The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database.

Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross-match and the post-transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA > 20%. Patients with a PRA > 20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross-match determined by flow cytometric method (P < .001). A PRA > 50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era.

The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation.

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.

Association of race and socioeconomic position with outcomes in pediatric heart transplant recipients.

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1-year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.

Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis.

BACKGROUND: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation. METHODS: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function. RESULTS: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006). CONCLUSIONS: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

Should status II patients be removed from the pediatric heart transplant waiting list? A multi-institutional study.

BACKGROUND: The survival benefit of cardiac transplantation (CTx) among Status 2 (stable outpatient) adult recipients has been questioned, but few studies have addressed this issue in pediatric patients. This study examined the following hypothesis: "Status 2 pediatric recipients have a survival benefit with CTx." METHODS: Between 1993 and 2003, 2,375 patients were listed for CTx at 24 institutions; 614 (26%) of these patients were Status 2. By multivariate competing outcomes hazard function analysis, death after listing and post-transplant survival were analyzed. RESULTS: A single-phase hazard function described the risk of death after listing, with 20% actual mortality within 2 months after Status 1 listing. The "natural history" of Status 2-listed patients was estimated by the risk of death, whereas waiting and risk of deterioration to Status 1 at CTx (weighted by the probability of death at 3 months after Status 1 listing). At 4 months after CTx, survival with CTx exceeded the predicted "natural Hx" survival in all diagnostic categories out to 4 years of follow-up. CONCLUSIONS: Pediatric patients currently listed as Status 2 have a survival benefit with transplant out to at least 4 years. A pediatric allocation system restricted to Status 1 patients could only be justified if the vast majority of such patients could be transplanted within 1 to 2 months.

Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: a multicenter study.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) commonly undergo cardiac transplantation as primary management. METHODS: We examined outcomes of primary transplantation for unpalliated HLHS. We analyzed data from the 20 institutions of the Pediatric Heart Transplant Study Group, from January 1, 1993, through December 31, 1998, using actuarial and parametric survival analysis and competing outcomes analysis. RESULTS: During the 6 years studied, 1,234 patients were listed for cardiac transplantation; 262 patients (21.2%) had unpalliated HLHS. The number (and percentage) of patients with HLHS decreased from 58 (27% of patients listed) in 1993 to 30 (14%) in 1998. Overall, 25% of infants with HLHS died while waiting; primary cause of death was cardiac failure (50%). Of the remaining patients awaiting transplantation, 23 (9%) underwent Norwood/Fontan-type surgeries as interim palliation: 52% died. Ultimately, 175 patients underwent cardiac transplantation (67%); 50% received organs by 2 months after listing. Post-transplant actuarial survival was 72% at 5 years, with 76% of deaths (35/46) occurring within 3 months; early mortality was caused primarily by graft failure within the first 30 days after transplantation (in 54%). Among 1-month survivors, survival at 1 and at 5 years was 92% and 85%, respectively. Of the 262 patients listed with unpalliated HLHS, overall survival, taking into account mortality after listing and after transplantation, was 68% at 3 months and 54% at 5 years. CONCLUSIONS: Cardiac transplantation offers good intermediate survival for infants with unpalliated HLHS.

Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.

BACKGROUND: Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. METHODS AND RESULTS: Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). CONCLUSIONS: Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study.

