Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Outcomes after initial heart failure consultation in Fontan patients.

BACKGROUND: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care. METHODS: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as "too late" (death or declined for transplant due to being too sick) and/or "care escalation" (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. "Late referral" was defined as those referred too late and/or had care escalation. RESULTS: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8-21.5, p=0.004). CONCLUSIONS: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Expanding use of the HeartMate 3 ventricular assist device in pediatric and adult patients within the Advanced Cardiac Therapies Improving Outcomes Network (ACTION).

BACKGROUND: We report current outcomes in patients supported with the HeartMate 3 (HM3) ventricular assist device in a multicenter learning network. METHODS: The Advanced Cardiac Therapies Improving Outcomes Network database was queried for HM3 implants between 12/2017 and 5/2022. Clinical characteristics, postimplant course, and adverse events were collected. Patients were stratified according to body surface area (BSA) (<1.4 m2, 1.4-1.8 m2, and >1.8 m2) at device implantation. RESULTS: During the study period, 170 patients were implanted with the HM3 at participating network centers, with median age 15.3years; 27.1% were female. Median BSA was 1.68 m2; the smallest patient was 0.73 m2 (17.7 kg). Most (71.8%) had a diagnosis of dilated cardiomyopathy. With a median support time of 102.5days, 61.2% underwent transplantation, 22.9% remained supported on device, 7.6% died, and 2.4% underwent device explantation for recovery; the remainder had transferred to another institution or transitioned to a different device type. The most common adverse events included major bleeding (20.8%) and driveline infection (12.9%); ischemic and hemorrhagic stroke were encountered in 6.5% and 1.2% of patients, respectively. Patients with BSA <1.4 m2 had a higher incidence of infection, renal dysfunction, and ischemic stroke. CONCLUSIONS: In this updated cohort of predominantly pediatric patients supported with the HM3 ventricular assist device, outcomes are excellent with <8% mortality on device. Device-related adverse events including stroke, infection, and renal dysfunction were more commonly seen in smaller patients, highlighting opportunities for improvements in care.

Out-of-pocket expenses associated with pediatric heart transplantation.

INTRODUCTION: Heart transplantation in children is associated with high resource utilization. However, the financial burden on families and the association with patient and demographic factors remains unclear. This study aims to examine out-of-pocket expenses associated with pediatric heart transplantation. METHODS: An anonymous REDCap survey was distributed to caregivers of children who have undergone heart transplantation using social media, national organizations, and during clinic encounters from May through August 2022. RESULTS: There were a total of 146 respondents. The median monthly out-of-pocket expense was $250 (IQR $75-$500) and 20 respondents (13.7%) reported monthly expenses of >$1000. Families with commercial insurance reported significantly higher out-of-pocket expenses compared to those with government-sponsored insurance (median $350 vs. $100, p < .001). Families with government-sponsored insurance were most happy with their insurance coverage, followed by commercial insurance and then coverage through the Affordable Care Act (p < .001 for all pairwise comparisons). There was no statistically significant difference in overall transplant-related out-of-pocket expenses based on total household income (p = .222). Monthly out-of-pocket expense was not associated with the number of medications, type of immunosuppressants, or post-transplant complications including rejection, PTLD, or CAV (p = NS for all). Cardiac catheterizations and unplanned admissions were reported as the events that incurred the highest out-of-pocket expense. CONCLUSION: Families of children who have undergone heart transplantation can incur significant out-of-pocket expenses and strategies to mitigate this financial burden should be investigated.

Rethinking status 1A criteria in pediatric cardiac transplantation: A case for the prioritization of patients with single ventricle anatomy supported by ventricular assist devices.

Over the past 2 years advancements in the techniques and technology of pediatric heart transplantation have exponentially increased. However, even as the number of pediatric donor hearts has grown, demand for this limited resource continues to far outpace supply. Thus, lifesaving support in the form of ventricular assist devices (VAD) has become increasingly utilized in bridging pediatric patients to cardiac transplant. In the current pediatric heart transplant listing criteria, adopted by the United Network for Organ Sharing (UNOS) in 2016, all pediatric patients with a VAD are granted 1A status and assigned top transplant priority regardless of their underlying pathology. However, should this be the case? We suggest that the presence of a VAD alone may not be sufficient for status 1A listing. In doing so, we specifically highlight the heightened acuity, resource utilization, risk profile, and diminished outcomes in patients with single ventricle physiology supported with VAD as compared to patients with structurally normal hearts who would both be listed under 1A status. Given this, from a distributive justice perspective, we further suggest that the lack of granularity in current pediatric cardiac transplant listing categories may inadvertently lead to an inequitable distribution of donor organs and hospital resources especially as it pertains to those with single ventricle anatomy on VAD support. We propose revisiting the current listing priorities in light of improved techniques, technology, and recent data to mitigate this phenomenon. By doing this, pediatric patients with single ventricle disease might be more equitably stratified while awaiting heart transplant.

