Longer Ischemic Time is Associated with Increased Ventricular Stiffness as Measured by Pressure-Volume Loop Analysis in Pediatric Heart Transplant Recipients.

BACKGROUND: The purpose of this study was to investigate the associations between clinical factors and cardiac function as measured by pressure-volume loops (PVLs) in a pediatric heart transplant cohort. METHODS: Patients (age < 20 years) who underwent heart transplantation presenting for a clinically indicated catheterization were enrolled. PVLs were recorded using microconductance catheters (CD Leycom®, Zoetermeer, Netherlands). Demographic data, serum B-type natriuretic peptide (BNP), time from transplant, ischemic time, presence of transplant coronary artery disease, donor-specific antibodies, and history of rejection were recorded at the time of catheterization. PVL data included contractility indices: end-systolic elastance and preload recruitable stroke work; ventricular-arterial coupling index; ventricular stiffness constant, Beta; and isovolumic relaxation time constant, tau. Associations between PVL measures and clinical data were investigated using non-parametric statistical tests. RESULTS: A total of 18 patients were enrolled. Median age was 8.7 years (IQR 5-14 years). There were ten males and eight females. Six patients had a history of rejection and ten had positive donor-specific antibodies. There was no transplant coronary artery disease. Median BNP was 100 pg/mL (IQR 46-140). Time from transplant to PVL obtained during catheterization procedure was 4.1 years (IQR 1.7-7.8 year). No single clinical characteristic was statistically significant when correlated with PVL data. However, longer ischemic time was associated with worse Beta (r = 0.49, p = 0.05). CONCLUSIONS: Our study found that longer ischemic times are associated with increased left ventricular stiffness. No other single clinical variable is associated with cardiac dysfunction as determined by PVL analysis.

Decline in ventricular function as a result of general anesthesia in pediatric heart transplant recipients.

Echocardiography is frequently performed under anesthesia during procedures such as cardiac catheterization with EMB in pediatric HTx recipients. Anesthetic agents may depress ventricular function, resulting in concern for rejection. The aim of this study was to compare ventricular function as measured by echocardiography before and during GA in 17 pediatric HTx recipients. Nearly all markers of ventricular systolic function were significantly decreased under GA, including EF (-4.2% ±1.2, P < .01) and RV FAC (-0.05 ± 0.02, P = .04). Subjects in the first post-transplant year (n = 9) trended toward a more significant decrease in EF vs those beyond the first post-transplant year (n = 8; -6.0% ±1.2 vs -2.1 ± 2.0, P = .1). This information quantifies a decline in biventricular function that should be expected in pediatric HTx recipients while under GA and can assist the transplant clinician in avoiding unnecessary treatment of transient GA-induced ventricular dysfunction.

Effect of Sildenafil on Pressure-Volume Loop Measures of Ventricular Function in Fontan Patients.

UNLABELLED: Sildenafil has been reported to improve exercise capacity in Fontan patients, but the physiologic mechanisms behind these findings are not completely understood. The objective of this study was to study the acute effect of sildenafil on pressure-volume loop (PVL) measures of ventricular function in Fontan patients. Patients after Fontan operation who were presenting for a clinically indicated catheterization were enrolled. Patients were randomized in a double-blinded fashion to receive placebo (n = 9) or sildenafil (n = 10) 30-90 min prior to catheterization. PVLs were recorded using microconductance catheters at baseline and after infusion of dobutamine (10 mcg/kg/min). The primary outcome was change in ventriculoarterial (VA) coupling. For the entire cohort, VA coupling trended toward improvement with dobutamine (1.4 ± 0.4 to 1.8 ± 0.9, p = 0.07). End-systolic elastance showed improvement (2.6 ± 0.9 to 3.8 ± 1.4 mmHg m(2)/ml, p < 0.01) with dobutamine infusion. The cohorts had similar VA coupling at baseline (p = 0.32), but the sildenafil cohort trended toward having less of an improvement in VA coupling with dobutamine stress (p = 0.06). There were no differences between PVL measures of systolic or diastolic function between treatment groups, both at baseline and after dobutamine infusion. Patients with Fontan circulation had improved contractility and trended toward improvement in VA coupling with dobutamine stress. Acute sildenafil administration was not associated with improved PVL measurements of ventricular function in this population. These results suggest that clinical improvements seen with administration of sildenafil in Fontan patients are not associated with an acute improvement in ventricular function. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov ; Clinicaltrials.gov Identifier: NCT01815502.

