Elimination of 15N-thymidine after oral administration in human infants.

BACKGROUND: We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15N-thymidine. We compared at-home label administration with in-hospital administration in infants with tetralogy of Fallot, a form of congenital heart disease, and infants with heart failure. METHODS: We examined urine samples from 18 infants who received 15N-thymidine (50 mg/kg body weight) by mouth for five consecutive days. We used Isotope Ratio Mass Spectrometry to determine enrichment of 15N relative to 14N (%) in urine. RESULTS/FINDINGS: 15N-thymidine dose administration produced periodic rises of 15N enrichment in urine. Infants with tetralogy of Fallot had a 3.2-fold increase and infants with heart failure had a 4.3-fold increase in mean peak 15N enrichment over baseline. The mean 15N enrichment was not statistically different between the two patient populations (p = 0.103). The time to peak 15N enrichment in tetralogy of Fallot infants was 6.3 ± 1 hr and in infants with heart failure 7.5 ± 2 hr (mean ± SEM). The duration of significant 15N enrichment after a dose was 18.5 ± 1.7 hr in tetralogy of Fallot and in heart failure 18.2 ± 1.8 hr (mean ± SEM). The time to peak enrichment and duration of enrichment were also not statistically different (p = 0.617 and p = 0.887). CONCLUSIONS: The presented results support two conclusions of significance for future applications: (1) Demonstration that 15N-thymidine label administration at home is equivalent to in-hospital administration. (2) Two different types of heart disease show no differences in 15N-thymidine absorption and elimination. This enables the comparative analysis of cellular proliferation between different types of heart disease.

Assessing Donor-Recipient Size Mismatch in Pediatric Heart Transplantation: Lessons Learned From Over 7,500 Transplants.

BACKGROUND: To date, no studies have identified an optimal metric to match donor-recipient (D-R) pairs in pediatric heart transplantation (HT). OBJECTIVES: This study sought to identify size mismatch metrics that predicted graft survival post-HT. METHODS: D-R pairs undergoing HT in Pediatric Heart Transplant Society database from 1993 to 2021 were included. Effects of size mismatch by height, weight, body mass index, body surface area, predicted heart mass, and total cardiac volume (TCV) on 1- and 5-year graft survival and morbidity outcomes (rejection and cardiac allograft vasculopathy) were evaluated. Cox models with stepwise selection identified size metrics that independently predicted graft survival. RESULTS: Of 7,715 D-R pairs, 36.0% were well matched (D-R ratio: -20% to +20%) by weight, 39.0% by predicted heart mass, 50.0% by body surface area, 57.0% by body mass index, 71.0% by height, and 93.0% by TCV. Of all size metrics, only D-R mismatch by height and TCV predicted graft survival at 1 and 5 years. Effects of D-R size mismatch on graft survival were nonlinear. At both 1 and 5 years post-HT, D-R undersizing and oversizing by height led to increased graft loss, with graft loss observed more frequently with undersizing. Moderately undersized donors by height (D-R ratio: <-30%) frequently experienced rejection post-HT (P < 0.001). Assessing D-R size matching by TCV, minimal donor undersizing was protective, while oversizing up to 25% was not associated with increased graft loss. CONCLUSIONS: In pediatric HT, D-R appear most optimally matched using TCV. Only D-R size mismatch by TCV and height independently predicts graft survival. Standardizing size matching across centers may reduce donor discard.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225 mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6 months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Short-term clinical outcomes and predicted cost savings of dd-cfDNA-led surveillance after pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB)-led surveillance is common after pediatric heart transplantation (HT), with some centers performing periodic surveillance EMBs indefinitely after HT. Donor derived cell-free DNA (dd-cfDNA)-led surveillance offers an alternative, but knowledge about its clinical and economic outcomes, both key drivers of potential utilization, are lacking. METHODS: Using single-center recipient and center-level data, we describe clinical outcomes prior to and since transition from EMB-led surveillance to dd-cfDNA-led surveillance of pediatric and young adult HT recipients. These data were then used to inform Markov models to compare costs between EMB-led and dd-cfDNA-led surveillance strategies. RESULTS: Over 34.5 months, dd-cfDNA-led surveillance decreased the number of EMBs by 81.8% (95% CI 76.3%-86.5%) among 120 HT recipients (median age 13.3 years). There were no differences in the incidences of graft loss or death among all recipients followed at our center prior to and following implementation of dd-cfDNA-led surveillance (graft loss: 2.9 vs. 1.5 per 100 patient-years; p = .17; mortality: 3.7 vs. 2.2 per 100 patient-years; p = .23). Over 20 years from HT, dd-cfDNA-led surveillance is projected to cost $8545 less than EMB-led surveillance. Model findings were robust in sensitivity and scenario analyses, with cost of EMB, cost of dd-cfDNA testing, and probability of elevated dd-cfDNA most influential on model findings. CONCLUSIONS: dd-cfDNA-led surveillance shows promise as a less invasive and cost saving alternative to EMB-led surveillance among pediatric and young adult HT recipients.