Clinical approach to vasoplegia in the transplant patient from the Pediatric Heart Transplant Society.

This manuscript outlines a clinical approach to vasoplegia incorporating the current state of knowledge regarding vasoplegia in pediatric patients immediately post-transplant and to identify modifiable factors both pre- and post-transplant that may reduce post-operative morbidity, end-organ dysfunction, and mortality. Centers participating in the Pediatric Heart Transplant Society (PHTS) were asked to provide their internal protocols and rationale for vasoplegia management, and applicable adult and pediatric data were reviewed. The authors synthesized the above protocols and literature into the following description of clinical approaches to vasoplegia highlighting areas of both broad consensus and of significant practice variation.

Clinical approach to mechanical circulatory support in the transplant patient from the Pediatric Heart Transplant Society.

The use of mechanical circulatory support (MCS) for pediatric patients who have undergone heart transplant has grown rapidly in the past decade. This includes support in the immediate post-transplant period and "rescue" therapy for patient later in their transplant course. Extracorporeal membrane oxygenation (ECMO) remains a standard modality of support for intraoperative concerns and for acute decompensation in the immediate post-transplant period. However, both pulsatile and continuous flow ventricular assist devices (VADs) have been used with increasing success in transplant patients for longer durations of support. Centers participating in the Pediatric Heart Transplant Society (PHTS) were queried to provide their internal protocols and rationale for mechanical circulatory support following heart transplant. These protocols coupled with evidence-based literature were used to provide the following description of clinical approaches to MCS in the transplant patient highlighting areas of both broad consensus and significant practice variation.

Cardiac magnetic resonance diastolic indices correlate with ventricular filling pressures in pediatric heart transplant recipients.

BACKGROUND: Atrial and ventricular filling pressures are routinely used in pediatric heart transplant (PHTx) recipients to assess graft function. We hypothesized that cardiac magnetic resonance (CMR) diastolic indices correlate with filling pressures, providing a noninvasive method of hemodynamic assessment. METHODS: Pediatric heart transplant recipients were prospectively enrolled at the time of cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured. CMR included standard volumetric analysis. Filling curves were calculated by contouring every phase in the short-axis stack. Global longitudinal and circumferential strain (GLS, GCS) were calculated using feature tracking. Atrial volumes and ejection fraction were calculated from 4-chamber and 2-chamber cine images. Correlations were analyzed using Spearman's Rho; modeling was performed with multivariable logistic regression. RESULTS: A total of 35 patients with a mean age of 15.5 years were included, 12 with acute rejection. The median time post-transplant was 6.2 years. Peak filling rate (PFR) and peak LV ejection rate/end-diastolic volume (PER/EDV) correlated with PCWP (rho = 0.48 p = .005, and rho = -0.35 p = .046, respectively) as did GLS and GCS (rho = 0.52 p = .002, and 0.40 p = .01). Indexed maximum and minimum left atrial (LA) volume correlated with PCWP (rho = 0.41, p = .01, rho = 0.41 p = .01), and LA ejection fraction inversely correlated with PCWP (rho = -0.40, p = .02). GLS and GCS correlated with RAP (rho = 0.55, p = .001 and rho = 0.43, p = .01). A model including LV GLS and PFR estimated PCWP ≥12 mmHg with an area under the curve of 0.84. CONCLUSIONS: Cardiac magnetic resonance can be a useful noninvasive modality to assess for signs of diastolic dysfunction after PHTx.

Right heart failure considerations in pediatric ventricular assist devices.

Right heart failure (RHF) is a vexing problem in children after left ventricular assist device (LVAD) implantation that can negatively impact transplant candidacy and survival. Anticipation, prevention, early identification and appropriate medical and device management of RHF are important to successful LVAD outcomes. However, there is limited pediatric evidence to guide practice. This pediatric-focused review summarizes the relevant literature and describes the harmonized approach to RHF from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION). This review seeks to improve RHF outcomes through the sharing of best practices and experience across the pediatric VAD community.