BACKGROUND: Rejection with severe hemodynamic compromise results in high mortality in adult transplant patients. This study determines the incidence, outcome and risk factors for rejection with severe hemodynamic compromise in a multi-institutional study of pediatric heart transplant recipients. METHODS: Data from 847 patients transplanted between 1/1/93 and 12/31/98 at 18 centers in the Pediatric Heart Transplant Study were analyzed. Rejection with severe hemodynamic compromise was defined as a clinical event occurring beyond 1 week postoperatively, which led to augmentation of immunosuppression and use of inotropic therapy. Actuarial freedom from such rejection and death after rejection were determined and risk factors sought. RESULTS: Among 1,033 rejection episodes in 532 patients, 113 (11%) episodes were associated with severe hemodynamic compromise in 95 patients. The highest risk for severe rejection was in the first year. Risk factors were older recipient age (p >.05) and non-white race (p >.001). Survival after an episode was poor (60%), and biopsy score did not affect outcome. Deaths were due to rejection (n = 14), other cardiac causes (n = 17), infection (n = 5), lymphoma (n = 2), pulmonary causes (n = 2), and thrombosis (n = 1). CONCLUSIONS: Rejection with severe hemodynamic compromise occurs in 11% of pediatric patients, irrespective of age, sex or biopsy score, and mortality is high. Non-white race and older recipient age are independent risk factors for rejection with severe hemodynamic compromise. Aggressive treatment and close surveillance should be crucial components of protocols aimed at reducing the high mortality.

Replacement of the aortic root in patients with Marfan's syndrome.

BACKGROUND: Replacement of the aortic root with a prosthetic graft and valve in patients with Marfan's syndrome may prevent premature death from rupture of an aneurysm or aortic dissection. We reviewed the results of this surgical procedure at 10 experienced surgical centers. METHODS: A total of 675 patients with Marfan's syndrome underwent replacement of the aortic root. Survival and morbidity-free survival curves were calculated, and risk factors were determined from a multivariable regression analysis. RESULTS: The 30-day mortality rate was 1.5 percent among the 455 patients who underwent elective repair, 2.6 percent among the 117 patients who underwent urgent repair (within 7 days after a surgical consultation), and 11.7 percent among the 103 patients who underwent emergency repair (within 24 hours after a surgical consultation). Of the 675 patients, 202 (30 percent) had aortic dissection involving the ascending aorta. Forty-six percent of the 158 adult patients with aortic dissection and a documented aortic diameter had an aneurysm with a diameter of 6.5 cm or less. There were 114 late deaths (more than 30 days after surgery); dissection or rupture of the residual aorta (22 patients) and arrhythmia (21 patients) were the principal causes of late death. The risk of death was greatest within the first 60 days after surgery, then rapidly decreased to a constant level by the end of the first year. CONCLUSIONS: Elective aortic-root replacement has a low operative mortality. In contrast, emergency repair, usually for acute aortic dissection, is associated with a much higher early mortality. Because nearly half the adult patients with aortic dissection had an aortic-root diameter of 6.5 cm or less at the time of operation, it may be prudent to undertake prophylactic repair of aortic aneurysms in patients with Marfan's syndrome when the diameter of the aorta is well below that size.

Gene polymorphisms for plasminogen activator inhibitor-1/tissue plasminogen activator and development of allograft coronary artery disease.

BACKGROUND: Impaired fibrinolytic activity has been linked to the presence and severity of allograft vasculopathy (Tx CAD). This impairment may be associated with the presence of certain fibrinolytic protein gene polymorphisms. METHODS AND RESULTS: To investigate the relation between donor-specific fibrinolytic protein genotypes and Tx CAD, we identified donor plasminogen activator inhibitor-1 (PAI-1) HindIII and tissue plasminogen activator (TPA) EcoRI restriction fragment length polymorphisms-based genotypes by Southern blot analysis in 48 recipients of cardiac allografts and correlated these genotypes with the development of CAD. No association was found between donor TPA genotypes and the presence of Tx CAD. Among the 48 patients, 17% were homozygous for the 1/1 PAI-1 genotype, 51% for the 2/2 PAI-1 genotype, and 32% for the 1/2 PAI-1 genotype. The actuarial freedom from any CAD for the recipients with each respective donor PAI-1 genotype at 12 and 24 months was 100% and 100% for the 1/1 PAI-1 genotype, 92% and 92% for the 1/2 PAI-1 genotype, and 75% and 45% for the 2/2 PAI-1 genotype (P=0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (P=0.02) than those recipients with a Tx CAD-free allograft. CONCLUSIONS: These data suggest that recipients with a 2/2 PAI-1 genotype are at a significant risk of developing Tx CAD. This genotype may serve as a useful screening tool for predicting the future development of Tx CAD.

Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database.

