Congenitally Corrected Transposition Presenting in the First Year of Life: Survival and Fate of the Systemic Right Ventricle.

INTRODUCTION: Knowledge gaps exist in the life expectancy and functional outcome of patients with congenitally corrected transposition (ccTGA) presenting early in life, which is relevant in the evaluation of early anatomic repair. METHODS: In a single-center analysis, 91 patients with ccTGA were identified over 25 years, of which 31 presented with biventricular anatomy in the first year of life and formed the study cohort. End points for analysis included survival, moderate or worse tricuspid valve regurgitation, and systemic right ventricle (RV) dysfunction. Median follow-up was 4.9 years (range: 7 days to 20 years). RESULTS: Among 31 patients presenting in the first year of life, 9 (29%) never received cardiac surgery, while 22 (71%) underwent 36 cardiac operations. Overall freedom from moderate or severe systemic RV dysfunction was 75% at 10 years. Overall survival was 82% at 10 years. Surgical mortality was 5.6% (2/36). Among survivors with a systemic RV, 23 (100%) of 23 were Ross or NYHA class I or II at last follow-up. CONCLUSIONS: Congenitally corrected transposition presenting in the first year of life and maintaining a systemic RV can expect (1) long-term survival of more than 80% at 10 years, (2) low expected surgical mortality (overall 6%), and (3) 75% late freedom from major RV dysfunction at 10 years. Pending multi-institutional analyses, this experience with a systemic RV in ccTGA provides an initial benchmark for comparison when considering early elective anatomic correction.

Performance of Noninvasive Assessment in the Diagnosis of Right Heart Failure After Left Ventricular Assist Device.

Right heart failure (RHF) after left ventricular assist device (LVAD) is associated with poor outcomes. Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) defines RHF as elevated right atrial pressure (RAP) plus venous congestion. The purpose of this study was to examine the diagnostic performance of the noninvasive Intermacs criteria using RAP as the gold standard. We analyzed 108 patients with LVAD who underwent 341 right heart catheterizations (RHC) between January 1, 2006, and December 31, 2013. Physical exam, echocardiography, and laboratory data at the time of RHC were collected. Conventional two-by-two tables were used and missing data were excluded. The noninvasive Intermacs definition of RHF is 32% sensitive (95% cardiac index (CI), 0.21-0.44) and 97% specific (95% CI, 0.95-0.99) for identifying elevated RAP. Clinical assessment failed to identify two-thirds of LVAD patients with RAP > 16 mm Hg. More than half of patients with elevated RAP did not have venous congestion, which may represent a physiologic opportunity to mitigate the progression of disease before end-organ damage occurs. One-quarter of patients who met the noninvasive definition of RHF did not actually have elevated RAP, potentially exposing patients to unnecessary therapies. In practice, if any component of the Intermacs definition is present or equivocal, our data suggest RHC is warranted to establish the diagnosis.

Long-term outcomes after transplantation after support with a pulsatile pediatric ventricular assist device.

BACKGROUND: There has been increasing use of durable ventricular assist devices (VAD) in children as a bridge to transplantation (BTT). The Berlin Heart investigational device exemption (IDE) trial was the first pediatric VAD trial to demonstrate excellent survival outcomes as a BTT. OBJECTIVES: Our aim was to compare the expanded post-transplant outcomes for children enrolled in the Berlin Heart IDE trial to a matched Pediatric Heart Transplant Study (PHTS) cohort not requiring mechanical circulatory support (MCS). SETTING: University Hospitals. METHODS: This was a retrospective review of linked PHTS and Berlin Heart IDE databases for pediatric (≤18 years) recipients transplanted from 2007-2011. Subjects with <5 years of follow up were excluded. VAD supported patients were matched 1:2 to non-VAD supported controls from the PHTS database. RESULTS: Among 109 Berlin Heart IDE study enrollees, 83 were merged with the PHTS database and matched to 166 non-MCS supported patients. There was no difference in diagnosis, status at listing, and age between groups with the expected difference in inotrope use in the non-MCS supported patients. Compared to their matched cohort, there was no statistical difference in 5-year patient survival between VAD and non-VAD patients (81% vs 88%; p = 0.09) nor was there a difference in freedom from rejection or infection. CONCLUSIONS: This data suggests that children supported with a Berlin Heart VAD had similar survival, infection and rejection rates compared to those not requiring MCS support. Continued surveillance of the Berlin Heart IDE trial population post heart transplantation is warranted.

