high risk for serious allograft rejection and should prompt more intensive rejection surveillance and consideration for additional immunotherapy.

Previous studies of allograft rejection have focused on early episodes and risk factors from pretransplant variables.This multiinstitutional study compared early (1 year) and late (1 year) rejection episodes and risk factors for recurrent rejection from variables both before and after transplantation among 1251 patients who underwent primary heart transplantation and available follow-up of greater than 1 year.There were a total of 1882 rejection episodes over a mean follow-up of 26 +/- 0.3 months. The hazard function (instantaneous risk per patient per month) peaked at 1 month followed by a low constant risk of rejection after 12 months. By multivariable analysis, the most dominant risk factors for recurrent rejection during the first posttransplantation year were a shorter time interval since transplantation and a shorter time since a previous rejection episode. Other factors included young age, female gender, female donor, positive cytomegalovirus serology, prior infections, and OKT3 induction. In contrast, after the first year, the dominant risk factors for rejection were a greater number of rejections during the first year and the presence of prior cytomegalovirus infections.These data show a striking time dependency for rejection episodes among heart transplant recipients. Factors that increase risk for rejection in the first year differ from risk factors for rejection in subsequent years. These data suggest that it may be possible to tailor rejection surveillance protocols and immunosuppression intensity, according to specific patient and time-related risk factors.

Quality of life is an important outcome to measure in patients with end-stage heart disease who are awaiting heart transplantation. The purposes of this study were threefold: (1) to assess life satisfaction in multiple areas, (2) to examine correlations between life satisfaction and demographic, physiologic, and psychosocial variables, and (3) to identify predictors of quality of life in patients with advanced heart failure who were awaiting heart transplantation.Data were collected from a convenience sample of 359 adult heart transplant candidates from a midwestern and a southern medical center. Eight instruments were used to gather data from patients. All tools had adequate psychometric support. Data were analyzed by using descriptive statistics, Pearson correlations, and stepwise multiple regression analysis.Results showed that patients were most satisfied with significant others (e.g., emotional support from others, children, and family's health) and least satisfied with their health and functioning (e.g., current health status, ability to travel, and energy for daily activities). Significant correlations were found between total life satisfaction and age, New York Heart Association Functional classification, total number of daily medications, functional disability, symptom distress, stress, coping, helpfulness of heart transplant team interventions, health perception, expectation of transplant success, and overall quality of life.Eleven of 19 variables were significant predictors of higher quality of life in patients with advanced heart failure awaiting heart transplantation and accounted for 49% of explained variance: less symptom distress, better health perception, greater helpfulness of heart transplant team interventions, less stress, better coping ability, less functional disability, less use of fatalistic coping, older age, greater effectiveness of optimistic coping, being unemployed, and the expectation of transplant success.

Prosthetic valve endocarditis, which is an uncommon but potentially fatal complication of valve replacement, may result in annular abscess formation (mechanical valves) or primarily leaflet infection (xenografts and homografts). Insertion of a mechanical or xenograft valve in the setting of aortic root infection carries a risk of reinfection, which is highest in the first 4 months after valve replacement. In contrast, the homograft aortic valve does not have this early risk of prosthetic valve endocarditis, but instead a constant and low risk across time. Because of this apparent intrinsic resistance to infection, the aortic homograft valve is the replacement device of choice for prosthetic valve endocarditis. An additional advantage of the homograft aortic valve for prosthetic valve endocarditis is the fact that this device has the flexibility to enable its use even in extensive aortic root destruction, including left ventriculo-aortic discontinuity. The homograft valve can be inserted as a root replacement after excision of the infected aortic root, or as a subcoronary or cylindrical technique for less extensive infection.