The Thoratec CentriMag for pediatric right ventricular failure.

Acute right ventricular failure post heart transplantation in the pediatric population has not been well documented. Treatment using medical therapies including inotropes and nitric oxide are often inefficient for pediatric patients. Extracorporeal membrane oxygenation has been traditionally used in children until a long-term decision can be made. As a result of the emergence of smaller assist devices, pediatric practitioners now have more options available to treat this patient population. We describe the successful use of the Thoratec CentriMag in a pediatric patient posttransplantation with acute right ventricular failure.

Partial heart transplantation for pediatric heart valve dysfunction: A clinical trial protocol.

Congenital heart defects are the most common type of birth defects in humans and frequently involve heart valve dysfunction. The current treatment for unrepairable heart valves involves valve replacement with an implant, Ross pulmonary autotransplantation, or conventional orthotopic heart transplantation. Although these treatments are appropriate for older children and adults, they do not result in the same efficacy and durability in infants and young children for several reasons. Heart valve implants do not grow with the. Ross pulmonary autotransplants have a high mortality rate in neonates and are not feasible if the pulmonary valve is dysfunctional or absent. Furthermore, orthotopic heart transplants invariably fail from ventricular dysfunction over time. Therefore, the treatment of irreparable heart valves in infants and young children remains an unsolved problem. The objective of this single-arm, prospective study is to offer an alternative solution based on a new type of transplant, which we call "partial heart transplantation." Partial heart transplantation differs from conventional orthotopic heart transplantation because only the part of the heart containing the heart valve is transplanted. Similar to Ross pulmonary autotransplants and conventional orthotopic heart transplants, partial heart transplants contain live cells that should allow it to grow with the recipient child. Therefore, partial heart transplants will require immunosuppression. The risks from immunosuppression can be managed, as seen in conventional orthotopic heart transplant recipients. Stopping immunosuppression will simply turn the growing partial heart transplant into a non-growing homovital homograft. Once this homograft deteriorates, it can be replaced with a durable adult-sized mechanical implant. The protocol for our single-arm trial is described. The ClinicalTrials.gov trial registration number is NCT05372757.

Right Ventricular Function is Important for Pulmonary Artery Banding in Left Ventricular Dysfunction.

Small infants with severe left ventricular dysfunction (LVD) carry a poor prognosis with limited therapeutic options. Although mechanical support and heart transplantation are definitive therapies, improvement of left ventricular function with reversible pulmonary artery banding (rPAB) has been described. We report two cases of LVD treated with rPAB. One was successfully temporized, and one progressed to requiring transplantation, indicating that appropriate patient selection is critical to this technique's success.

Cardiac allograft vasculopathy and graft failure in pediatric heart transplant recipients after rejection with severe hemodynamic compromise.