Berlin Heart EXCOR and ACTION post-approval surveillance study report.

BACKGROUND: The Berlin Heart EXCOR Pediatric (EXCOR) ventricular assist device (VAD) was introduced in North America nearly 2 decades ago. The EXCOR was approved under Humanitarian Device Exemption status in 2011 and received post-market approval (PMA) in 2017 from Food and Drug Administration. Since the initial approval, the field of pediatric mechanical circulatory support has changed, specifically with regard to available devices, anticoagulation strategies, and the types of patients supported. This report summarizes the outcomes of patients supported with EXCOR from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry. These data were part of the PMA surveillance study (PSS) required by the Food and Drug Administration. METHODS: ACTION is a learning collaborative of over 40 pediatric heart failure programs worldwide, which collects data for all VAD implantations as one of its initiatives. All patients in North America with EXCOR implants reported to ACTION from 2018 to 2020 (n = 72) who had met an outcome were included in the EXCOR PSS group. This was compared with a historical, previously reported Berlin Heart EXCOR study group (Berlin Heart study [BHS] group, n = 320, 2007‒2014). RESULTS: Patients in the PSS group were younger, were smaller in weight/body surface area, were more likely to have congenital heart disease, and were less likely to receive a bi-VAD than those in the BHS group. Patients in the PSS group were less likely to be in Interagency Registry for Mechanically Assisted Circulatory Support Profile 1 and were supported for a longer duration. The primary anticoagulation therapy for 92% of patients in the PSS group was bivalirudin. Success, defined as being transplanted, being weaned for recovery, or being alive on a device at 180 days after implantation, was 86% in the PSS group compared with 76% in the BHS group. Incidence of stroke was reduced by 44% and the frequency of pump exchange by 40% in the PSS group compared with those in the BHS group. Similarly, all other adverse events, including major bleeding, were reduced in the PSS group. CONCLUSIONS: The PSS data, collected through ACTION, highlight the improvement in outcomes for patients supported with EXCOR compared with the outcomes in a historical cohort. These findings may be the result of changes in patient care practices over time and collaborative learning.

Fontan-associated plastic bronchitis waitlist and heart transplant outcomes: A PHTS analysis.

Plastic bronchitis is a rare post-Fontan complication with limited treatment options. Heart transplantation has evolved as a potential curative option, but outcomes have not been well-defined. This study aims to assess contemporary waitlist and post-transplant outcomes in patients with plastic bronchitis. All Fontan patients were identified in the PHTS database (2010 - 2018). Waitlist and post-transplant outcomes were compared between Fontan patients with and without plastic bronchitis. Competing outcomes and Kaplan-Meier analyses were used to assess the impact of plastic bronchitis on waitlist and post-transplant survival. A secondary analysis excluded those with PLE from the comparison cohort. Of 645 Fontan patients listed for heart transplant, 69 (11%) had plastic bronchitis. At listing, patients with plastic bronchitis were younger (8.9 vs 11.1 years, P = .02), but had few other differences in baseline characteristics. A fewer Fontan patients with plastic bronchitis were listed in the more recent era (46 [15.4%] in 2010-2014 vs 23 [6.6%] in 2015-2018, P < .01). Overall, there was no difference in waitlist (P = .30) or post-transplant (P = .66) survival for Fontan patients with and without plastic bronchitis. The results were similar after excluding patients with PLE. Contrary to prior reports, this relatively large series showed that plastic bronchitis did not have a negative impact on survival to or after heart transplantation in Fontan patients. Our study also found a 50% reduction in listing in the current era, which may indicate evolution in management of Fontan patients.

Discharge and Readmissions After Ventricular Assist Device Placement in the US Pediatric Hospitals: A Collaboration in ACTION.