HLA mismatch has been shown to influence survival after heart transplantation. No large multicenter study has examined the effect of HLA mismatch on cardiac allograft rejection. HLA mismatch and other potential risk factors for rejection were analyzed in data from 27 institutions (1719 patients) participating in the Cardiac Transplant Research Database between January 1, 1990, and June 30, 1992. Complete HLA information on the A, B, and DR loci was available for both donor and recipient in 1190 patients. Of these, 619 (52%) had five or six mismatches; 68 (6%) had zero, one, or two mismatches. The mean number of mismatches was 4.4 and did not differ, regardless of donor-recipient race match (4.3 versus 4.8, p = 0.19). According to multivariate analysis, risk factors for time to first rejection included younger recipient age (p0.0001), female gender of both donor and recipient (p0.0006), number of HLA mismatches (p = 0.013) and black recipient race (p0.004). Patients with zero, one, or two mismatches (n = 67) had a 54% freedom from rejection at 1 year versus 36% for patients with three or more mismatches (n = 1005, p = 0.02). HLA mismatch number did not affect time to first rejection or rejection frequency among black patients. Risk factors (by multivariate analysis) for death or retransplantation because of rejection included female recipient gender (p = 0.008) and black recipient race (p = 0.006). The probability of rejection-related death or retransplantation by 2 years was 0% with zero, one, or two HLA mismatches versus 5% for three to six mismatches (p = 0.14). These findings should stimulate further investigation of methods to clarify the HLA effect in heart transplantation and eventually the use of HLA typing in donor-recipient selection.

The successes achieved in bridging patients to transplantation and to recovery of the native heart argue strongly for further development and wider application of mechanical circulatory assist devices. It is possible that even higher success rates can be achieved with earlier use of VADs, particularly in patients who cannot separate from cardiopulmonary bypass. There are several important questions and problems that must be addressed before the wider application of VADs in acute heart failure. How can one reliably and expeditiously distinguish patients who will separate from bypass and survive if given additional time on conventional cardiopulmonary bypass from patients who are destined to require mechanical assistance? How can the problems with post-bypass organ damage be minimized, and how can patients with irreversible organ injury be distinguished from patients with reversible dysfunction? How can the problems with post-implant bleeding, infection, and thromboembolism be minimized? Perhaps the most important problem is how to treat patients who survive VAD implantation, but whose hearts fail to recover. The only alternatives at the present time are removal of the device with almost certain death, or cardiac transplantation. The development of chronically implantable VADs (ie, expected duration of support 5 years or more) will provide an excellent alternative for patients who are not optimal transplant recipients or for whom there is not a donor heart available. The number of patients that will be in this category and the cost per patient year of survival are factors that will weight heavily in the decisions made by the federal government regarding clinical application of this technology.

Fifty-four consecutive patients underwent aortic valve replacement with a pulmonary autograft (Ross operation) over an 18-month period. It was inserted as an intra-aortic cylinder in 13 patients and as a total aortic root replacement in 41; unwrapped in 16, partially wrapped with autologous pericardium in 12 and completely wrapped with bovine pericardium in 13. There were two cardiac deaths, one death from mediastinitis, and two early reoperations to replace an incompetent autograft. Comparison of postoperative echocardiographic data showed a higher incidence of moderate and severe autograft incompetence in the intra-aortic cylinder group and also in the subset without previous operation which had a total root replacement without a complete wrap. Autograft function was best in the group which received a total root replacement with a complete wrap and in those with previous cardiac surgery who received an unwrapped autograft. This preliminary information with short follow up supports the use of complete wrapping of the autograft when it is used as a total root replacement particularly in older patients without previous cardiac surgery in whom future autograft growth is not desirable.