Hyperthyroidism is Underdiagnosed and Undertreated in 3336 Patients: An Opportunity for Improvement and Intervention.

OBJECTIVE: The aim of this study was to determine the prevalence of undiagnosed and untreated hyperthyroidism among patients with suppressed thyroid-stimulating hormone (TSH). BACKGROUND: Hyperthyroidism can significantly diminish patient quality of life and increase the financial burden on patients and health systems. We hypothesized that many patients with hyperthyroidism remain undiagnosed because physicians fail to recognize and evaluate suppressed TSH as the first indication of disease. METHODS: We reviewed administrative data on 174011 patients with TSH measured at a tertiary referral center between 2011 and 2017 to identify individuals with hyperthyroidism (TSH <0.05 mU/L) and their subsequent outcomes: evaluation (measurement of T4, T3, radioactive iodine (RAI) uptake scan, thyroid-stimulating immunoglobulin, thyroid peroxidase antibodies) diagnosis, referral and treatment. We used Kaplan-Meier methods and multivariable time-related parametric hazard modeling to measure our outcomes. RESULTS: We found 3336 patients with hyperthyroidism. The mean age of our cohort was 52 ±â€Š17 years, with 79% females and 59% whites. Only 1088 patients (33%) received any appropriate evaluation and hyperthyroidism remained undiagnosed in 37% of patients who had the appropriate workup. Among those diagnosed with hyperthyroidism, only 21% were referred for surgery and 34% received RAI. Predictors for hyperthyroidism diagnosis include lower TSH (0.01u/L), younger age, African-American race, private commercial insurance, being seen in an outpatient setting, absence of medical comorbidities, presentation with ophthalmopathy, or weight loss. CONCLUSIONS: Hyperthyroidism is frequently unrecognized and untreated, which can lead to adverse outcomes and increased costs. Improved systems for detection and treatment of hyperthyroidism are needed to address this gap in care.

High Right Atrial Pressure and Low Pulse Pressure Predict Gastrointestinal Bleeding in Patients With Left Ventricular Assist Device.

BACKGROUND: Gastrointestinal bleeding (GIB) remains a major morbid event during continuous flow left ventricular assist device (LVAD) support. This study investigated whether a common hemodynamic profile is associated with GIB in patients with LVADs. METHODS AND RESULTS: A single institution analysis reviewed all patients who underwent right heart catheterization (RHC) following LVAD implant between January 1, 2006, and December 31, 2013, with follow-up through June 2015. Kaplan-Meier and multiphase hazard statistical methods were employed. Among 108 patients with 341 RHC, 55 hospitalizations for GIB occurred within 1 year of RHC. Freedom from GIB at 6 months was 92% in patients with pulse pressure ≥35 mmHg, compared with 76% with pulse pressure <35 mmHg. By multivariable analysis, the significant predictors of GIB were: older age at implant, number of prior GIB, lower pulse pressure, lower mean arterial pressure, and higher right atrial pressure (all P < .05). The magnitude of effect is influenced by pulse pressure. CONCLUSIONS: Greater pulsatility and less venous congestion, along with other factors, are associated with a lower risk for GIB. It is reasonable to adjust therapeutic strategies to target this hemodynamic profile in patients with a propensity for GIB.

Late Left Ventricular Outflow Tract Obstruction Following the Rastelli Operation: Expectations Out to 20 Years.

