Long-term studies on safety of beta-blockers in pediatric heart failure (HF) are scant. We describe the safety profile, dose ranges, and tolerability of carvedilol in pediatric dilated cardiomyopathy (DCM). The Pediatric Cardiomyopathy Registry (PCMR) was used to identify patients with DCM, treated with carvedilol from 1997 to 2005. Descriptive statistics were analyzed and echocardiographic parameters were compared longitudinally using ANOVA. Total 118 patients were included with median age 4.4 years (interquartile range (IQR) 1.0–13.3). The etiology of DCM was idiopathic (66

Donor-derived cell-free DNA (dd-cfDNA) is a biomarker used to screen for rejection, but its significance when elevated without rejection remains unclear in pediatric recipients. We performed a single-center retrospective study of 81 pediatric heart transplant recipients with ≥1 dd-cfDNA measurement. Samples associated with rejection, as defined by decision-to-treat with increased immunosuppression were excluded. Associations were analyzed using linear mixed-effects models and generalized estimating equations to account for repeated sampling within patients. Elevated dd-cfDNA was associated with concurrent donor-specific antibodies (median 0.33% vs 0.11%; β=1.5, 95% CI 0.97-2.2, p=0.071) and history of cardiac allograft vasculopathy (median 0.48% vs 0.11%, p=0.005; β=1.8, 95% CI 0.99-3.3, p=0.052). Donor specific antibodies and cardiac allograft vasculopathy were more prevalent among dd-cfDNA samples exceeding 0.2%. In pediatric heart transplantation, elevated dd-cfDNA without rejection may reflect subclinical alloimmune or vascular injury. Donor-derived cell-free DNA levels may possess utility beyond screening for rejection.

Myocarditis remains a challenging disease in children. Clinicians must be aware of the various disease phenotypes and have a high index of suspicion for timely diagnosis. While the mainstay of treatment remains supportive, there is continued controversy regarding the use of immunomodulatory therapies for acute and chronic diseases. Newer diagnostic tools, such as cardiac MRI, have emerged, while routine endomyocardial biopsy is utilized less frequently. Most patients will survive and recover normal cardiac function, but a substantial portion will either die or undergo heart transplantation. However, some data suggest that patients with myocarditis may have related sequela, including increased risk of fatal rejection, even after heart transplant.

Purpose HLA sensitization significantly limits donor availability and increases waitlist mortality in pediatric heart transplantation (HT). Current desensitization strategies are largely ineffective or equivocal. Recent adult studies show that a dual approach with Carfilzomib (CFZ), a proteasome inhibitor, and Belatacept (BELA), a costimulation blocker, reduces class I and II HLA antibodies (Abs). This study will evaluate the clinical utility of CFZ and BELA in reducing HLA antibody type and strength in pediatric and young adult patients. Methods This prospective, observational study will include about 30 patients from 6 pediatric clinical sites, an HLA core and a mechanistic core lab. Patients aged 10-24 years, highly sensitized with class I and/or class II cPRA ≥ 50% (MFI > 4000), will be included. Exclusion criteria: EBV seronegative, HIV+, and a history of hematologic malignancy. Secondary endpoints include mechanistic studies on how desensitization affects cellular subsets producing HLA Abs, whether reductions in antibody strength persist until transplant, and post-transplant outcomes such as antibody mediated rejection and graft survival. Results The study’s unique design harmonizes the use of a novel protocol across sites using a central IRB and is the first prospective, registry-based investigation in pediatric HT using the Pediatric Heart Transplant Society (PHTS) registry. The HLA core will measure antibody response through MFIs, titers, and cPRA, while the mechanistic core will use advanced investigations to support the trial's clinical endpoints. Conclusion This multicenter study aims to establish a transformative, standardized approach to desensitization and antibody evaluation.

