Although evidence links HLA allele mismatching to worse outcomes in pediatric heart transplantation, no studies to our knowledge have applied the quantification of structural HLA differences between ...donor and recipient to risk evaluation. We examine the association between molecular-level HLA mismatching and long-term graft loss in pediatric recipients of heart transplants.
HLA Matchmaker was used to quantify the number of mismatched class-specific HLA eplets among 4,851 heart transplant recipients ≤18 years of age in the Scientific Registry of Transplant Recipients (1987-2012). Survival analysis was used to compare long-term probabilities of graft loss by number of eplet mismatches and allele mismatches stratified by eplet mismatches.
Recipients with 10 to 20 or >20 class I (HLA-A and HLA-B) eplet mismatches experienced increased long-term graft loss compared with recipients with <10 class I eplet mismatches (adjusted hazard ratio = 1.23 95% confidence interval = 1.06-1.42, adjusted hazard ratio = 1.27 95% confidence interval = 1.08-1.50, respectively). Recipients with 2 to 4 class I allele mismatches had increased long-term graft loss compared with recipients with 0 to 1 class I allele mismatches. Neither class II (HLA-DR) eplet mismatching nor class II allele mismatching was associated with graft loss. On stratification by allele and structural eplet mismatching, only recipients with 2 to 4 class I allele mismatches and ≥10 class I eplet mismatches had an increased probability of graft loss compared with recipients with 0 to 1 class I allele mismatches (adjusted hazard ratio = 1.42 95% confidence interval = 1.09-1.57).
Molecular-level HLA mismatching may aid in identifying recipients at increased risk of long-term graft loss who could benefit from intensified post-transplant surveillance and management.
Tachycardia-induced cardiomyopathy (TIC) carries significant risk of morbidity and mortality, although full recovery is possible. Little is known about the myocardial recovery pattern.
The purpose of ...this study was to determine the time course and predictors of myocardial recovery in pediatric TIC.
An international multicenter study of pediatric TIC was conducted. Children ≤18 years with incessant tachyarrhythmia, cardiac dysfunction (left ventricular ejection fraction LVEF <50%), and left ventricular (LV) dilation (left ventricular end-diastolic dimension LVEDD z-score ≥2) were included. Children with congenital heart disease or suspected primary cardiomyopathy were excluded. Primary end-points were time to LV systolic functional recovery (LVEF ≥55%) and normal LV size (LVEDD z-score <2).
Eighty-one children from 17 centers met inclusion criteria: median age 4.0 years (range 0.0-17.5 years) and baseline LVEF 28% (interquartile range 19-39). The most common arrhythmias were ectopic atrial tachycardia (59%), permanent junctional reciprocating tachycardia (23%), and ventricular tachycardia (7%). Thirteen required extracorporeal membrane oxygenation (n = 11) or ventricular assist device (n = 2) support. Median time to recovery was 51 days for LVEF and 71 days for LVEDD. Two (4%) underwent heart transplantation, and 1 died (1%). Multivariate predictors of LV systolic functional recovery were age (hazard ratio HR 0.61, P = .040), standardized tachycardia rate (HR 1.16, P = .015), mechanical circulatory support (HR 2.61, P = .044), and LVEF (HR 1.33 per 10% increase, p=0.005). For normalization of LV size, only baseline LVEDD (HR 0.86, P = .008) was predictive.
Pediatric TIC resolves in a predictable fashion. Factors associated with faster recovery include younger age, higher presenting heart rate, use of mechanical circulatory support, and higher LVEF, whereas only smaller baseline LV size predicts reverse remodeling. This knowledge may be useful for clinical evaluation and follow-up of affected children.