Cytomegalovirus infection is a major cause of morbidity and rehospitalization after heart transplantation. To assess its incidence and risk factors in the current era of heart transplantation, we analyzed cytomegalovirus infection data in 1553 patients from 26 institutions (Cardiac Transplant Research Database Group) undergoing primary heart transplantation between Jan. 1, 1990, and June 30, 1992. There were 230 treated cytomegalovirus infections in 200 patients, of which 16 were fatal (6%; 70% confidence limits 5% to 9%). Actuarial freedom from cytomegalovirus infection was 98% 1 month, 88% 3 months, and 83% 24 months after transplantation, with a peak incidence of initial infection at 2 months. Twenty-five (12%) of 200 patients with cytomegalovirus infection had recurrent cytomegalovirus infection during a mean follow-up of 13.9 months. The primary location of cytomegalovirus infection was blood in 100 infections (43%), lung in 69 (30%), gastrointestinal tract in 54 (23%), and other sites in seven patients (3%). Cytomegalovirus pneumonia exhibited the highest mortality rate (13%). Risk factors by multivariate analysis for earlier development of cytomegalovirus infection included pretransplantation cytomegalovirus serology (positive donor, negative recipient [p0.0001]; positive donor, positive recipient [p = 0.0002]; and negative donor, positive recipient [p = 0.02]) and cytolytic induction therapy (p = 0.05). A cytomegalovirus-positive recipient with a cytomegalovirus-positive donor had a 15% chance of having cytomegalovirus infection, whereas a cytomegalovirus-negative recipient with a cytomegalovirus-positive donor had a 24% chance. Ganciclovir treatment was administered in 227 (99%) of 230 infections. By multivariable analysis, the likelihood of a fatal cytomegalovirus infection was increased with a higher number of infections of any type during the first post transplantation month (p0.0001). There was no increased mortality rate in cytomegalovirus infections associated with cytomegalovirus-positive donor and cytomegalovirus-negative recipient (6% mortality rate) versus all other cytomegalovirus infections (6% mortality rate) (p = 0.9) or with OKT3 induction therapy (0% mortality rate) versus all others (noninduction and induction with other than OKT3) (1.4%) (p = 0.03). In conclusion, the biggest determinant of cytomegalovirus infection is donor and recipient pretransplantation cytomegalovirus serologic results with cytolytic induction therapy adding a small additional risk. The overall mortality rate from cytomegalovirus infections is low (7%) in the current era with rapid culture techniques and ganciclovir therapy. Cytomegalovirus infections are more likely to be fatal if there are more frequent preceding infections of any type, but mortality rates are not increased by OKT3 induction or with a cytomegalovirus-positive donor organ transplanted into a cytomegalovirus-negative recipient.

Mycophenolate mofetil (RS-61443), a derivative of mycophenolic acid, is a new immunosuppressive agent that inhibits de novo purine synthesis in activated lymphocytes. In a clinical trial of mycophenolate mofetil in the treatment of recurrent or persistent heart rejection, 17 patients 0.6 to 104 months (median 5.4 months) after transplantation received a daily oral dose of mycophenolate mofetil of 3000 mg, with seven patients increasing to 3500 mg daily. Azathioprine was routinely discontinued at the start of mycophenolate mofetil treatment. One patient in shock from acute rejection required retransplantation before starting mycophenolate mofetil and died 68 days later of cytomegalovirus sepsis. Another patient died 72 days after mycophenolate mofetil of protracted multisystem failure (present before mycophenolate mofetil). One patient required early cessation of mycophenolate mofetil, and the other 14 patients were alive and well 5 to 10 months after initiating mycophenolate mofetil treatment. Three patients required transient dose reduction and one patient required discontinuation of mycophenolate mofetil because of nausea, diarrhea, or abdominal cramps. No other clinical side effects were noted. Frequency of rejection decreased from 0.67 rejection episodes per patient per month before mycophenolate mofetil to 0.27 rejection episodes per patient per month after mycophenolate mofetil (p0.0001). Frequency of infection was unchanged after mycophenolate mofetil (p = 0.9). Renal function was not affected by mycophenolate mofetil (creatinine clearance 1.8 mg/dl before mycophenolate mofetil vs 1.7 mg/dl after mycophenolate mofetil; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Little information is available regarding donor-specific parameters that predict success or failure after heart transplantation. Furthermore, with increasing numbers of patients awaiting heart transplantation, there is tremendous pressure to expand the donor pool by stretching the margins of donor acceptability. To gain insight into donor-related and donor-recipient interrelated predictors of death after transplantation, 1719 consecutive primary transplantations performed at 27 institutions between Jan. 1, 1990, and June 30, 1992, were analyzed. Mean follow-up of survivors was 13.9 months, and actuarial survival was 85% at 1 year. By multivariable analysis, risk factors for death included younger recipient age (p = 0.006), older recipient age (p = 0.0005), ventilator support at time of transplantation (p = 0.0006), higher pulmonary vascular resistance (p = 0.02), older donor age (p0.0001), smaller donor body surface area (female donor heart placed into larger male patient) (p = 0.003), greater donor inotropic support (p = 0.01), donor diabetes mellitus (p = 0.01), longer ischemic time (p = 0.0003), diffuse donor heart wall motion abnormalities by echocardiography (p = 0.06), and, for pediatric donors, death from causes other than closed head trauma (p = 0.02). The overall 30-day mortality rate was 7% but increased to 11% when donor age exceeded 50 years and was 12% when inotropic support exceeded 20 micrograms/kg/min dopamine plus dobutamine and 22% with diffuse echocardiographic wall motion abnormalities. The interaction of donor risk factors was such that the heart of a smaller female donor given high-dose inotropes placed into a larger male recipient produced a predicted 30-day mortality rate of 26% and the heart of a 25-year-old male donor given high-dose inotropes with diffuse echocardiographic wall motion abnormalities transplanted into a 50-year-old male recipient led to a predicted 30-day mortality rate of 17%. This analysis supports cautious extension of criteria for donor acceptance but with an anticipated greater risk in the presence of diffuse echocardiographic wall motion abnormalities and long anticipated ischemic time, particularly in older donors given inotropic support.