BACKGROUND: Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC. METHODS: Data from 3,259 heart transplant (HT) recipients between January 2005 and December 2015 in the Pediatric Heart Transplant Study (PHTS) were analyzed. Predictors for RSHC and outcome after RSHC were sought. Time to RSHC was analyzed using the Cox proportional hazards regression model. Cardiac allograft vasculopathy (CAV) after HT and CAV after RSHC were analyzed as time-dependent covariates. Timing of RSHC was analyzed as occurring before and after 4 years after RSHC. RESULTS: There were 309 patients (9.5%) with ≥ 1 RSHC episodes. In 143 patients with RSHC, the first episode was within 1 year after HT. Independent risk factors for RSHC were age 1 to 5 years at HT (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.04-2.18), age > 10 years at HT (HR, 1.83; 95% CI, 1.29-2.60), black race (HR, 1.64; 95% CI, 1.25-2.15), prior cardiac surgery (HR, 1.55; 95% CI, 1.03-2.31), ventricular assist device support at HT (HR, 1.65; 95% CI, 1.18-2.29), maintenance steroids (HR, 1.39; 95% CI, 1.06-1.82), and recipient on inotropes, pressors, or thyroid hormones (HR, 1.45; 95% CI, 1.09-1.94). Graft survival at 5 years after RSHC was 45.7%. RSHC was a greater risk factor for earlier CAV (HR, 7.78; 95% CI, 5.82-10.40) than other rejection types (HR, 2.31; 95% CI, 1.79-3.00). Patients with late RSHC, after 1 year after RSHC had increased risk of graft loss 4 years after RSHC (HR, 7.12; 95% CI, 2.18-23.22). The 5-year graft survival after RSHC was 50.5% for early RSHC and 39.0% for late RSHC. CONCLUSIONS: Mortality after RSHC is high in the current treatment era. Many patient risk factors for RSHC cannot be modified, including age, race, prior cardiac surgery, and ventricular assist device support. After RSHC, CAV is the only predictor of graft failure. Patients who have late RSHC fare worse than those who have RSHC within the first year after HT.

Validation of a Simple Score to Determine Risk of Early Rejection After Pediatric Heart Transplantation.

OBJECTIVES: This study aimed to develop a reliable and feasible score to assess the risk of rejection in pediatric heart transplantation recipients during the first post-transplant year. BACKGROUND: The first post-transplant year is the most likely time for rejection to occur in pediatric heart transplantation. Rejection during this period is associated with worse outcomes. METHODS: The United Network for Organ Sharing database was queried for pediatric patients (age <18 years) who underwent isolated orthotopic heart transplantation from January 1, 2000 to December 31, 2012. Transplantations were divided into a derivation cohort (n = 2,686) and a validation (n = 509) cohort. The validation cohort was randomly selected from 20% of transplantations from 2005 to 2012. Covariates found to be associated with rejection (p < 0.2) were included in the initial multivariable logistic regression model. The final model was derived by including only variables independently associated with rejection. A risk score was then developed using relative magnitudes of the covariates' odds ratio. The score was then tested in the validation cohort. RESULTS: A 9-point risk score using 3 variables (age, cardiac diagnosis, and panel reactive antibody) was developed. Mean score in the derivation and validation cohorts were 4.5 ± 2.6 and 4.8 ± 2.7, respectively. A higher score was associated with an increased rate of rejection (score = 0, 10.6% in the validation cohort vs. score = 9, 40%; p < 0.01). In weighted regression analysis, the model-predicted risk of rejection correlated closely with the actual rates of rejection in the validation cohort (R(2) = 0.86; p < 0.01). CONCLUSIONS: The rejection score is accurate in determining the risk of early rejection in pediatric heart transplantation recipients. The score has the potential to be used in clinical practice to aid in determining the immunosuppressant regimen and the frequency of rejection surveillance in the first post-transplant year.

Effect of human leukocyte antigen-C and -DQ matching on pediatric heart transplant graft survival.

