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Background: The Fontan procedure is a successful palliation for children with single-ventricle physiology; however, many will eventually require heart transplantation. The purpose of this study was to determine risk factors for death awaiting transplantation and to examine results after transplantation in Fontan patients., Methods and Results: A retrospective, multi-institutional review was performed of 97 Fontan patients <18 years of age listed at 17 Pediatric Heart Transplant Study centers from 1993 to 2001. Mean age at listing was 9.7 years (0.5 to 17.9 years); 25% were <4 years old; 53% were United Network for Organ Sharing status 1; 18% required ventilator support. Pretransplantation survival was 78% at 6 months and 74% at 12 months and was similar to 243 children with other congenital heart disease (CHD) and 747 children without congenital heart disease (No-CHD), who were also awaiting transplantation. Patients who were younger, status 1, had shorter interval since Fontan, or were on a ventilator were more likely to die while waiting. At 6 months, the probability of receiving a transplant was similar for status 1 and 2 (65% versus 68%); however, the probability of death was higher for status 1 (22% versus 5%). Seventy patients underwent transplantation. Survival was 76% at 1 year, 70% at 3 years, and 68% at 5 years, slightly less than CHD and No-CHD patients. Causes of death included infection (30%), graft failure (17%), rejection (13%), sudden death (13%), and graft coronary artery disease (9%). Protein-losing enteropathy (present in 34 patients) resolved in all who survived >30 days after transplantation., Conclusions: Heart transplantation is an effective therapy for pediatric patients with a failed Fontan. Although early posttransplantation survival is slightly lower than other patients with CHD, long-term results are encouraging, and protein-losing enteropathy can be expected to resolve.

Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.

Background: 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., Methods and Results: 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)., Conclusions: Contemporary survival for pediatric heart transplant recipients > or = 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.

Background: The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium., Methods and Results: Ten hearts from humans with end-stage heart failure and two hearts from patients without heart failure were harvested at the time of orthotopic cardiac transplantation. Microvessels were sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused dose-dependent increases in nitrite, a response that was blocked by NG-nitro-L-arginine methyl ester and receptor-specific antagonists (atropine and HOE 140, respectively). In addition, the production of nitrite by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with norepinephrine or the alpha2-adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B2-receptor antagonist HOE 140. This implicated local kinin synthesis as an intermediate step in the production of nitric oxide in response to alpha2-adrenoceptor stimulation. The production of nitric oxide was also prevented by the addition of serine protease inhibitors, which blocked the action of local kallikrein, again suggesting a role for local kinin synthesis., Conclusions: Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.

Background: Accelerated coronary atherosclerosis after heart transplantation (TCAD) is a major cause of late death. It is progressive and eventually fatal, and currently no therapy exists. The purpose of this study was to determine the incidence as well as the clinical and age-dependent characteristics of pediatric patients with TCAD., Methods and Results: Pediatric heart transplantation centers were surveyed on patient outcome and incidence of TCAD from August 1974 to March 1993. A follow-up questionnaire was sent to examine patient-specific details, including age at transplantation and at death, time to diagnosis, and rejection history. Data on coronary angiography and autopsy findings were requested. Replies were received from 17 US centers that performed 815 pediatric heart transplantations (including 188 neonates), with 560 survivors (69%). TCAD was identified in 58 patients (7.3%) by either coronary angiography, autopsy, or both. Detailed data were available for 45 patients. The mean age at diagnosis of TCAD was 9.9 years (0.2 to 26 years), and mean posttransplantation time was 2.2 years (0.1 to 7.7 years). TCAD occurred in 16 patients who received transplants before age 2 years. Many deaths were sudden and unexpected. Only 9 of 58 patients are alive, including 5 who had a second transplant. Four or more treated cellular rejection episodes and one or more courses of monoclonal antibody were used in 60% of patients with TCAD. Angiography was performed in 45 and was normal in 15 patients who later died of TCAD. An autopsy, performed in 36 of the 49 who died, showed severe coronary stenosis in 28 (78%) and concurrent cellular rejection in 26 (72%)., Conclusions: TCAD is a serious problem in transplant recipients and may affect patients of any age, even neonates. Diagnosis is difficult, and incidence of TCAD may be under-estimated. TCAD appears to be associated with cellular rejection; thus, higher surveillance in patients with frequent rejection episodes is indicated. Better surveillance methods, such as intravascular ultrasound and quantitative analysis of angiographic data, are needed to improve detection and assess new treatment strategies.