Pediatric heart failure (HF) is associated with significant morbidity and mortality. Medical treatment for pediatric HF is largely derived from adult studies. Previously, there has been no described ...use of dapagliflozin in pediatric HF patients. We describe our single-center experience using dapagliflozin in addition to standard HF medical therapy in 38 pediatric HF patients since January 2020. Median age was 12.2 years (interquartile range 6.2–17.5). Majority of patients had dilated cardiomyopathy (68.4%) and reduced left ventricular ejection fraction (LVEF) of 40% or less (65.8%). HF regimens commonly included sacubitril/valsartan, beta-blocker, mineralocorticoid receptor antagonist, and loop diuretic. Median follow-up from dapagliflozin initiation for the whole cohort was 130 days (IQR 76–332). Median B-type natriuretic peptide decreased significantly from 222 to 166 pg/mL at latest clinical follow-up (
P
= .04). Estimated glomerular filtration rate trended lower at latest follow-up but was not significant from baseline. There were no clinically significant changes in blood chemistries or vital signs after initiation of dapagliflozin. No patients experienced symptomatic hypoglycemia or hypovolemia. Six patients (15.8%) experienced a symptomatic urinary tract infection necessitating antibiotic treatment. In a separate analysis of 16 patients with dilated cardiomyopathy who received dapagliflozin for a median of 313 days (IQR 191–414), median LVEF increased significantly from 32 to 37.2% (
P
= .006). Dapagliflozin, when added to a background of guideline-directed medical therapy, appears well tolerated in children with HF. Larger studies are needed to evaluate safety and efficacy of dapagliflozin in this population.
Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 ...aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18 years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6 months from VN in those who received ASA monotherapy (
n
= 113). Median age was 1.8 years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6 mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (
n
= 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, 95% CI: 9.8, 92.2,
p
= 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (
p
< 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children.
Background
The diagnosis of myocarditis presenting as isolated acute chest pain with elevated troponins but normal systolic function is challenging with significant drawbacks even for the ...gold-standard endomyocardial biopsy.
Objective
This study aimed to evaluate the diagnostic role of strain imaging by echocardiography and cardiac MRI in these patients.
Materials and methods
This was a retrospective review of children with cardiac MRI for acute chest pain with elevated troponins compared to normal controls. Echocardiographic fractional shortening, ejection fraction, speckle-tracking-derived peak longitudinal, radial, and circumferential strain were compared to cardiac MRI ejection fraction, T2 imaging, late gadolinium enhancement, speckle-tracking-derived peak longitudinal strain, radial strain, and circumferential strain.
Results
Group 1 included 10 subjects diagnosed with myocarditis, 9 (90%) males with a median age of 15.5 years (range: 14-17 years) compared with 10 age-matched controls in group 2. All subjects in group 1 had late gadolinium enhancement consistent with myocarditis and troponin ranged from 2.5 to >30 ng/ml. Electrocardiogram changes included ST segment elevation in 6 and abnormal Q waves in 1. Qualitative echocardiographic function was normal in both groups and mean fractional shortening was similar (35±6% in group 1 vs. 34±4% in group 2,
P
=0.70). Left ventricle ejection fraction by cardiac MRI, however, was lower in group 1 (52±9%) compared to group 2 at (59±4%) (
P
=0.03). Cardiac MRI derived strain was lower in group 1 vs. group 2 for speckle-tracking-derived peak longitudinal strain (-12.8±2.8% vs. -17.1±1.5%,
P
=0.001), circumferential strain (-12.3±3.8% vs. -15.8±1.2%,
P
=0.020) and radial strain (13.6±3.7% vs. 17.2±3.2%,
P
=0.040). Echocardiography derived strain was also lower in group 1 vs. group 2 for speckle-tracking-derived peak longitudinal strain (-15.6±3.9% vs. -20.8±2.2%,
P
<0.002), circumferential strain (-16±3% vs. -19.8±1.9%,
P
<0.003) and radial strain (17.3±6.1% vs. 24.8±6.3%,
P
=0.010).
Conclusion
In previously asymptomatic children, myocarditis can present with symptoms of acute chest pain suspicious for coronary ischemia. Cardiac MRI and echocardiographic strain imaging are noninvasive, radiation-free tests of immense diagnostic utility in these situations. Long-term studies are needed to assess prognostic significance of these findings.
Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level ...(C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC.
Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21 years old who underwent MPA AUC between 2011 and 2021.
Median age was 4 years (IQR .6-12.1). Median time from transplant to MPA AUC sampling was 15 days (IQR 11-19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC
(r = .3 and .383, respectively). MPA C0 had weak association (r = .451) with Trapezoidal MPA AUC
. LSS with two pharmacokinetic sampling time points at 90 (C
) and 360 (C
) min after MMF administration (estimated AUC
= 32.82 + 4.12 × C
+ 11.53 × C
) showed strong correlation with Trapezoidal MPA AUC
(r = .87).
MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC
. We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.
Cytomegalovirus (CMV) is an important complication of heart transplantation and has been associated with graft loss in adults. The data in pediatric transplantation, however, is limited and ...conflicting. We conducted a large-scale cohort study to better characterize the relationship between CMV serostatus, CMV antiviral use, and graft survival in pediatric heart transplantation.
4,968 pediatric recipients of solitary heart transplants from the Scientific Registry of Transplant Recipients were stratified into three groups based on donor or recipient seropositivity and antiviral use: CMV seronegative (CMV-) transplants, CMV seropositive (CMV+) transplants without antiviral therapy, and CMV+ transplants with antiviral therapy. The primary endpoint was retransplantation or death.
CMV+ transplants without antiviral therapy experienced worse graft survival than CMV+ transplants with antiviral therapy (10-year: 57 vs 65%). CMV+ transplants with antiviral therapy experienced similar survival as CMV- transplants. Compared to CMV seronegativity, CMV seropositivity without antiviral therapy had a hazard ratio of 1.21 (1.07-1.37 95% CI,
-value = .003). Amongst CMV+ transplants, antiviral therapy had a hazard ratio of .82 (0.74-.92 95% CI,
-value < .001). During the first year after transplantation, these hazard ratios were 1.32 (1.06-1.64 95% CI,
-value .014) and .59 (.48-.73 95% CI,
-value < .001), respectively.
CMV seropositivity is associated with an increased risk of graft loss in pediatric heart transplant recipients, which occurs early after transplantation and may be mitigated by antiviral therapy.
Introduction
The prevalence of iron deficiency and anemia in the setting of modern‐day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to ...determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors.
Methods
Single‐center, cross‐sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1‐year post‐HTx at the time of annual protocol biopsy.
Results
Median age at transplant was 3 years (IQR .5–12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients.
Conclusion
Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients.
Background
Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients.
...Methods
Single‐center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients <21 years of age with up to 2 years follow‐up between 2009 and 2020.
Results
Eighty‐seven patients were included, with 52 (59.8%) receiving EVL and 35 (40.2%) receiving SRL. Tacrolimus with PSI was the most common regimen. Intergroup comparison revealed lower baseline estimated glomerular filtration rate (eGFR) and greater increase in eGFR from baseline to 6 months and latest follow‐up in SRL cohort compared to EVL cohort. There was greater increase in HDL cholesterol in SRL cohort compared to EVL cohort. Intragroup analysis revealed eGFR and HDL cholesterol increased significantly within SRL cohort, triglycerides and glycosylated hemoglobin increased in EVL cohort, and LDL cholesterol and total cholesterol increased in both cohorts (all p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE.
Conclusion
Low‐dose PSIs in calcineurin inhibitor minimization regimens appear well‐tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population.
To describe the clinical and hemodynamic characteristics of Fontan failure in children listed for heart transplant.
In a nested study of the Pediatric Heart Transplant Society, 16 centers contributed ...information on Fontan patients listed for heart transplant between 2005and 2013. Patients were classified into four mutually exclusive phenotypes: Fontan with abnormal lymphatics (FAL), Fontan with reduced systolic function (FRF), Fontan with preserved systolic function (FPF), and Fontan with "normal" hearts (FNH). Primary outcome was waitlist and post-transplant mortality.
177 children listed for transplant were followed over a median 13 (IQR 4-31) months, 84 (47%) were FAL, 57 (32%) FRF, 22 (12%) FNH, and 14 (8%) FPF. Hemodynamic characteristics differed between the 4 groups: Fontan pressure (FP) was most elevated with FPF (median 22, IQR 18-23, mmHg) and lowest with FAL (16, 14-20, mmHg); cardiac index (CI) was lowest with FRF (2.8, 2.3-3.4, L/min/m
). In the entire cohort, 66% had FP >15 mmHg, 21% had FP >20 mmHg, and 10% had CI <2.2 L/min/m
. FRF had the highest risk of waitlist mortality (21%) and FNH had the highest risk of post-transplant mortality (36%).
Elevated Fontan pressure is more common than low cardiac output in pediatric failing Fontan patients listed for transplant. Subtle hemodynamic differences exist between the various phenotypes of pediatric Fontan failure. Waitlist and post-transplant mortality risks differ by phenotype.