Discharging children on ventricular assist device (VAD) support offers advantages for quality of life. We sought to describe discharge and readmission frequency in children on VAD support. All VAD-implanted patients aged 10-21 years at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers were identified from the Pediatric Health Information System database (2009-2018). Discharge frequency on VAD was calculated. Patients discharged on VAD were compared with those not discharged. Freedom from readmission was assessed using the Kaplan-Meier method. A total of 298 VAD-implanted patients from 25 centers were identified, of which 163 (54.7%) were discharged. Discharges increased over time (36.9% [2009-2012] vs. 59.7% [2013-2018], p = 0.001). Of 144 discharged patients with follow-up, 96 (66.7%) were readmitted for reasons other than transplantation. Heart failure was the most common reason for readmission (27.7%), followed by infection (25.8%) and hematologic concerns (16.8%). In-hospital mortality on readmission was uncommon (1.8%) and the median length of stay was 6 days (interquartile range 2-19 days). Discharge of children on VAD support has increased over time, although variability exists across centers. Readmissions are common with diverse indications; however, the risk of mortality is low. Further interventions, including collaboration in ACTION, are critical to increasing discharges and optimizing outpatient management.

The impact of psychiatric disorders on outcomes following heart transplantation in children.

Psychiatric disorders are common in pediatric HTx recipients. However, the impact of psychiatric comorbidities on patient outcomes is unknown. We aimed to assess the impact of disorders of adjustment, depression, and anxiety on HTx outcomes in children; hypothesizing that the presence of psychiatric disorders during or preceding HTx would negatively impact outcomes. All pediatric HTx recipients ≥8 years of age who survived to hospital discharge were identified from a novel linkage between the PHIS and SRTR databases (2002-2016). Psychiatric disorders were identified using ICD codes during or preceding the HTx admission. Post-transplant graft survival, freedom from readmission, and freedom from rejection were analyzed using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to adjust for covariates. A total of 1192 patients were included, of which 133 (11.2%) had depression, 197 (16.5%) had anxiety, and 218 (18.3%) had adjustment disorders. The presence of depression was independently associated with higher rates of readmission (60.9% vs 54.1% at 6 months) (AHR 1.63, 95% CI 1.22-2.18, P = .001) and inferior graft survival (70.2% vs 83.4% at 5 years) (AHR 1.62, 95% CI 1.14-2.3, P = .007). Anxiety was independently associated with higher rates of readmission (60.4% vs 53.9% at 6 months) (AHR 1.46, 95% CI 1.09-1.94, P = .01). Anxiety and depression in the pretransplant period are independently associated with outcomes following HTx in children. Evaluation and management of psychiatric comorbidities represents an important component of care in this vulnerable population.

Pericardial effusion following hematopoietic stem cell transplantation in children: Incidence, risk factors, and outcomes.

PCE is a complication of HSCT that has previously been described in small single-center studies. This study aimed to assess the frequency of, risk factors for, and outcomes of children with a PCE following HSCT across a large multi-center cohort. All patients ≤21 years undergoing first HSCT (1/2005-9/2015) were identified from the Pediatric Health Information System. ICD-9 codes were used to identify patients with a PCE during or following the transplant encounter. Multivariable modeling assessed risk factors for developing a PCE and assessed the impact of PCE on patient outcome. Of 10 455 included patients, 739 (7.1%) developed a PCE (median 69 days post-HSCT, interquartile range 33-165 days). PCE developed more commonly in allogeneic vs autologous HSCT recipients (9.1% vs 2.9%, P < .001). Among allogeneic HSCT recipients, independent risk factors for PCE included thrombotic microangiopathy (AHR 2.94, 95% CI 2.16-4.00), heart failure (AHR 2.07, 95% CI 1.61-2.66), PCE pre-HSCT (AHR 1.92, 95% CI 1.19-3.09), arrhythmia (AHR 1.76, 95% CI 1.44-2.16), graft-versus-host disease (AHR 1.31, 95% CI 1.05-1.62), female sex (AHR 1.28, 95% CI 1.07-1.52), and malignancy (AHR 1.28, 95% CI 1.02-1.60). Allogeneic HSCT patients with PCE demonstrated worse survival than those without PCE (5-year survival 50.8% vs 76.9%, P < .001). PCE was independently associated with mortality (AHR 1.96, 95% CI 1.62-2.37) following allogeneic HSCT and was not impacted by pericardial intervention. PCE occurs more commonly in patients following allogeneic (vs autologous) HSCT and is associated with inferior outcomes.

Rehospitalization Following Pediatric Heart Transplantation: Incidence, Indications, and Risk Factors.