BACKGROUND: Consensus is lacking regarding the optimal operation for transposition, ventricular septal defect, and pulmonary stenosis. METHODS: Between 1968 and 2012, a total of 76 patients underwent the Rastelli procedure, with 52 mid- or long-term survivors. A bracketing analysis was used to estimate the likelihood of late left ventricular outflow tract obstruction (LVOTO). RESULTS: Early mortality decreased over the period of study, with no hospital mortality since 2000. Among one year survivors, 10- and 20-year survival was 90% and 72%, respectively. Freedom from reoperation for LVOTO was 87% at 20 years, with no increase in risk among patients having the procedure before 5 years of age. Available late echocardiographic or catheterization data indicated mild or no LVOTO at a median of 14.3 years in a subset of 38 patients. Estimated freedom from major LVOTO at 20 years is bracketed between the estimate of 87% freedom from reoperation for LVOTO at 20 years and the 78% freedom from reoperation for LVOTO or cardiac death by 20 years. CONCLUSION: The Rastelli operation can be performed in the current era with an early mortality that approaches 0% and with 20-year survival that exceeds 70%. The late risk of important LVOTO appears to range from about 13% to 22% at 20 years, with no increase in risk among patients operated upon before the age of 5 years.

Extracorporeal Membrane Oxygenation as a Bridge to Pediatric Heart Transplantation: Effect on Post-Listing and Post-Transplantation Outcomes.

BACKGROUND: Current organ allocation algorithms direct hearts to the sickest recipients to mitigate death while waiting. This may result in lower post-transplant (Tx) survival for high-risk candidates mandating close examination to determine the appropriateness of different technologies as a bridge to Tx. METHODS AND RESULTS: We analyzed all patients (<18 years old) from the Pediatric Heart Transplant Study (PHTS) database listed for heart Tx (1993-2013) to determine the effect of extracorporeal membrane oxygenation (ECMO) support at the time of listing and the time of Tx on waitlist mortality and post-Tx outcomes. Eight percent of patients were listed on ECMO, and within 12 months, 49% had undergone Tx, 35% were deceased, and 16% were alive waiting. Survival at 12 months after listing (censored at Tx) was worse in patients on ECMO at listing (50%) compared with ventricular assist device at listing (76%) or not on ECMO or ventricular assist device at listing (76%; P<0.0001). Two hundred three (5%) patients underwent Tx from ECMO; 135 (67%) had been on ECMO since listing, and 67 (33%) had deteriorated to ECMO support while waiting. Survival after Tx was worse in patients who underwent Tx from ECMO (3 years: 64%) versus on ventricular assist device at Tx (3 years: 84%) or not on ECMO/ventricular assist device at Tx (3 years: 85%; P<0.0001). Patients transplanted from ECMO at age <1 year had the worst survival. CONCLUSIONS: Pediatric patients requiring ECMO support before heart Tx have poor outcomes. Prioritization of donor hearts to children waitlisted on ECMO warrants careful consideration because of ECMO's high pre- and post-Tx mortality.

Hypoalbuminemia and poor growth predict worse outcomes in pediatric heart transplant recipients.

Children with end-stage cardiac failure are at risk of HA and PG. The effects of these factors on post-transplant outcome are not well defined. Using the PHTS database, albumin and growth data from pediatric heart transplant patients from 12/1999 to 12/2009 were analyzed for effect on mortality. Covariables were examined to determine whether HA and PG were risk factors for mortality at listing and transplant. HA patients had higher waitlist mortality (15.81% vs. 10.59%, p = 0.015) with an OR of 1.59 (95% CI 1.09-2.30). Survival was worse for patients with HA at listing and transplant (p ≤ 0.01 and p = 0.026). Infants and patients with congenital heart disease did worse if they were HA at time of transplant (p = 0.020 and p = 0.028). Growth was poor while waiting with PG as risk factor for mortality in multivariate analysis (p = 0.008). HA and PG are risk factors for mortality. Survival was worse in infants and patients with congenital heart disease. PG was a risk factor for mortality in multivariate analysis. These results suggest that an opportunity may exist to improve outcomes for these patients by employing strategies to mitigate these risk factors.

