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ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

ImportanceThe advanced ambulatory heart failure (HF) population comprises patients who have progressed beyond the pillars of recommended stage C HF therapies but can still find meaningful life-years ahead. Although these patients are commonly encountered in practice, national databases selectively capture the small groups accepted for heart transplant listing or left ventricular assist devices. The epidemiology, trajectories, and therapies for other ambulatory patients with advanced HF are poorly understood.ObservationsIn December 2022, the National Heart, Lung and Blood Institute convened a team of experts to identify knowledge gaps and research priorities for the ambulatory population with limiting daily symptoms and transition toward refractory end-stage D HF, designated as stage C2D. This article summarizes the findings from that 3-day workshop. Workshop participants surveyed the initial challenges and knowledge gaps for (1) recognition of ambulatory C2D HF, (2) estimation of the magnitude of the affected population and identifiable subpopulations, and (3) physiologic phenotypes, such as low cardiac output, right HF, cardiorenal syndromes, congestive hepatopathy and frailty, which offer distinct targets for existing and emerging therapies. Social drivers of HF and patient preferences for quality/length of survival were highlighted as essential modifiers for personalization of therapies.Conclusions and RelevanceTen key points summarized workshop findings, with target cohorts for study proposed as a crucial next step. This workshop summary is intended as a call for action to address knowledge gaps and develop new strategies to improve outcomes in the large ambulatory population with C2D HF.

AbstractBackgroundNutritional status in pediatric patients undergoing heart transplantation (HT) is frequently a focus of clinical management and requires high resource utilization. Pre‐operative nutrition status has been shown to affect post‐operative mortality but no studies have been performed to assess how nutritional status may change and the risk of developing nutritional comorbidities long‐term in the post‐transplant period.MethodsA single‐center retrospective chart review of patients ≥2 years of age who underwent heart transplantation between 1/1/2005 and 4/30/2020 was performed. Patient data were collected at listing, time of transplant, 1‐year, and 3‐year follow‐up post‐transplant. Nutrition status was classified based on body mass index (BMI) percentile in the primary analysis. Alternative nutritional indices, namely the nutrition risk index (NRI), prognostic nutrition index (PNI), and BMI z‐score, were utilized in secondary analyses.ResultsOf the 63 patients included, the proportion of patients with overweight/obese status increased from 21% at listing to 41% at 3‐year follow‐up. No underweight patients at listing became overweight/obese at follow‐up. Of patients who were overweight/obese at listing, 88% maintained that status at 3‐year follow‐up. Overweight/obese status at listing, 1‐year, and 3‐year post‐transplantation were significantly associated with developing metabolic syndrome. In comparison to the alternative nutritional indices, BMI percentile best predicted post‐transplant metabolic syndrome.ConclusionsThe results suggest that pediatric patients who undergo heart transplantation are at risk of developing overweight/obesity and related nutritional sequelae (ie, metabolic syndrome). Improved surveillance and interventions targeted toward overweight/obese HT patients should be investigated to reduce the burden of associated comorbidities.

Evidence from medicine and other fields has shown that gender diversity results in better decision making and outcomes. The incoming workforce of congenital heart specialists (especially in pediatric cardiology) appears to be more gender balanced, but past studies have shown many inequities. Gender‐associated differences in leadership positions, opportunities presented for academic advancement, and recognition for academic contributions to the field persist. In addition, compensation packages remain disparate if evaluated based on gender with equivalent experience and expertise. This review explores these inequities and has suggested individual and institutional changes that could be made to recruit and retain women, monitor the climate of the institution, and identify and eliminate bias in areas like salary and promotions.

Importance Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge. Objective To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy. Evidence Review At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations. Findings The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy. Conclusions and Relevance Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.

Abstract Background Management of infants with pulmonary atresia/intact ventricular septum (PA/IVS) is variable. Because of higher mortality in more severe forms, heart transplant (HT) is an acceptable approach, but waitlist and post‐transplant outcomes are unclear. This study compared outcomes of infants with PA/IVS vs. other single ventricle (SV) anatomies listed for HT. Methods Data from the Pediatric Heart Transplant Society (1993–2018) were analyzed for survival and risk factors for mortality. Results Of 1617 SV infants, 300 had PA/IVS (19%) and 1317 had other SV (81%). Overall, 1‐, 5‐, and 10‐year survival was higher among PA/IVS (74%, 65%, 61%) versus other SV infants (62%, 54%, 50%, p = .004). While waitlist mortality was similar between groups ( p = .09), PA/IVS was an independent predictor of improved waitlist survival (HR 0.68, p = .03), and PA/IVS infants had higher incidence of waitlist removal (8% vs. 5.5%, p = .03), most commonly for being “too well.” Post‐transplant survival was superior among PA/IVS versus other SV infants (1‐ and 5‐year survival 93% and 81% vs. 80% and 71%, p < .0001). Risk factors for PA/IVS waitlist mortality (2008–2018) included extracorporeal membrane oxygenation and mechanical ventilation. Prior aortopulmonary (AP) shunt among PA/IVS infants was associated with improved waitlist survival. Conclusions Overall survival among PA/IVS infants listed for HT exceeds that of other SV infants with PA/IVS identified as an independent predictor of improved waitlist and post‐transplant survival. Prior AP shunt among listed PA/IVS infants was associated with improved waitlist outcomes, though, which may reflect a listing selection bias.