BACKGROUND:Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality rates, including heart failure, multisystem end-organ disease, and need for heart transplant. Specific FCF morbidities have not been rigorously defined, limiting study of how FCF morbidities affect pre-heart transplant and post-heart transplant outcomes. We hypothesized that FCF-related morbidities affect survival from heart transplant waitlisting through 1 year after heart transplant.METHODS:This 20-center, retrospective cohort study collected demographic, medical/surgical history, waitlist, and peri- and post-heart transplant data, and a priori defined FCF-specific morbidities, in Fontan patients who were listed for heart transplant from 2008 through 2022. Univariate 2-group statistics compared surviving individuals with those who died anytime from waitlisting to 1 year after heart transplant, died on the waitlist, or underwent transplant and died within 1 year after transplant. Using covariates from both univariate analyses, multivariable logistic regression determined the primary study outcome of independent FCF risk factors for death between waitlist and 1 year after heart transplant.RESULTS:Of 409 waitlisted patients, 24 (5.9%) died on the waitlist. Of the 341 (83.4%) who underwent transplant, 27 (8.5%) did not survive to 1 year. Univariate risk factors for waitlist death included higher aortopulmonary collateral burden, >1 hospitalization in the previous year, younger age, sleep apnea, higher New York Heart Association class, nonenrollment in school or work, and single-parent home. Risk factors for 1-year post-heart transplant mortality included hypoplastic left heart syndrome diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry <90%), polycythemia, portal variceal disease, mental health condition requiring treatment, and higher human leukocyte antigen class II panel reactive antibody. Of the patients not surviving from waitlisting to 1 year after heart transplant, independent risk factors for death included >1 hospitalization in the year before waitlisting (adjusted odds ratio, 2.0 [95% CI, 1.0-4.1]; P=0.05) and clinical cyanosis (adjusted odds ratio, 5.0 [95% CI, 1.8-13.4]; P=0.002).CONCLUSIONS:Patients with Fontan palliation selected for heart transplant have substantial mortality rates from waitlisting through transplant. Among FCF-specific morbidities, cyanosis is associated with worsened survival and necessitates further study. Clinical morbidity of any type requiring repeated hospital admission also should prompt consideration of heart transplant.

The use of ventricular assist devices (VADs) in children with restrictive (RCM) and hypertrophic cardiomyopathy (HCM) remains rare. We describe the outcomes of patients with RCM and HCM supported by VAD in the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry from March 2012 to December 2024. Thirty-four patients were identified: 20 left-sided VAD (LVAD), 13 biventricular VAD (BiVAD), and 1 total artificial heart (TAH). Median age at implant was 2.5 years (0.3–17.5), weight was 11.8 kg (4.5–81.8), and body surface area (BSA) was 0.54 m 2 (0.26–2.01). Diagnoses included RCM in 25 (73.5%) patients and HCM in 9 (26.5%). Illness severity at implant was high with 38.2% Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1, 41.2% on extracorporeal membrane oxygenation (ECMO), 52.9% on ventilator support, 88.2% treated with greater than or equal to 1 inotrope, and 52.9% supported with TPN. Four patients (11.8%) died on device, 25 (73.5%) were transplanted, 4 (11.8%) were alive on device, and 1 (2.9%) was transferred to another center. Patients who died all had HCM diagnosis, required BiVAD support, and experienced adverse events. The cause of death was inadequate support (1), infection (2), and multi-organ failure (1). Ventricular assist device support is a reasonable strategy for select RCM and HCM patients, although outcomes in HCM are less favorable.

Recent data demonstrate worse heart transplant (HTx) outcomes in children with shorter VAD durations, but do not account for VAD adverse events (AEs)Es. We compared outcomes of patients bridged to HTx with < 30 vs. ≥ 30 days of VAD support in an earlier era by assessing both VAD and HTx risk factors. We merged data from the PediMACS and Pediatric Heart Transplant Study registries to compare one-year post-HTx mortality in patients with < 30 vs. ≥ 30 days of pre-HTx VAD support between 2012 and 2018. We used inverse probability of treatment weighting using propensity scores (PS) to control for confounders, including age, blood type, allosensitization, cardiac diagnosis (cardiomyopathy, congenital heart disease, or myocarditis), VAD support type (left, right, single, or biventricular VAD), and pre-Tx mechanical ventilation and vasoactive support. Among 271 patients, there were 60 in the < 30-days and 211 in the ≥ 30-days groups. At HTx, the < 30-days group used more ventilation (34