The effects of mechanical left ventricular assist on the nonassisted right ventricle have not been fully elucidated. Current information indicates that the right ventricle benefits from a lower left atrial pressure; however, ventricular septal shifting and increased venous return caused by left ventricular assist impair right ventricular function. Acute intraoperative alterations in mitral and tricuspid valve regurgitation (MR and TR, respectively) may occur as a result of mechanical left ventricular assist but have not yet been documented.Eight patients undergoing implantation of a left ventricular assist device (LVAD) as a bridge to transplantation were studied during surgery by transesophageal echocardiography. MR was present in seven of eight patients, and TR was present in eight of eight patients before LVAD implant (mean MR jet area, 10.6 +/- 2.4 cm2, mean TR jet area, 4.8 +/- 1.0 cm2). Immediately after LVAD placement, MR was still present in seven of eight patients, and TR was present in eight of eight patients (mean MR jet area, 4.2 +/- 0.9 cm2; mean TR jet area, 8.4 +/- 1.9 cm2) (P.05 preimplant versus postimplant jet area). These changes in MR and TR were associated with a decrease in left ventricular end-systolic dimension (62 +/- 4 versus 48 +/- 3 mm) and an increase in right ventricular end-systolic dimension (31 +/- 4 versus 40 +/- 5 mm) (P.05 preimplant versus postimplant end-systolic dimension). No patients developed progressive right ventricular failure during 70 to 279 days of LVAD support.Mechanical left ventricular assist causes an acute decrease in preexisting MR. However, left ventricular assist may acutely worsen TR, presumably by shifting the ventricular septum leftward and increasing venous return to the right ventricle.

Total lymphoid irradiation (TLI) is an effective adjunct in the therapy of recurrent allograft rejection in adult patients. Between Jan. 3, 1990, and Feb. 5, 1992, TLI was used in 43 heart transplant patients 4 days to 67 months (mean, 6 months) after heart transplantation for recurrent allograft rejection. A mean TLI dose of 700 cGy (range, 40 to 1120 cGy-) was administered during a mean of 7 weeks with adjustment in overall dose and duration determined in part by leukopenia, thrombocytopenia, or both. Among patients who received TLI therapy within 1 month of transplantation (n = 12), the rejection rate decreased from 1.9 episodes per patient per month before TLI to 0.1 episodes per patient per month after TLI (p0.001). Sixty percent of patients had no further rejection episodes for 6 months after TLI. Peripheral blood mononuclear cells from two patients were specifically unreactive toward donor stimulator cells in mixed-lymphocyte cultures at 2.5 and 6 months after TLI. During this experience three pediatric patients (ages 10 to 17 years) received TLI at 0.5, 0.8, and 0.9 months after heart transplantation for recurrent allograft rejection. The total TLI dosage for each patient was 720, 800, and 800 cGy. The rejection frequency fell from 1.8 episodes per patient per month before TLI to 0.1 episodes after TLI (p0.01). During follow-up of 6 to 25 months after TLI, no adverse sequelae of TLI were identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for death after heart transplantation were identified by analyzing the total primary heart transplantation experience (n = 911) among 25 institutions from January 1, 1990, through June 30, 1991. Overall actuarial survival was 93% at 1 month and 84% at 12 months. The hazard function for death was highest early after heart transplantation and fell rapidly over the first 6 months, with a gradually declining hazard thereafter. The two most common causes of death were infection (n = 29) and early graft failure (n = 28), accounting for 45% of the overall deaths. By multivariable analysis, risk factors for death during the study period included very young recipient age (p = 0.004), advanced age (p = 0.009), ventilator support at time of transplantation (p = 0.09), abnormal renal function (p = 0.1), lower pretransplantation cardiac output (p = 0.009), higher pulmonary vascular resistance in children (p = 0.006), longer donor ischemic time (p = 0.001), older donor age (p = 0.001), and donor and recipient not both blood type O (p = 0.009). The recipient age effect was greatest in patients under 5 years of age (1-year survival rate 68% versus 85% for all others, p = 0.002). Patients aged 60 years and older had a 1-year survival rate of 81%. Patients who were ventilator dependent at transplantation fared especially poorly, with a 3-month survival rate of 65%. Transplantation of a blood group O heart into a non-O recipient had a somewhat lower 1-year survival rate than did blood group O into an O recipient (82% versus 88%, p = 0.06). The adverse effect of a longer ischemic time was most notable after 4 hours (1-month survival rate 71% for more than 4 hours versus 85% for less than 4 hours, p = 0.0003). Inference: These multiinstitutional-derived risk factors for early-term death after heart transplantation may help improve patient and donor selection and focus further scientific investigations to increase the safety of heart transplantation.