BACKGROUND: 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. METHODS: 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 was > 70% or 2 or more primary vessels stenoses were > 70% or branch stenoses were > 70% in all 3 systems. RESULTS: 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. CONCLUSIONS: 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.

Risk of death or incapacitation after heart transplantation, with particular reference to pilots.

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.

Pretransplantation risk factors for death after heart transplantation: the Henri Mondor experience.

BACKGROUND AND METHODS: Risk factors for death after primary heart transplantation were identified by analyzing our total experience with 234 patients who underwent transplantation at our institution from May 28, 1979, to May 27, 1996. RESULTS: There were 205 male and 29 female patients. Mean recipient age was 48.5+/-10.9 years (standard deviation). Recipient diagnosis included ischemic cardiomyopathy in 103 (44%), idiopathic cardiomyopathy in 98 (42%), valvular heart disease in 17 (7%), congenital heart disease in 4 (2%), and other diagnoses in 12 (5%) patients. Donor age was 32+/-10.2 years. Graft ischemic time was 138.1+/-51.8 minutes. The operative mortality rate was 23.5%. Actuarial survival estimates for all patients at 1, 5, and 10 years were 62%, 50%, and 44%, respectively. The three most common causes of death (both early and late) after primary heart transplantation were infection (27.4%), acute rejection (18.9%), and early graft failure (17.9%). Multivariate logistic regression analysis identified older recipient age (p = 0.007), higher preoperative pulmonary vascular resistance (p = 0.01), recipient preoperative hepatic insufficiency (p = 0.001), and gender mismatch (p = 0.02) as independent predictors of early death (within 3 months of the procedure). Multivariate proportional hazard regression analysis revealed that recipient idiopathic cardiomyopathy (p = 0.02) and recipient preoperative liver failure (p = 0.01) were independent risk factors for late death (after 3 months). CONCLUSION: These results underscore the importance of adequate recipient selection and recipient/donor matching for short- and long-term survival after primary heart transplantation.

A prospective algorithm for the management of air leaks after pulmonary resection.

BACKGROUND: Air leaks (ALs) are a common complication after pulmonary resection, yet there is no consensus on their management. METHODS: An algorithm for the management of chest tubes (CT) and ALs was applied prospectively to 101 consecutive patients who underwent elective pulmonary resection. Air leaks were graded daily as forced expiratory only, expiratory only, inspiratory only, or continuous. All CTs were kept on 20 cm of suction until postoperative day 2 and were then converted to water seal. On postoperative day 3, if both a pneumothorax and AL were present, the CT was placed to 10 cm H2O of suction. If a pneumothorax was present without an AL, the CT was returned to 20 cm H2O of suction. Air leaks that persisted after postoperative day 7 were treated with talc slurry. RESULTS: There were 101 patients (67 men); on postoperative day 1, 26 had ALs and all were expiratory only. Univariable analysis showed a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (p = 0.005), increased age (p = 0.007), increased ratio of residual volume to total lung capacity (RV/TLC) (p = 0.04), increased RV (p = 0.02), and an increased functional residual capacity (FRC) (p = 0.02) to predict the presence of an AL on postoperative day 1. By postoperative day 2, 22 patients had expiratory ALs. After 12 hours of water seal, 13 of the 22 patients' ALs had stopped, and 3 more sealed by the morning of postoperative day 3. However, 2 of the 6 patients whose ALs continued experienced a pneumothorax. Five of the 6 patients with ALs on postoperative day 4 still had ALs on postoperative day 7, and all were treated by talc slurry through the CT. All ALs resolved within 24 hours after talc slurry. CONCLUSIONS: Most ALs after pulmonary resection are expiratory only. A low FEV1/FVC ratio, increased age, increased RV/TLC ratio, increased RV, and an increased FRC were predictors of having an ALs on postoperative day 1. Conversion from suction to water seal is an effective way of sealing expiratory AL, and pneumothorax is rare. If an expiratory AL does not stop by postoperative day 4 it will probably persist until postoperative day 7, and talc slurry may be an effective treatment.