Cardiac MRI-Derived Inferior Vena Cava Cross-Sectional Area Correlates with Measures of Fontan-Associated Liver Disease.

There is currently no clear consensus on screening techniques to evaluate the presence or severity of Fontan-associated liver disease (FALD). Cardiac MRI (CMR) is used routinely for post-Fontan surveillance, but CMR-derived measures that relate to the severity of FALD are not yet defined. This was a cross-sectional single-center study of post-Fontan patients who underwent a CMR. CMR exams were re-analyzed by a single pediatric cardiologist. Surrogates of FALD included Gamma-Glutamyl Transferase (GGT), Fibrosis-4 laboratory score (FIB-4), and imaging findings. Findings consistent with cirrhosis on liver ultrasound included increased liver echogenicity and/or nodularity. Statistical analyses were performed to investigate potential relationships between CMR parameters and markers of FALD. Sixty-one patients were included. A larger inferior vena cava cross-sectional area (IVC-CSA) indexed to height was significantly associated with a higher FIB-4 score (Spearman's ρ = 0.28, p = 0.04), a higher GGT level (Spearman's ρ = 0.40, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04). None of the other CMR parameters were associated with markers of FALD. A larger indexed IVC-CSA was associated with higher systemic ventricle end-diastolic pressure (EDP) on cardiac catheterization (Spearman's ρ = 0.39, p = 0.018) as well as older age (Spearman's ρ = 0.46, p = < 0.001). Indexed IVC-CSA was the only CMR parameter that was associated with markers of FALD. This measure has the potential to serve as an additional non-invasive tool to improve screening strategies for FALD. Visual abstract summarizing the primary findings of this paper.

Responsiveness to second and third dose of mRNA COVID-19 vaccination in adolescent and young adult heart transplant recipients.

BACKGROUND: Third-dose mRNA COVID-19 vaccine is currently recommended in the United States for SOT recipients based in part on data showing diminished immune response, including Ab production, after a two-dose regimen. Data on vaccine response in adolescent and young adult SOT recipients are limited, including no data reported on third-dose responsiveness. METHODS: Results of serologic testing in a convenience sample of 28 vaccinated adolescent and young adult HT recipients at a single institution were collected from the medical record and summarized. RESULTS: At a median of 98.5 days (IQR 59-150) after second dose, 17 (61%) had an Ab response. Among 12 who had serology before and after third-dose vaccination, four of seven who were negative prior to third dose became positive at a median of 34 days (IQR 31-39.5) following third dose. No myocarditis, acute rejection, graft dysfunction, graft loss, or deaths were observed. CONCLUSIONS: These findings support recommendations for the routine administration of three doses of mRNA vaccines in adolescent and young adult HT recipients and show a potential subpopulation in whom the fourth dose should be contemplated.

Early findings after integration of donor-derived cell-free DNA into clinical care following pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). METHODS: We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed. RESULTS: Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1). CONCLUSIONS: dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

Impact of the 2016 revision of US Pediatric Heart Allocation Policy on waitlist characteristics and outcomes.

US Pediatric Heart Allocation Policy was recently revised, deprioritizing candidates with cardiomyopathy while maintaining status 1A eligibility for congenital heart disease (CHD) candidates on "high-dose" inotropes. We compared waitlist characteristics and mortality around this change. Status 1A listings decreased (70% to 56%, P < .001) and CHD representation increased among status 1A listings (48% vs 64%, P < .001). Waitlist mortality overall (subdistribution hazard ratio [SHR] 0.96, P = .63) and among status 1A candidates (SHR 1.16, P = .14) were unchanged. CHD waitlist mortality trended better (SHR 0.82, P = .06) but was unchanged for CHD candidates listed status 1A (SHR 0.92, P = .47). Status 1A listing exceptions increased 2- to 3-fold among hypertrophic and restrictive cardiomyopathy candidates and 13.5-fold among dilated cardiomyopathy (DCM) candidates. Hypertrophic (SHR 6.25, P = .004) and restrictive (SHR 3.87, P = .03) cardiomyopathy candidates without status 1A exception had increased waitlist mortality, but those with DCM did not (SHR 1.26, P = .32). Ventricular assist device (VAD) use increased only among DCM candidates ≥1 years old (26% vs 38%, P < .001). Current allocation policy has increased CHD status 1A representation but has not improved their waitlist mortality. Excessive DCM status 1A listing exceptions and continued status 1A prioritization of children on stable VADs potentially diminish the intended benefits of policy revision.