Cryopreserved aortic valve homografts have become an accepted aortic valve substitute, but long-term studies with echocardiographic assessment of valve function are largely unavailable. Between 1981 and January 1, 1991, a total of 178 patients aged 9 months to 80 years (median 46 years) underwent implantation of a cryopreserved aortic valve homograft. Serial two-dimensional Doppler echocardiographic studies were obtained in 149 patients. Overall survival was 91% at 1 year and 85% at 8 years. Survival of patients undergoing isolated primary infracoronary aortic valve replacement was 99% at 1 month and 94% at 8 years. Twelve patients underwent homograft explanation. Freedom from explantation for leaflet degeneration was 95% at 8 years. Freedom from presumed leaflet failure (valve degeneration at explantation or aortic insufficiency grade 3/4 or more without reoperation on echocardiography) was 94% at 5 years and 85% at 8 years. By multivariable analysis younger recipient age was the only risk factor identified for leaflet failure. Ninety-five percent of patients followed up for 4 or more years were in New York Heart Association class I or II.

To better understand the phenomenon of acute rejection in the current era of heart transplantation, complete rejection data (918 rejection episodes) from 25 institutions were analyzed for all 911 patients undergoing primary heart transplantation between January 1, 1990, and July 1, 1991. During a mean follow-up of 8.1 months (maximum, 18 months), 54% of the patients had one or more rejection episodes. The mean cumulative number of rejection episodes per patient was 0.8 at 3 months, 1.10 at 6 months, and 1.3 at 12 months after transplantation. By univariate analysis, female donor hearts (irrespective of recipient sex) (p0.01) and the use of induction therapy (p0.01) were associated with greater cumulative rejection frequency. By multivariate analysis, younger donor age and female donor gender were risk factors for earlier rejection. Solution of the multivariate equation predicted an 85% probability of rejection at 1 month for a 5-year-old female with a female donor and 50% for a 50-year-old man with a male donor. Inferences: (1) In the current era, over 40% of patients appear to be free of rejection during the first year after transplantation. (2) Younger recipient age and female donors are associated with earlier onset of allograft rejection, but the precise immunologic basis for these observations remains unknown. (3) In this experience, induction therapy did not delay the onset of first rejection nor did it reduce the cumulative number of rejection episodes. Further studies are indicated to examine the need for induction therapy.