Background: Coronary artery disease (CAD) is a limiting factor to long-term survival in cardiac transplant recipients, affecting from 30% to 50% of patients by 4 years after surgery. Can the incidence of CAD be lowered with augmentation of immunosuppression?, Methods and Results: We compared the incidence of CAD in our pediatric transplant population with nine potential risk factors, including immunosuppressive regimen. The study group consisted of 55 patients who survived more than 1 year (or to first angiogram) or had autopsies. Coronary angiograms were performed yearly and compared sequentially. The mean follow-up of 55 patients was 36 months. Mean age was 10.3 +/- 6 years (range, 4 months to 18 years). Thirteen patients received double immunosuppression with cyclosporine and prednisone, and 42 received triple therapy with cyclosporine, prednisone, and azathioprine. Significant CAD occurred in 10 grafts (6 deaths and 3 retransplants). Cause for graft loss in 6 patients with CAD was acute rejection. CAD was detected by angiogram in only 2 patients. Nine of 10 patients received double therapy (P < .001). There was no difference in mean follow-up between immunosuppression groups. There was a higher rejection frequency for double therapy (0.19 +/- 0.16 rejections per patient month) compared with triple therapy (0.07 +/- 0.11). Ten patients were rejection free in the triple therapy group., Conclusions: We experienced a significant decrease in the incidence of CAD in our pediatric cardiac transplant recipients using increased immunosuppressive therapy. Type of immunosuppressive regimen (double) and rejection frequency were independent predictors for CAD by multivariate analysis.

Background: Children awaiting heart transplantation have severe limitations in their ability to exercise. The purpose of this study was to assess exercise capacity after pediatric heart transplantation and to identify factors influencing exercise performance., Methods and Results: Progressive cycle ergometry testing was performed in 31 patients at 1.3 +/- 0.8 years after transplantation, and in 16 patients, follow-up studies were performed at 3.3 +/- 1.3 years after transplantation. Maximum work load (Wmax), peak oxygen consumption (VO2), and maximum heart rate (HRmax) were measured. Exercise capacity was defined as normal if Wmax was > or = 75% of predicted values and decreased if Wmax was < 75% of predicted values. Differences in age at transplantation, sex, diagnosis, duration of heart failure, New York Heart Association class before transplantation, resting cardiac index, body mass index, and rejections per patient month were compared between patients with normal and decreased exercise capacity. At initial study, Wmax was 62 +/- 38 W or 61% of that predicted, peak VO2 was 20 +/- 6 mL.kg-1 x min-1 (63% of that predicted), and HRmax was 136 +/- 22 beats per minute (66% of that predicted) for all 31 patients. Six patients had normal exercise capacity, and 25 patients had decreased exercise capacity. Peak VO2 was significantly higher in the normal versus the decreased exercise capacity patients (26 +/- 5 vs 19 +/- 5 mg.kg-1 x min-1). The mean age at transplantation was significantly less in patients with normal exercise capacity: 8.2 +/- 4.6 versus 12.5 +/- 3.6 years for patients with decreased capacity. On follow-up study, no significant differences in Wmax, peak VO2, or HRmax were found from the initial test., Conclusions: Similar to results obtained in adult patients, exercise capacity was decreased but stable in pediatric patients after heart transplantation.