Improving paediatric cardiologists' awareness about the needs of childhood cancer survivors: results of a single-centre directed educational initiative.

BACKGROUND: Cardiovascular disease is a leading cause of morbidity and mortality in childhood cancer survivors. Cardiologists must be aware of risk factors and long-term follow-up guidelines, which have historically been the purview of oncologists. Little is known about paediatric cardiologists' knowledge regarding the cardiotoxicity of cancer treatment and how to improve this knowledge. METHODS: A total of 58 paediatric cardiologists anonymously completed a 21-question, web-based survey focused on four cardio-oncology themes: cancer treatment-related risk factors (n = 6), patient-related risk factors (n = 6), recommended surveillance (n = 3), and cardiac-specific considerations (n = 6). Following the baseline survey, a multi-disciplinary team of paediatric cardiologists and cancer survivor providers developed an in-person and web-based educational intervention. A post-intervention survey was conducted 5 months later. RESULTS: The response rate was 41/58 (70.7%) pre-intervention and 30/58 (51.7%) post-intervention. On the baseline survey, the percentage of correct answers was 68.8 ± 10.3%, which improved to 79.2 ± 16.2% after the intervention (p = 0.009). The theme with the most profound knowledge deficit was surveillance; however, it also had the greatest improvement after the intervention (49.6 ± 26.7 versus 66.7 ± 27.7% correct, p = 0.025). Individual questions with the largest per cent improvement pertained to risk of cardiac dysfunction with time since treatment (52.4 versus 93.1%, p = 0.002) and the role of dexrazoxane (48.8 versus 82.8%, p = 0.020). CONCLUSION: Specific knowledge deficits about the care of paediatric cancer survivors were identified amongst cardiologists using a web-based survey. Knowledge of surveillance was initially lowest but improved the most after an educational intervention. This highlights the need for cardio-oncology-based educational initiatives among paediatric cardiologists.

Neutropenia in pediatric heart transplant recipients.

Neutropenia has been reported in pediatric heart transplant recipients, but its association with infectious morbidity and mortality is unknown. We sought to determine neutropenia's prevalence and impact on infection, rejection, and survival. A retrospective analysis of pediatric heart transplant recipients from March 2005 to August 2015 was performed. Demographics, medications, infection, and rejection data were collected. Of 142 pediatric heart transplant recipients, 77 (54.2%) developed neutropenia within 4.7 months [3.3-12.1 months] of transplant. In all patients, the adjusted 5-year cumulative incidence of neutropenia was 30.2%. Fifty-one patients (66.2%) had recurrent neutropenia. Six of 14 tested had positive antineutrophil antibodies. Medications associated with neutropenia were decreased in 15 (19.5%) and discontinued in 42 (54.4%) patients with no change in 1-year rejection rates compared to published data. Fifteen patients developed infection within 30 days of neutropenia and two from 30 days to 1 year, with an infection rate similar to the non-neutropenic group. There was no significant difference in survival, ANC, rate of rejection or PTLD in neutropenic patients with and without infection at median follow-up (5.5 years). Neutropenia is common in pediatric heart transplant recipients. Neutropenia had <20% risk of associated infection, similar to non-neutropenic patients. Infection in neutropenic patients did not increase mortality.

Cardio-oncology Related to Heart Failure: Pediatric Considerations for Cardiac Dysfunction.

Although tremendous advances in pediatric cancer treatment have improved the survival of many children, these patients remain at increased risk of early morbidity and mortality with cardiovascular disease as a leading cause of death. Heightened awareness in providers with increased surveillance and improvement in cardiovascular imaging modalities have led to earlier detection of cardiac dysfunction, but the outcomes remain poor once this has dysfunction developed. A great deal of work remains to be done to refine screening and identify high-risk patients more precisely, and to develop more evidence-based strategies for effective primary and secondary cardioprotection and treatment.

Preoperative Use of CT Angiography in Infants With Coarctation of the Aorta.