Heart transplantation may well be the most successful transplantation procedure performed today. One-year patient survival rates now exceed 80%. Many factors are thought to account for differences in outcomes among transplantation centers. No attempt has been made to assess consensus among transplantation program directors regarding the major determinants of patient outcome. In the National Cooperative Transplantation Study we evaluated consensus through a detailed survey of all heart transplantation programs active in the United States in 1988. Of the eligible programs, 104 (91%) returned completed surveys. Data on the medical and surgical determinants of outcomes have been analyzed descriptively. Considerable consensus occurred among program directors about the importance of several factors. For example, over 90% of the respondents felt that heart biopsy should be used as the standard rejection monitoring technique and that left and right heart catheterization should be performed annually with coronary arteriography. Over 60% believed that the availability of a left ventricular assist device for temporary use would also enhance patient outcome. Several approaches were considered to have little beneficial effect on outcome. These included cytoimmunologic monitoring and electrocardiography as standard rejection monitoring techniques. Nearly one half of the respondents opposed steroid discontinuation after transplantation. On several other approaches there was a lack of consensus including the use of heterotopic heart transplantation and conversion from cyclosporine because of renal dysfunction. Consensus conferences are now regarded as a means by which technologic innovations can be evaluated and medical practice guidelines can be set. This analysis suggests that consensus is a useful approach toward assessing medical and surgical practices in heart transplantation.

The determinants of early and repeated episodes of acute rejection after cardiac transplantation remain elusive.To gain insight into this phenomenon, a multivariate analysis for repeated events was applied to 229 patients receiving 249 transplanted hearts between 1981 and July 1, 1991 (595 rejection episodes). The mean frequency of rejection per patient after initial cardiac transplantation was 1.2 at 3 months, 1.8 at 1 year, and 2.8 at 5 years. The pattern of rejection was characterized by an early period of higher risk (greatest during the first month) followed by a low constant risk that continued throughout the period of follow-up (maximum, 9.5 years). By multivariate analysis, risk factors were identified for the likelihood of subsequent rejection after a previous rejection episode (or time of transplantation). Triple-drug immunosuppression plus induction therapy yielded a higher risk of early subsequent rejection compared with other baseline immunotherapy protocols, but it also provided the greatest freedom (95%) from rejection-related death during the first year. Risk factors in the constant phase of hazard included younger age at transplant, female donor and/or recipient, longer donor ischemic time, greater HLA donor-recipient mismatch, and an increased number of previous rejection episodes.Immunologic and other patient-specific characteristics as well as rejection history predict the likelihood of future rejection events. The value of any antirejection protocol must be evaluated both in terms of rejection episodes and rejection-related deaths. Future analyses may identify specific high- and low-risk patient subsets for rejection, which may provide a more rational basis for altering the amount of chronic immunosuppressive therapy.

Despite cytolytic induction therapy and triple-drug immunosuppression, acute allograft rejection continues to cause important morbidity and occasional death after heart transplantation. Between November 1, 1988, and May 1, 1990, 24 patients received methotrexate pulse therapy for recurrent or persistent acute rejection despite methylprednisolone, OKT3, or antithymocyte globulin therapy. Methotrexate was administered as a daily oral dose of 2.5 to 15 mg on 1 day/week over 3 weeks (longer in 15 patients because of either severe leukopenia with temporary interruption of therapy or recurrent rejection during methotrexate therapy) with reduction or discontinuation of azathioprine. Rejection incidence was reduced from 1.1 episodes/patient month before methotrexate therapy to 0.2 episodes/patient month after completion of therapy (p = 0.0001). Two patients died within 3 months after treatment, one of cytomegalovirus pneumonia and one of lymphoma. Mean white blood count (WBC) fell from 6900 per ml before methotrexate therapy to 3700 during the first month of methotrexate therapy (p = 0.0005). The lowest WBC typically occurred about 3 weeks after starting methotrexate therapy, and a transient WBC of less than 1000/ml developed in seven patients. By multivariable analysis, the WBC 1 month after starting methotrexate therapy was significantly related to greater bone marrow suppression (lower WBC), immediately before methotrexate therapy, greater overall immunosuppression (more rejection episodes) during the 3 months before methotrexate therapy, and a higher total dose of methotrexate. The following conclusions can be drawn: (1) Methotrexate is a useful adjunct in the treatment of recurrent or persistent rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to quantitate the uncertainty inherent in the electrophysiologic mapping of ventricular preexcitation as seen in Wolff-Parkinson-White syndrome. An ink-coated needle electrode was constructed to serve as a point source of unipolar stimulation along the atrioventricular junction. Activation times for 11 ventricular mapping sites at the atrioventricular junction were measured for each stimulation point. Maps were successfully completed for 18 right free wall and 14 posterior septal stimulation points. The activation time at the mapping site closest to the stimulation point was termed the index activation time. Activation times identical to the index activation time were noted at 1.3 +/- 0.5 mapping sites for each free wall stimulation point and 1.9 +/- 0.9 mapping sites for each septal stimulation point (p0.05, septal versus free wall stimulation points). Activation times falling within 5 msec of the index activation time were noted at 2.4 +/- 1.0 mapping sites for each free wall stimulation point and at 3.9 +/- 1.4 mapping sites for each septal stimulation point (p0.05, septal versus free wall stimulation points). The uncertainty of electrophysiologic mapping can be quantitated, and this error should be considered when making inferences regarding the anatomy of accessory pathways based on electrophysiologic data. A knowledge of the uncertainty inherent in the localization of accessory atrioventricular connections by electrophysiologic mapping can be used to plan borders of surgical dissection that will account for this uncertainty at a 95% confidence level.

Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered before organ transplantation. Anecdotal reports in clinical transplantation have suggested efficacy of TLI in the treatment of recurrent rejection after heart transplantation. To further assess the safety and efficacy of TLI, 19 patients were entered into a protocol of TLI for the treatment of recurrent or early severe rejection despite conventional therapy. Rejection rate decreased from 1.3 episodes/month before TLI to 0.53 during TLI and 0.07 after TLI (p0.0001). Infections increased during TLI (possibly related to recent augmented immunosuppression before TLI), but all infections were successfully treated. One death occurred after TLI from acute allograft rejection. White blood cell (WBC) and platelet counts were depressed during and after (3 months) TLI. Frequent adjustments of dosing interval and, occasionally of the dosage were required to control WBC and platelet counts. Five patients experienced transient WBC of less than 1000/ml. More rejection episodes (and thus greater overall immunosuppression) before TLI and a lower tolerated dose of azathioprine before TLI predicted (by multivariate analysis) a lower WBC during TLI.(1) TLI is an effective adjunct for the intermediate control of early or recurring acute allograft rejection. (2) Close surveillance of WBC and platelets with appropriate adjustment of TLI dose and interval is necessary during TLI therapy. (3) The long-term benefits, possible late deleterious effects, and potential role of TLI as induction therapy remain to be elucidated.

Previous descriptions of the four anatomic regions of dissection in Wolff-Parkinson-White syndrome have been largely qualitative. In this study quantitative data describing this anatomy are presented, together with statistical analysis of selected anatomic relationships. Fourteen human hearts were dissected. The borders of the posteroseptal dissection along the mitral anulus, tricuspid anulus, and epicardium were measured. A positive correlation between the mitral and tricuspid annular dimensions was found (r = 0.55; p = 0.04); however, the length of epicardial dissection was more variable. The dimensions of the anteroseptal space and the position of the right coronary artery within this space were measured. These measurements emphasize the proximity of the aortic sinuses of Valsalva to the right atrial endocardium near the posteromedial extent of the dissection. The dimensions of the right and left free walls and the position of the coronary arteries within these spaces were measured. A positive correlation was found between the width of the atrioventricular groove and the length of the dissection necessary to separate the atrioventricular groove fat from the ventricular surface (r = 0.89; p = 0.0001, right free wall; r = 0.87; p = 0.0001, left free wall). The quantitative data presented in this article are intended to enhance the surgeon's appreciation of the anatomy relevant to the treatment of Wolff-Parkinson-White syndrome. The knowledge gained from this quantitative analysis may improve accuracy in the electrophysiologic localization and surgical disruption of accessory atrioventricular connections.