As the Fontan population grows, understanding successful strategies for ventricular assist device (VAD) support of the failing Fontan circulation is needed. We performed a retrospective analysis of patients with Fontan circulation and systemic VAD support in the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry. Competing outcomes and Kaplan-Meier estimated survival methods were used. Between January 2012 and December 2022, 106 Fontan patients underwent VAD implant (median age 10 years, 20% age ≥18 years). At time of implant, 58% were on greater than or equal to 2 inotropes, 26% on extracorporeal membrane oxygenation (ECMO), and 41% intubated. Since 2018, there have been more patients implanted at INTERMACS profile 1 or 2 (88% vs . 71%, p = 0.02) and on inotropic support (95% vs . 76%, p = 0.01). Median duration of VAD support was 113 (interquartile range (IQR): 43-266) days. At 12 months post-VAD implant, 53% were transplanted, 27% were alive on device, 2% had successful recovery, and 18% had died. Overall, 75% experienced greater than or equal to 1 adverse event, with bleeding, infection, and neurologic dysfunction most common. Despite high acuity at the time of VAD implant and high rate of adverse events, the majority of Fontan patients were transplanted or still alive on device at 12 months post-VAD implant.

Combined heart liver transplantation (CHLT) for patients with congenital heart disease (CHD) poses unique challenges for health care professionals as evidence-based guidelines on candidate evaluation, selection, and follow-up are limited with evaluation and listing strategies.1 CHLT evaluation in the CHD population is particularly challenging due to the poor performance of the usual liver fibrosis evaluation tools in this patient population. For example, hepatic venous pressure gradient has been shown to be unreliable in estimating the degree of portal hypertension, and fibrosis is geographically heterogeneous, making liver biopsy not reliable.

BACKGROUNDPEDIMACS provides detailed understanding on pediatric patients supported with ventricular assist devices (VADs). We sought to identify important variables affecting the incidence of stroke in pediatric VADs.METHODSBetween 2012-2022, 1,463 devices in 1,219 patients were reported to PEDIMACS s from 40 Centers in patients<19yrs at their first VAD implantation. Multiphase parametric hazard modeling was used to identify risk factors for stroke among all device types.RESULTSOf the 1,219 patients, the most common devices were implantable continuous (472 [39%]), followed by paracorporeal pulsatile (342 [28%]), paracorporeal continuous (327 [27%]). Overall freedom from stroke at 6 months was higher in the recent era (2012-2016; 80.2% [77.1%-82.9%] vs 2017-2023; 87.9% [86.2%-89.4%], p=0.009). Implantable Continuous had the highest freedom from stroke at 3 (92.7% [91.1%-93.9%]) and 6 (91.1% [89.3%-92.6%]) months, followed by Paracorporeal Pulsatile (87.0% [84.8%-88.9%] and 82.8% [79.8%-85.5%]), and Paracoporeal Continuous (76.0% [71.8%-79.5%] and 69.5% [63.4%-74.8%]). Parametric modeling identified risk factors for stoke early post implant and later. Overall, and particularly for Paracorporal Pulsatile devices, early stroke risk has decreased in the most recent era (HR 5.01). Among Implantable Continuous devices, cardiogenic shock was the major risk factor. For patients<10kg, early hazard was only seen in previous era. For congentail patients, early hazard was seen in non-implantable device use and use of ECMO.CONCLUSIONSOverall stroke rate has decreased from 20% to 15% at 6 months, with particular improvement among PP devices. Risk factor analyses offer insights for identification of higher stroke risk subsets and further management refinements.