BACKGROUND: Computed tomographic angiography (CTA) and echocardiography (echo) are used preoperatively in coarctation of the aorta to define arch hypoplasia and great vessel branching. We sought to determine differences in quantitative measurements, as well as surgical utility, between modalities. METHODS: Infants (less than six months) with both CTA and echo prior to coarctation repair from 2004 to 2013 were included. Measurements were compared and correlated with surgical approach. Three surgeons reviewed de-identified images to predict approach and characterize utility. Computed tomographic angiography radiation dose was calculated. RESULTS: Thirty-three patients were included. No differences existed in arch measurements between echo and CTA ( z-score: -2.59 vs -2.43; P = .47). No differences between modalities were seen for thoracotomy ( z-score: -2.48 [echo] vs -2.31 [CTA]; P = .48) or sternotomy ( z-score: -3.13 [echo] vs -3.08 [CTA]; P = .84). Computed tomographic angiography delineated great vessel branching pattern in two patients with equivocal echo findings ( P = .60). Surgeons rated CTA as far more useful than echo in understanding arch hypoplasia and great vessel branching in cases where CTA was done to resolve anatomical questions that remain after echo evaluation. Two of three surgeons were more likely to choose the surgical approach taken based on CTA (surgeon A, P = .02; surgeon B, P = .01). Radiation dose averaged 2.5 (1.6) mSv and trended down from 2.9 mSv (1.8 mSv; n = 20) to 1.6 mSv (0.5 mSv; n = 7) ( P = .06) with new technology. CONCLUSION: Although CTA and echo measurements of the aorta do not differ, CTA better delineates branching and surgeons strongly prefer it for three-dimensional arch anatomy. We recommend CTA for patients with anomalous arch branching patterns, diffuse or complex hypoplasia, or unusual arch morphology not fully elucidated by echo.

Appropriateness of Outpatient Echocardiograms Ordered by Pediatric Cardiologists or Other Clinicians.

OBJECTIVE: To assess the appropriateness and diagnostic yield of TTEs ordered by various pediatric providers according to the pediatric appropriate use criteria (AUC) for outpatient transthoracic echocardiography (TTE) before its release. STUDY DESIGN: Clinic notes of patients aged ≤18 years who underwent initial outpatient TTE between April and September 2014 were reviewed to determine the AUC indication, and appropriateness was assigned based on the AUC document. Ordering physicians were categorized into cardiologists, primary care physicians (PCPs; including pediatricians and family practitioners [FPs]), and noncardiology subspecialists. RESULTS: Of the 1921 TTEs ordered during the study period, 84.6% were by cardiologists, 9.2% by pediatricians, 3.4% by FPs, and 2.8% by noncardiology subspecialists. The appropriateness rate for cardiologists was higher than that for PCPs (86% vs 64%; P < .001) but not noncardiology subspecialist (86% vs 87%; P = .80). PCPs had a significantly higher proportion of studies that could not be classified compared with cardiologists (35% vs 5%; P < .001) and noncardiology subspecialists (35% vs 11%; P < .001), owing primarily to a lack of adequate clinical information. The likelihood of an abnormal finding was higher in TTEs ordered by a cardiologist vs those ordered by a noncardiologist (OR, 4.8; 95% CI, 2.1-10.9; P < .001). CONCLUSIONS: Compared with PCPs, cardiologists ordered more TTEs, had the highest yield of abnormal findings, and had greater appropriateness of TTE orders. A large proportion of TTEs ordered by PCPs were unclassifiable owing to insufficient information. This study lays a framework for provider education and improvement in the TTE order intake process.

Appropriate Use and Clinical Impact of Echocardiographic "Evaluation of Murmur" in Pediatric Patients.

OBJECTIVE: To determine the appropriateness and yield of transthoracic echocardiograms (TTE) for murmur evaluation based on the pediatric Appropriate Use Criteria (AUC) and study the influence of patient age and physician experience on TTE appropriateness, yield, and ordering frequency. DESIGN: Retrospective review of medical records of patients referred to our practice for murmur evaluation from April to September 2014. Data collected included indication for TTE, patient age, physician experience since fellowship, TTE findings and exit diagnosis. Appropriateness was assigned based on the AUC document. SETTING: Pediatric cardiology clinics affiliated with a large pediatric cardiology practice. PATIENTS: One thousand seven hundred one consecutive patients (≤ 18 years) referred to our practice for murmur evaluation. INTERVENTIONS: Not applicable OUTCOME MEASURES: The primary outcome was appropriateness of TTE orders. The secondary outcomes were the yield of abnormal TTE findings and the influence of patient age and physician experience on appropriateness, yield, and frequency of ordering TTEs. RESULTS: Of the 1701 patients referred for a murmur, 526 (30.9%) had a TTE [441/526 (83.8%) Appropriate; 85/526 (16.2%) Rarely Appropriate]. Abnormal findings were present in 130/441 rated Appropriate and none rated Rarely Appropriate. Infants <3 months had the highest rate of TTEs rated Appropriate and the highest yield of abnormal findings. Physicians with >20 years of experience not only had the lowest TTE ordering rate but also the lowest appropriateness rate with no difference in the yield of abnormal findings. CONCLUSIONS: Most TTEs ordered for murmur were for indications rated Appropriate. Abnormal findings were present in one-fourth and only those rated Appropriate. Patient age and physician experience can significantly influence TTE utilization. This information is helpful in designing quality initiatives to optimize TTE utilization for murmur evaluation.