Management of heart transplant patients who are being given cyclosporine is complicated by the variety of methods available for measuring cyclosporine levels and the current trend toward exclusive use of monoclonal assays. To facilitate clinical decisions regarding cyclosporine levels when converting from a polyclonal system to monoclonal system, 79 heart transplant patients underwent a prospective study to compare the polyclonal radioimmunoassay with the monoclonal-specific parent compound and nonspecific radioimmunoassays. Multivariable regression analyses were performed to generate best-fit equations for conversion of one assay to another. The closest correlation was noted in converting the measurement of cyclosporine parent compound with metabolites by the polyclonal method to the monoclonal method (nonspecific), R2 = 0.93. Considerable variability existed in the relationship between polyclonal and monoclonal-specific levels (R2 = 0.66) and between monoclonal-nonspecific and monoclonal-specific levels (R2 = 0.66), and both relationships were affected by hepatic function. Inferences: (1) The conversion of numeric cyclosporine levels from parent compound to parent plus metabolites is not completely predictable and must be empirically determined with the generation of appropriate regression equations. (2) Caution is advisable when a transplant team adopts a new cyclosporine assay for clinical use; formal study between existing assay methods and any newly adopted assay is warranted to prevent inadvertent underdosing or overdosing with cyclosporine.

The effects of low and high osmolality ionic contrast agents on the transplanted heart were studied in 75 consecutive patients. Renal function remained unchanged 24 hours after coronary angiography in both groups. Hemodynamic changes were transient and more pronounced after administration of the high osmolality agent; ECG changes and cineangiography quality were similar after both agents. The manyfold increase in cost of the low osmolality contrast agents may not be justified for use in stable patients after heart transplantation.

Survival after entry and survival after repair (94%, 91%, and 91% at 1 month, 1 year, and 5 years, respectively) were similar in two institutions treating 196 consecutive patients, and there was no advantage (and a possible disadvantage) of a protocol of preliminary shunting and later repair in very young patients. Size and configuration of the right and left pulmonary arteries had no demonstrable effect on survival, prevalence of transannular patching, or postrepair right ventricular-left ventricular pressure ratio. Small size of the pulmonary "anulus" and trunk were risk factors for death, transannular patching, and high postrepair pressure ratio. High postrepair pressure ratio was a risk factor for death after repair. Very young age (less than about 3 months) was a risk factor for death after repair, particularly when other risk factors coexisted. The prevalence of transannular patching in patients with mild infundibular and pulmonary anulus and trunk hypoplasia decreased across the time of the study, without ill effect. The usefulness of measuring postrepair right ventricular-left ventricular pressure ratio is emphasized by the data.

Elevated pulmonary vascular resistance is a known risk factor for early death from acute right ventricular failure after orthotopic cardiac transplantation. Patients in whom the elevated pulmonary vascular resistance is due primarily to increased left atrial pressure ("reactive") frequently have normalization of resistance after transplantation, but few studies have detailed the time course and magnitude of these changes. To analyze the response of pulmonary vascular resistance to cardiac transplantation, we analyzed data from 4353 right heart catheterizations on all 182 patients undergoing cardiac transplantation between 1981 and Jan. 1, 1990. Before transplantation 18% of patients had a pulmonary vascular resistance greater than 4 WU, 16% had a pulmonary artery systolic pressure greater than 60 mm Hg, and 16% had a transpulmonary gradient greater than 14 mm Hg. In the overall group of patients, pulmonary vascular resistance (mean value 2.63 WU), transpulmonary gradient (mean value 9.9 mm Hg), and pulmonary artery systolic pressure (mean value 48.0 mm Hg) were normalized within 1 week of cardiac transplantation. In patients with a high preoperative pulmonary vascular resistance (greater than or equal to 4 WU), the resistance fell promptly within 1 week of transplantation but continued to be slightly elevated throughout the period of follow-up. By multiple regression analysis, pulmonary vascular resistance at 1 week and 1 year after transplantation was significantly correlated with the pretransplantation resistance. Pulmonary vascular resistance anytime after transplantation was related to preoperative resistance, body surface area, and pulmonary artery diastolic pressure. Inferences: (1) As a group, cardiac transplant recipients have a normal pulmonary vascular resistance, transpulmonary gradient, and pulmonary artery systolic pressure within 1 week after transplantation with little change thereafter for at least several years. (2) Patients with reversible elevation of pulmonary vascular resistance before cardiac transplantation typically have a reactive and a fixed component. Cardiac transplantation relieves the reactive but not the fixed component. As a result, pulmonary vascular resistance early (within 1 week) and late after transplantation will have fallen but not completely normalized.