BACKGROUND: A higher degree of human leukocyte antigen (HLA) matching at the A, B, and DR loci has been associated with improved long-term survival after pediatric heart transplantation in multiple International Society for Heart and Lung Transplantation registry reports. The aim of this study was to investigate the association of HLA matching at the C and DQ loci with pediatric graft survival. METHODS: The United Network of Organ Sharing database was queried for isolated heart transplants that occurred from 1988 to 2012 with a recipient age of 17 or younger and at least 1 postoperative follow-up encounter. When HLA matching at the C or DQ loci were analyzed, only transplants with complete typing of donor and recipient at the respective loci were included. Transplants were divided into patients with at least 1 match at the C locus (C-match) vs no match (C-no), and at least 1 match at the DQ (DQ-match) locus vs no match (DQ-no). Primary outcome was graft loss. Univariate analysis was performed with the log-rank test. Cox regression analysis was performed with the following patient factors included in the model: recipient age, ischemic time; recipient on ventilator, extracorporeal membrane oxygenation, ventricular assist device, or inotropes at transplant; recipient serum bilirubin and creatinine closest to transplant, ratio of donor weight to recipient weight, underlying cardiac diagnosis, crossmatch results, transplant year, and HLA matching at the A, B, and DR loci. RESULTS: Complete typing at the C locus occurred in 2,429 of 4,731 transplants (51%), and complete typing at the DQ locus occurred in 3,498 of 4,731 transplants (74%). Patient factors were similar in C-match and C-no, except for year of transplant (median year, 2007 [interquartile range, 1997-2010] vs year 2005 [interquartile range, 1996-2009], respectively; p = 0.03) and the degree of HLA matching at the A, B, and DR loci (high level of HLA matching in 11.9% vs 3%, respectively; p < 0.01). Matching at the C locus was not associated with a decreased risk of graft loss (median graft survival: 13.1 years [95% confidence interval {CI}, 11.5-14.8] in C-no vs 15.1 years [95% CI, 13.5-16.6) in C-match, p = 0.44 log-rank; hazard ratio, 0.93; 95% CI, 0.76-1.15; p = 0.52). DQ-match did not differ from DQ-no in any of the analyzed patient factors, except DQ-match was more likely to have high degree of matching at the A, B, and DR loci vs DQ-no (9.8% vs 3.2%, p < 0.01). Matching at the DQ locus was not associated with decreased risk of graft loss (median graft survival: DQ-no, 13.1 years [95% CI, 11.7-14.6) vs DQ-match, 13.0 years [95% CI, 11.4-14.6], p = 0.80, log-rank; hazard ratio, 0.95; 95% CI, 0.81-1.1; p = 0.51. CONCLUSIONS: Complete typing at the C locus of both donor and recipient occurs less often then typing at the DQ locus. A higher degree of donor-recipient HLA matching at the C locus or the DQ locus appears not to confer any graft survival advantage.

Association of human leukocyte antigen donor-recipient matching and pediatric heart transplant graft survival.

BACKGROUND: The effect of donor-recipient human leukocyte antigen (HLA) matching on outcomes remains relatively unexplored in pediatric patients. The objective of this study was to investigate the effects of donor-recipient HLA matching on graft survival in pediatric heart transplantation. METHODS AND RESULTS: The UNOS (United Network for Organ Sharing) database was queried for heart transplants occurring between October 31, 1987, and December 31, 2012, in a recipient aged ≤17 years with ≥1 postoperative follow-up visit. Retransplants were excluded. Transplants were divided into 3 donor-recipient matching groups: no HLA matches (HLA-no), 1 or 2 HLA matches (HLA-low), and 3 to 6 HLA matches (HLA-high). Primary outcome was graft loss. Four thousand four hundred seventy-one heart transplants met the study inclusion criteria. High degree of donor-recipient HLA matching occurred infrequently: HLA-high (n=269; 6%) versus HLA-low (n=2683; 60%) versus HLA-no (n=1495; 34%). There were no differences between HLA matching groups in the frequency of coronary vasculopathy (P=0.19) or rejection in the first post-transplant year (P=0.76). Improved graft survival was associated with a greater degree of HLA donor-recipient matching: HLA-high median survival, 17.1 (95% confidence interval, 14.0-20.2) years; HLA-low median survival, 14.2 (13.1-15.4) years; and HLA-no median survival, 12.1 (10.9-13.3 years) years; P<0.01, log-rank test. In Cox-regression analysis, HLA matching was independently associated with decreased graft loss: HLA-low versus HLA-no hazard ratio, 0.86 (95% confidence interval, 0.74-0.99), P=0.04; HLA-high versus HLA-no, 0.62 (95% confidence interval, 0.43-0.90), P<0.01. CONCLUSIONS: Decreased graft loss in pediatric heart transplantation was associated with a higher degree of donor-recipient HLA matching, although a difference in the frequency of early rejection or development of coronary artery vasculopathy was not seen.