Donor-derived cell-free DNA (dd-cfDNA) has been increasingly used to detect acute rejection (AR). We aimed to compare our institutional dd-cfDNA results to previously published adult and pediatric dd-cfDNA AR cutoffs. We also hypothesized that in the absence of AR, elevated dd-cfDNA would be associated with CAV and positive DSA. Patients (pt) < 18 years at transplant with > 1 dd-cfDNA between 2021-2023 were included. Using dd-cfDNA levels from this cohort, sensitivity, specificity, NPV, and PPV were calculated. False positives and false negatives (FN) were determined using published dd-cfDNA thresholds. AR was defined as decision-to-treat with increased immunosuppression, which was independent of dd-cfDNA in our cohort. In pt without AR, t -test was used to compare the means of dd-cfDNA levels in pt with and without DSA. χ 2 testing was then performed to evaluate the association between dd-cfDNA levels above and below 0.2% and the presence/absence of DSA and CAV. DSA was defined as allele-specific DSA identified by single antigen bead with mean fluorescence intensity >1000, and CAV as any disease by angiography. There were 379 samples among 163 pt, a median of 2 samples per pt, and 32 samples obtained at time of AR. Performance of dd-cfDNA in our cohort vs published dd-cfDNA thresholds is shown in Table 1. The FN rate ranged from 16 to 37% as the dd-cfDNA threshold increased. Mean dd-cfDNA was higher in patients with positive DSA versus those without (0.83% vs 0.19%, p<0.001). In patients that did not meet AR criteria, dd-cfDNA levels > 0.2% were associated with a higher prevalence of positive DSA (n=66) (48% vs 13%, p<0.001), and trended towards a higher prevalence of CAV (n=20) (15% vs 11%, p=0.08). Dd-cfDNA had high sensitivity and NPV for AR but the FN rate using published dd-cfDNA cutoffs was high in our validation cohort. The clinical utility of dd-cfDNA may extend beyond AR screening given increased frequency of DSA and CAV in pt with elevated levels that are negative for AR. We speculate that monitoring intra-pt dd-cfDNA variability will reduce the FN rate when screening for AR in addition to enhancing its clinical utility when monitoring for CAV and DSA.

Introduction: Fontan circulatory failure (FCF) is associated with poor long-term survival. The impact of Fontan-specific morbidities on outcomes in those evaluated for heart transplant (HT) are not well understood. Hypothesis: FCF-specific morbidities, their degree of severity, and the accumulation of morbidities are associated with mortality in individuals undergoing HT. Methods: This 20 center, retrospective cohort study of individuals with FCF from 2008-2023 collected data on FCF-specific morbidities, waitlist (WL), and post-HT outcomes. Each unique FCF morbidity was defined with graded severities (absent, mild, moderate, severe, and life-threatening) via a prior effort. The primary outcome was survival from WL to 1-year post-HT. Appropriate 2-group statistics and multivariable logistic regression compared surviving with those who died. Receiver operating characteristic curve determined the most discriminating value of total cumulative morbidities on mortality. Results: Of the 340 patients included, 51(15%) died between WL and 1 year post-HT. On univariate analysis, 7 of 27 FCF morbidities were associated with the mortality (p < 0.2) including: anatomic Fontan pathway obstruction, clinical hypoxia, chronic pleural effusions, sleep apnea, portal variceal disease, acute kidney injury within 1 year prior to WL, and mental health disorders. On multivariable analysis, only clinical hypoxia and portal variceal disease emerged as independent risk factor for mortality (adjusted odds ratio [aOR]: 2.48, p = 0.03 and aOR 2.74 P=0.02 respectively). When assessing the impact of increasing severity of each morbidity, again worsening clinical hypoxia (aOR 1.42 increase with each increase in grade, p=0.01) and portal variceal disease (aOR 1.80 with each increase in grade, p=0.01) had differential effects on mortality. Risk of death increased with greater number of FCF morbidities. Having 2 or more of the 7 univariately significant morbidities was the value best discriminating survivors from those who died (Area under the curve 0.67; sensitivity 78%, negative predictive value 93%). Conclusion: Clinical hypoxia and portal variceal disease confer independent risk for non-survival in patients with Fontan from WL to 1 year after HT. Additionally, the magnitude of mortality risk for both hypoxia and varices worsens as disease severity worsens. Given the impact, consistent evaluation for these morbidities and timely referral for heart failure evaluation is warranted.