AbstractBackgroundProtein‐losing enteropathy (PLE) is a devastating complication of the Fontan circulation. Although orthotopic heart transplantation (HTx) typically results in resolution of PLE symptoms, isolated cases of PLE relapse have been described after HTx.MethodsPatients with Fontan‐related PLE who had undergone HTx at participating centers and experienced relapse of PLE during follow‐up were retrospectively identified. Available data related to pre‐ and post‐HTx characteristics and PLE events were collected.ResultsEight patients from four different centers were identified. Median time from Fontan procedure to the development of PLE was 8 years, and median age at HTx was 17 years (range 7.7–21). In all patients, PLE resolved at a median time of 1 month after HTx (0.3–5). PLE recurrences occurred at a median time of 7.5 months after HTx (2–132). Each occurrence was associated with one or more significant clinical events; most commonly cellular‐ or antibody‐mediated rejection; and less commonly graft dysfunction, infection, thrombosis, and posttransplant lymphoproliferative disease. PLE recurrences resolved after the successful treatment of the concomitant event, after a median time of 2 months in seven cases, while persisted and recurred in one patient in association with atypical mycobacterium infection and subsequent PTLD onset and relapses. Six patients were alive during follow‐up at a median time of 4 years (1.3–22.5) after HTx.ConclusionsThis is the largest series of PLE recurrence after HTx. All cases were associated with one or more concomitant and significant clinical events. PLE typically resolved after resolution of the inciting clinical event.

Background: Guidelines recommend involvement of palliative care (PC) for patients with cardiovascular (CV) disease and their families. Little is known about the current integration of PC and CV services. Research Objectives: Our national survey aimed to describe current practices and to identify benefits, challenges, and barriers with collaboration. Methods: Qualitative content analysis of open-response questions in an investigator-developed electronic survey study of CV and PC providers (MDs, NPs, PAs, and other allied health) using email listservs, social media, and crowdsourcing. Frequencies were tabulated using SAS statistical software. Results: Of 134 respondents, most were physicians (n=56, 57%) or advanced practice RNs or PAs (n=37, 28%), from 52 U.S. institutions, representing 33 states. The most common care for which PC was integrated were mechanical circulatory support, advanced heart failure, and heart transplantation; the least common care for which PC was integrated were TAVR, ECMO, and pulmonary hypertension. Integrated practice (n=80, 61%), PC identification of goals of care (n=20, 15%) and PC aid in patient/family communication (n=15, 11%) were the most commonly identified as positives in current practice. PC provider workforce (n=22, 16%), underutilization of PC referrals (n=20, 15%), late disease PC referral (n=19, 14%), and fundamental knowledge deficit of specialty scope (n=18, 14%) were most frequently identified as challenges. Other barriers specifically noted were underdeveloped health infrastructure and limited allocated resources (n=23,17%) and mis-/negative perception of services (n=15, 11%). Conclusion: PC and CV collaboration occurs for a high proportion of CV patients and is viewed as overwhelming positive, despite the challenges of limited PC specialists availability, underdeveloped healthcare infrastructure, limited understanding of specialty practice, and late referrals. Priorities includes increasing PC provider availability, expanding knowledge of PC services, educating providers on models of collaboration, and improving institutional support.

While clinical status at the time of ventricular assist device (VAD) implant can negatively affect outcomes, it is unclear if early improvement after implant can have a positive effect. Therefore, the objectives of this study were to describe the clinical status of pediatric patients supported with a VAD and determine the impact of clinical status on the 1-month follow-up form on survival and ability to discharge. This was a retrospective analysis of data collected prospectively by the Pediatric Interagency Registry for Mechanical Circulatory Support Registry (Pedimacs) Registry. The Pedimacs database was queried for patients implanted between September 19, 2012, and September 30, 2019, who were alive on VAD support at 1-month postimplant on either a paracorporeal pulsatile or intracorporeal continuous device. Four factors on the 1-month follow-up were the focus of this study: mechanical ventilation, supplemental nutritional support, inotropic support, and ambulatory status. These factors were regarded as present if detected between 1-week and 1-month postimplant and were analyzed to determine their impact on survival following 1 month of VAD support and on successful discharge from hospital in patients with implantable continuous-flow devices. The eligible study cohort consisted of 414 patients with a mean age of 9.6 ± 6.2 years, weight of 40.8 ± 32.3 kg with the majority being male (56.7%) and having cardiomyopathy (68%). An isolated left ventricular assist device (LVAD) was the most common implant (85.5%). At implant, 40% were ventilated, 57% required nutritional support, 93% were on inotropes, and 58% were nonambulating. On the 1-month postimplant form, there were significant improvements in all four categories (14% ventilator support, 46% nutritional support, 53% on inotropes, and 25% nonambulating). However, there was no significant early change in the percentage of patients requiring supplemental nutrition in the paracorporeal pulsatile devices (88% vs. 82%; p = 0.2). Presence of these clinical parameters in early follow-up postimplant had a significant negative impact on survival and on the ability of patients with continuous-flow devices to be discharged. Presence of four specific clinical parameters early after VAD placement is associated with worse overall survival and an inability to discharge patients on VAD support. Ongoing work is needed for optimization of patients before implant and aggressive rehabilitation after implant to help improve long-term outcomes.

Background During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia. Conclusions To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.