Rehospitalization following pediatric heart transplantation is common. However, existing data remain somewhat limited. Using a novel linkage between administrative and clinical databases, pediatric heart transplant (HT) recipients from 29 centers who survived to discharge were retrospectively reviewed to determine the frequency, timing of, and indication for all-cause rehospitalizations in the year following transplant discharge. Of 2870 pediatric HT recipients, 1835 (63.9%) were rehospitalized in the first year post-discharge (5429 total readmissions). Rehospitalization rates varied significantly across centers (46% to 100%) and were inversely correlated to center transplant volume (r2 0.25, p < 0.01). The median number of rehospitalizations per patient was 2 (IQR 1-4) and the median time to first rehospitalization was 29 days (IQR 9-99 days). Independent risk factors for rehospitalization included younger age at HT (HR 0.99, 95% CI 0.97-0.99), congenital heart disease (HR 1.2, 95% CI 1.1-1.4), listing status 1B at transplant (HR 1.3, 95% CI 1.1-1.5), and post-transplant complications including rejection prior to discharge (HR 1.5 95% CI 1.3-1.8) and chylothorax (HR 1.3, 95% CI 1.0-1.6). Cardiac diagnoses were the most common indication for rehospitalization (n = 1600, 29.5%), followed by infection (n = 1367, 25.2%). These findings may serve to guide the development of interventions aimed at reducing post-HT hospitalizations.

Patients and their family members prioritize post-transplant survival over waitlist survival when considering donor hearts for transplantation.

Heart transplant providers often focus on post-transplant outcomes when making donor decisions, potentially at the expense of higher waitlist mortality. This study aimed to assess public opinion regarding the selection of donor hearts and the balance between pre- and post-transplant risk. The authors generated a survey to investigate public opinion regarding donor acceptance. The survey was shared freely online across social media platforms in April-May 2019. A total of 718 individuals responded to the survey, with an equal distribution between patients and family members. Respondents consistently favored post-transplant outcomes over waitlist outcomes. About 83.9% of respondents favored a hospital with longer waitlist times, worse waitlist outcomes, but excellent post-transplant survival over a hospital with short waitlist times, a high waitlist survival, and inferior post-transplant survival. This preference was no different between pediatric and adult populations (P = .7), patient and family members (P = .935), or those with a pre- vs post-transplant perspective (P = .985). Patients and their family members consistently favor improved post-transplant survival over waitlist survival when considering the risks of accepting a donor organ. These findings suggest that current practice patterns of donor selection align with the opinions of patients and family members with heart failure or who have undergone heart transplantation.

Disorders of Adjustment, Mood, and Anxiety in Children and Adolescents Undergoing Heart Transplantation and the Association of Ventricular Assist Device Support.

OBJECTIVE: To assess the prevalence of psychiatric disorders and associated therapies in children during their heart transplantation admission. STUDY DESIGN: All pediatric heart transplant recipients (1999-2016) were included from a linked administrative and clinical registry database. Psychiatric disorders and associated therapies were identified using International Classification of Diseases or billing codes during the transplant admission. Data were analyzed using standard descriptive statistics. Multivariable logistic regression assessed factors independently associated with psychiatric disorders or therapies. RESULTS: A total of 3073 pediatric heart transplant recipients were included. Psychiatric disorders were present in 434 (14.1%) patients during the heart transplant admission, with adjustment disorders being the most common. Antidepressant therapy was prescribed to 212 patients (6.9%) and selective serotonin reuptake inhibitors were most commonly used. Psychiatric diagnoses (8.4% vs 18.1%; P < .001) and the use of antidepressants (4.5% vs 8.9%; P < .001) increased over time (era 1, 1999-2009 vs era 2, 2010-2016). Psychiatric disorders were present in 39.8% of patients ≥8 years of age requiring ventricular assist device support at heart transplantation. The need for ventricular assist device support was independently associated with psychiatric diagnoses (aOR, 1.57; 95% CI, 1.18-2.1; P = .002) and antidepressant therapy (aOR, 2.11; 95% CI. 1.43-3.12; P < .001). CONCLUSIONS: Psychiatric disorders are common in pediatric heart transplant recipients, especially among those bridged with ventricular assist device support. Psychiatric diagnoses and the use of antidepressants has increased over time, likely representing improved recognition of psychiatric comorbidities in this vulnerable population. Access to psychiatric services represents an important component of the multidisciplinary team caring for pediatric heart transplant recipients.

Heart Transplantation in Children with Mitochondrial Disease.

OBJECTIVES: To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease. STUDY DESIGN: Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease. RESULTS: A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P < .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03). CONCLUSIONS: Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.