Donors' characteristics and impact on outcomes in pediatric heart transplant recipients.

Organ availability and acceptability limit pediatric HTx. What characteristics define an unacceptable or high-risk pediatric donor remains unclear. The purpose of this study was to characterize a large cohort of pediatric donors and determine the donor risk factors, including cumulative risk, that affect recipient survival. Data from the PHTS, a prospective multicenter study, were used to examine the impact of donor factors on the outcomes of patients listed <18 yr of age who received a HTx between 1993 and 2009. Donor data were available for 3149 of 3156 HTx (99.8%). Donor cause of death, need for inotropes, or CPR did not affect survival outcomes (p = 0.05). Ischemic time also did not have an impact on overall recipient survival; however, longer ischemic times negatively impacted one-yr post-transplant survival (p < 0.0001). There was no impact of cumulative risk factors on survival (p = 0.8). Although used in a minority of cases, hormonal therapy in the donor positively impacted survival (p = 0.03). In multivariate analysis, the only donor factor associated with decreased survival was smaller donor BSA, the other factors being related to the recipient characteristics. When analyzed by recipient age, there were no donor-related factors that affected survival for those who received a transplant at <6 months of age. Longer ischemic time (p < 0.0001) and greater age difference between the recipient and donor (p = 0.0098) were donor-related factors impacting early-phase survival for recipients who received a graft at ≥10 yr of age. Factors perceived to define a marginal or high-risk pediatric heart donor including inotrope use, CPR and donor cause of death may have less impact on outcomes than previously thought. Longer ischemic times did impact one yr, but not overall survival, and this impact was much greater with older donors. Parameters for accepting a donor heart can potentially be expanded, especially in the infant age group, but strong consideration should always be given to the interaction between ischemic time and donor age.

Outcomes of fetal listed patients awaiting heart transplantation.

HTx in neonates is mainstay therapy for those with severe cardiomyopathies and congenital heart disease. Fetal listing for HTx has been proposed as a way to increase the potential window for a donor with outcomes predicted to be similar to the neonatal population. Data from the PHTS, a prospective multicenter study, were used to examine the outcomes of fetuses listed between 1993 and 2009. Four thousand three hundred and sixty-five children were listed for HTx during this period. Fetuses comprised 1% and neonates 19.8% of listed patients. In those patients listed as fetus and transplanted, the median wait time from listing to HTx was 55 days (range 4-255), with a median of 25 days (range 0-233) after birth. By six months post-listing, a higher proportion of fetal listed patients had undergone HTx with a lower waitlist mortality when compared with neonate. There was no significant difference in survival following HTx between the two group (p = 0.4). While the results of this study may be less applicable to current practice due to changes in referrals for fetal listing, they do indicate that fetal listing can be a reasonable option. These results are of particular interest at the present time given the ongoing public discourse on the proposed elimination of fetal listing within UNOS.

Ten yr of pediatric heart transplantation: a report from the Pediatric Heart Transplant Study.

The PHTS was founded in 1991 as a not-for-profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2000-December 31, 2009) and summarize the changes, trends, outcomes, and lessons learned.

Comparison of risk factors and outcomes for pediatric patients listed for heart transplantation after bidirectional Glenn and after Fontan: an analysis from the Pediatric Heart Transplant Study.

BACKGROUND: Patients listed for transplant after the bidirectional Glenn (BDG) may have better outcomes than patients listed after Fontan. This study examined and compared outcomes after listing for BDG and Fontan patients. METHODS: All patients listed for transplant after the BDG in the Pediatric Heart Transplant Study between January 1993 and December 2008 were evaluated. Comparisons were made with Fontan patients and with a matched cohort of congenital heart disease patients. Competing outcomes analysis and actuarial survival were evaluated for the study populations, including an examination of various risk factors. RESULTS: Competing outcomes analysis for BDG and Fontan patients after listing were similar. There was no difference in actuarial survival after listing or transplant among the 3 cohorts. Mechanical ventilation, United Network of Organ Sharing status, and age were risk factors for death after listing in BDG and Fontan patients, but ventilation at the time of transplant was significant only for the Fontan patients. Mortality was increased in Fontan patients listed < 6 months after surgery compared with patients listed > 6 months after surgery, but no difference was observed in BDG patients. There was a trend toward improved survival after listing for both populations across 3 eras of the study, but this did not reach statistical significance. CONCLUSION: Outcomes after listing for BDG and Fontan patients are similar. Mechanical ventilation at the time of transplant remains a significant risk factor for death in the Fontan population, as does listing for transplant soon after the Fontan, suggesting that some patients may benefit from transplant instead of Fontan completion.