Purpose While numerous adult heart failure (HF) registries generate data that lead to practice change and improved adult HF outcomes, no such pediatric HF registry currently exists. Despite increased inpatient mortality and resource use for children compared to adults with HF, detailed data regarding pediatric HF profiles and outcomes are lacking. ACTION sought to determine the feasibility of establishing a pediatric HF registry. Methods ACTION developed a pediatric HF hospitalization registry to prospectively enroll children admitted with acute decompensated HF at 13 pilot sites. Demographic information, laboratory and echo data, hospital outcomes, and hospital re-admission data were collected. A pilot study was launched to assess feasibility using the ACTION infrastructure. Results There were 112 patients enrolled. The composition of the cohort is described in table 1; 40% had dilated cardiomyopathy. The outcome of the HF hospitalization is depicted in Figure 1; 21 (19%) patients underwent VAD and 29 (26%) patients underwent heart transplant (HT). Overall, 55% of the cohort was discharged without a VAD or HT with a median length of stay of 22 days (Q1-Q3 9-46), and a 30-day re-admission rate of 18%. Conclusion Establishment of a robust and sustainable multicenter pediatric HF registry is feasible through ACTION that is capable of capturing a wide diversity of pediatric HF syndromes. This effort stands to significantly broaden the reach of ACTION to improve the outcomes of children with HF. HF medication usage has been identified as a priority area for future quality improvement work as an updated version of the registry is currently being expanded to the entire network.

Adequate nutrition is an essential factor in healing and immune support in pediatric patients undergoing surgery, but its importance in this setting is not consistently recognized. Standardized institutional nutrition protocols are rarely available, and some clinicians may be unaware of the importance of assessing and optimizing nutritional status. Moreover, some clinicians may be unaware of updated recommendations that call for limited perioperative fasting. Enhanced recovery protocols have been used in adult patients undergoing surgery to ensure consistent attention to nutrition and other support strategies in adult patients before and after surgery, and these are now under evaluation for use in pediatric patients as well. To support better adoption of ideal nutrition delivery, a multidisciplinary panel of experts in the fields of pediatric anesthesiology, surgery, gastroenterology, cardiology, nutrition, and research have gathered and reviewed current evidence and best practices to support nutrition goals in this setting.

BACKGROUND:Renal function is reduced in patients undergoing heart transplant due to hemodynamic compromise, cardiorenal syndrome, and nephrotoxin exposure. No current studies evaluate renal function in retransplants. METHODS:We reviewed all heart transplants at our center from 1995 to 2021 and matched first-time heart transplants with retransplants, based on age at transplant, sex, and race. Estimated glomerular filtration rate (eGFR) was derived from CKiD-U25 calculator using creatinine and measured prior to transplant, 1-week post-transplant, 1-3, 6, and 12 months post-transplant, and recent follow-up. Changes in eGFR were measured within and between patients using a piecewise linear mixed effect model with matching. Exploratory univariate analysis was performed to evaluate pre-transplant risk factors for decreased eGFR. RESULTS:The unmatched cohort included 393 heart transplant recipients, with 47 being retransplants. Thirty-eight patients in both groups with at least 1 year of follow-up underwent matching. Both retransplants and first-time transplants had an initial decline in eGFR. eGFR rebounded to baseline or above baseline at 1-3 months post-transplant, but eGFR in retransplants remained significantly lower. At 1-year post-transplant, the average eGFR was 67.8 ± 4.3 mL/min/1.73 m2 versus 104.7 ± 4.3 mL/min/1.73 m2 (p < .001) in the retransplants and first-time transplants group, respectively. CONCLUSION:This study provides data on anticipated renal trajectory following retransplantation.

Advances in cancer therapeutics have revolutionized survival outcomes in patients with cancer. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Recent studies have uncovered excess risks of these cardiotoxic events, especially in traditionally underrepresented populations. Despite advances in strategies to limit the risks of cardiovascular events among cancer survivors, relatively limited guidance is available to address the rapidly growing problem of disparate cardiotoxic risks among women and underrepresented patient populations. Previously decentralized and sporadic evaluations have led to a lack of consensus on the definitions, investigation, and potential optimal strategies to address disparate cardiotoxicity in contemporary cancer care (eg, with immunotherapy, biologic, or cytotoxic therapies) settings. This scientific statement aims to define the current state of evidence for disparate cardiotoxicity while proposing uniform and novel methodological approaches to inform the identification and mitigation of disparate cardio-oncology outcomes in future clinical trials, registries, and daily clinical care settings. We also propose an evidence-based integrated approach to identify and mitigate disparities in the routine clinical setting. This consensus scientific statement summarizes and clarifies available evidence while providing guidance on addressing inequities in the era of emerging anticancer therapies.