Late complications occurring more than 3 months after cardiac transplantation were analyzed in 29 pediatric patients in whom 31 cardiac transplantations were performed. Age at transplantation ranged from 3 months to 18 years (mean, 11.3 years) with follow-up ranging from 3.5 to 54 months (mean, 21.6 months). There were seven late deaths and two patients with retransplantations. Of nine grafts lost, eight were due to acute rejection, and one was due to coronary disease. Four of the grafts lost were secondary to patient noncompliance with prescribed immunosuppression. The mean rejection frequency more than 1 year after cardiac transplantation was significantly higher in those patients who eventually lost their grafts; however, these patients could not be distinguished by their rejection frequency in the first year. Eight patients had coronary disease, with five diagnosed at autopsy, two at cardiac retransplantation, and one by angiography. All eight patients were on double immunosuppression; none of the 19 patients on triple therapy had coronary disease with similar follow-up. There were 12 serious infections in eight patients (four associated with OKT3) with no deaths. Five patients had arrhythmias requiring treatment including two pacemakers; four of the five were associated with rejection episodes. Twelve of 29 patients developed early hypertension, and five developed late hypertension (greater than 1 year). There were two malignancies; one patient with Hodgkin's lymphoma was cured with chemotherapy, and one patient with histiocytic lymphoma was discovered at autopsy. Two patients had cholecystectomies, and five patients required laser gingivectomies.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe elevation of pulmonary vascular resistance has been considered a contraindication to cardiac transplantation. Most centers exclude patients with pulmonary vascular resistance greater than 6 Wood units. Wood units, however, do not correct for variations in body size and therefore may not be the best measure for use in comparison of patients. We performed a retrospective analysis of 82 cardiac transplant recipients and compared preoperative pulmonary vascular resistance (PVR) calculated in two ways to the incidence of right ventricular failure and death. Our data show that the PVR index unit (PVRI) identifies those patients that are at risk for right heart failure better than the Wood unit, which does not correct for body size. Four patients died of right heart failure with resistance less than 6 Wood units, but had PVRI greater than 6 units. High resistance is not an absolute contraindication to cardiac transplantation; 28 of 33 patients operated on with a PVRI greater than 6 survived. The degree of elevation of PVR did not correlate with survival. Ten of 12 patients with a PVRI greater than 9 survived. Testing with nitroprusside at cardiac catheterization was helpful in determining reversibility of pulmonary vascular obstruction. No patients with a PVRI less than 6 developed right heart failure.

Despite success in adults, heart transplantation (HT) is still considered by many as only desperation therapy for children with end-stage heart disease. Thus, of 30 pediatric patients undergoing HT at our center, only seven (23%) patients had not developed pulmonary hypertension with increased pulmonary vascular resistance (PH) or hemodynamic decompensation (HD) requiring inotropic support at the time of transplantation. We have retrospectively reviewed the effect of preoperative PH, HD, and seven other potential risk factors on survival of our pediatric heart transplant recipients. All 30 patients, aged 5 days to 18 years, had New York Heart Association class III or IV symptoms. Twenty had idiopathic cardiomyopathy, nine had congenital lesions, and one infant had a large left ventricular tumor. A univariate and multivariate Cox proportional-hazards analysis was performed examining the effects of nine variables on survival after transplantation: PH, HD, age, need for hospitalization, congenital heart disease, need for surgical pulmonary artery reconstruction, prior stroke, history of cardiac arrest(s), and mechanical ventilator dependence. One-year actuarial survival for the entire series was 66% and was 100% for the seven patients with neither PH nor HD. None of the nine potential risk factors was a statistically significant predictor of risk, yet the combined presence of PH and HD represented a highly significant predictor of mortality (relative risk, 4.08: 1; p less than 0.002). One-year actuarial survival of the 10 patients with this combination was 30% versus 84% of those without the combination.(ABSTRACT TRUNCATED AT 250 WORDS)