Sudden death after pediatric heart transplantation: analysis of data from the Pediatric Heart Transplant Study Group.

BACKGROUND: Sudden death is a well-recognized complication of heart transplantation. Little is known about the incidence and risk factors for sudden death after transplant in children. The purpose of this study was to determine the incidence of and risk factors for sudden death. METHODS: This retrospective multicenter cohort study used the Pediatric Heart Transplant Study Group (PHTS) database, an event-driven registry of children aged <18 at listing undergoing heart transplantation between 1993 and 2007. Standard Kaplan-Meier and parametric analyses were used for survival analysis. Multivariate analysis in the hazard-function domain was used to identify risk factors for sudden death after transplant. RESULTS: Of 604 deaths in 2,491 children who underwent heart transplantation, 94 (16%) were classified as sudden. Freedom from sudden death was 97% at 5 years, and the hazard for sudden death remained constant over time at 0.01 deaths/year. Multivariate risk factors associated with sudden death included black race (hazard ratio [HR], 2.6; p < 0.0001), United Network of Organ Sharing (UNOS) status 2 at transplant (HR, 1.8; p = 0.008), older age (HR, 1.4/10 years of age; p = 0.03), and an increased number of rejection episodes in the first post-transplant year (HR, 1.6/episode; p = 0.03). CONCLUSION: Sudden death accounts for 1 in 6 deaths after heart transplant in children. Older recipient age, recurrent rejection within the first year, black race, and UNOS status 2 at listing were associated with sudden death. Patients with 1 or more of these risk factors may benefit from primary prevention efforts.

Allosensitization and outcomes in pediatric heart transplantation.

BACKGROUND: Allosensitization among children being considered for heart transplantation remains a great challenge. Controversy exists as to the best approach for those with elevated panel-reactive antibody (PRA) titers. We sought to define the association between elevated PRA and outcomes using data from the multi-institutional Pediatric Heart Transplant Study Group. METHODS: Between January 1993 and December 2008, 3,016 patients (>1 month of age) were listed for heart transplantation. PRA data at listing were available for 2,500 (83%) patients, and 2,237 underwent transplantation with PRA data being available for 1,904 (85%). Because various PRA assays were employed (e.g., cell-based and solid phase) we entered the highest value regardless of methodology. RESULTS: Among the factors associated with high PRA at transplant were Status 1 at listing, previous sternotomy and prior Norwood procedure. An elevated PRA at listing was associated with higher risk of death while waiting. Of subjects with PRA ≥ 50% only 57% were transplanted by 1 year on the waitlist, as compared with 76% of those with PRA <10%. Waitlist mortality for the highly allosensitized subjects (≥ PRA 50%) was 19% by 12 months. Survival at 1 year after transplantation was significantly lower in those with PRA ≥ 50% versus those with PRA <10% (73% vs 90%, respectively, p < 0.0001). Those with elevated PRA who had a negative prospective crossmatch had no difference in survival compared with those without allosensitization. There was no significant association between PRA levels and time to first rejection or development of coronary allograft vasculopathy. CONCLUSIONS: Significant allosensitization is associated with more than a 2-fold increased risk of death within the first transplant year. Although prospective crossmatching abrogates the risk of post-transplant mortality, it may contribute to higher pre-transplant attrition due to longer waitlist times. There is a critical need for strategies to minimize the impact of allosensitization and antibody-mediated rejection immediately after transplantation.