ACTION-ARC Pediatric and Adult Congenital Heart Disease Ventricular Assist Device Adverse Event Definitions-2023.

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions. This ACTION-ARC international expert panel of trialists, clinicians, patients, families, statisticians, biomedical engineers, device developers, and regulatory agencies drafted and iterated definitions harmonized to ACTION data and existing literature during sessions conducted between December 2022 and May 2023, followed by dissemination across clinical/research audiences and professional organizations and further revision. Both email-linked, internet-based surveys and in-person discussions were used as a modified Delphi process. Nineteen AE types were identified and defined, including seven new event types and six event types that were deleted and will no longer be collected, achieving consensus. ACTION-ARC paired rigorous development with methodical stakeholder involvement and dissemination to define pediatric VAD AEs to facilitate assimilation of data across future clinical trials and evaluation of devices for VAD-supported children and adults with CHD.

Deep Learning for Automated Measurement of Total Cardiac Volume for Heart Transplantation Size Matching.

Total Cardiac Volume (TCV)-based size matching using Computed Tomography (CT) is a novel technique to compare donor and recipient heart size in pediatric heart transplant that may increase overall utilization of available grafts. TCV requires manual segmentation, which limits its widespread use due to time and specialized software and training needed for segmentation. This study aims to determine the accuracy of a Deep Learning (DL) approach using 3-dimensional Convolutional Neural Networks (3D-CNN) to calculate TCV, with the clinical aim of enabling fast and accurate TCV use at all transplant centers. Ground truth TCV was segmented on CT scans of subjects aged 0-30 years, identified retrospectively. Ground truth segmentation masks were used to train and test a custom 3D-CNN model consisting of a DenseNet architecture in combination with residual blocks of ResNet architecture. The model was trained on a cohort of 270 subjects and a validation cohort of 44 subjects (36 normal, 8 heart disease retained for model testing). The average Dice similarity coefficient of the validation cohort was 0.94 ± 0.03 (range 0.84-0.97). The mean absolute percent error of TCV estimation was 5.5%. There is no significant association between model accuracy and subject age, weight, or height. DL-TCV was on average more accurate for normal hearts than those listed for transplant (mean absolute percent error 4.5 ± 3.9 vs. 10.5 ± 8.5, p = 0.08). A deep learning-based 3D-CNN model can provide accurate automatic measurement of TCV from CT images. This initial study is limited as a single-center study, though future multicenter studies may enable generalizable and more accurate TCV measurement by inclusion of more diverse cardiac pathology and increasing the training data.

Impact of inflammation and steroids on anti-coagulation in children supported on a ventricular assist device.

Critically ill pediatric patients supported on ventricular assist devices (VADs) are increasingly being anticoagulated on bivalirudin, but with difficulty monitoring anticoagulation. Activated partial thromboplastin time (aPTT) has recently been shown to poorly correlate with bivalirudin plasma concentrations, while dTT had excellent correlation. However, aPTT is the more common monitoring test and dTT testing is rarely used. In addition, effects of frequent clinical VAD scenarios (such as inflammation) on the accuracy of aPTT and dTT testing remains uncertain. We reviewed the effects of clinical scenarios (infection/inflammation, chylothorax, and steroids administration) on anticoagulation monitoring in 10 pediatric VAD patients less than 3 years at Cincinnati Children's Hospital Medical Center from 10/27/2020 to 5/6/2022 using bivalirudin for anticoagulation. There were 16 inflammation/infection, 3 chylothorax, and 6 steroids events. Correlation between dTT and aPTT was significantly lower after infection/inflammation, with dTT increasing prior to inflammation/infection while aPTT remained unchanged. In addition, steroids are administered to VAD patients to reduce inflammation and thus additionally stabilize anticoagulation. However, this anticoagulation stabilization effect was reflected more accurately by dTT compared to aPTT. In children requiring VAD support utilizing bivalirudin anticoagulation, inflammation/infection is a common occurrence resulting in anticoagulation changes that may be more accurately reflected by dTT as opposed to aPTT.

Cardiac atrial pathology in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Duchenne muscular dystrophy (DMD) is characterized by fibrofatty replacement of muscle. This has been documented in the ventricular myocardium of DMD patients, but there is limited description of atrial involvement. The purpose of this study is to examine the arrhythmia and ectopy burden in patients with DMD and non-DMD dilated cardiomyopathy (DCM) and to characterize the cardiac histopathologic changes in DMD patients across the disease spectrum. METHODS: This was a retrospective analysis of age-matched patients with DMD and non-DMD DCM who received a Holter monitor and cardiac imaging within 100 days of each other between 2010 and 2020. Twenty-four-hour Holter monitors were classified based on the most recent left ventricular ejection fraction at the time of monitoring. Cardiac histopathologic specimens from whole-heart examinations at the time of autopsy from three DMD patients and one DCM patient were reviewed. RESULTS: A total of 367 patients with 1299 Holter monitor recordings were included over the study period, with 94% representing DMD patients and 6% non-DMD DCM. Patients with DMD had more atrial ectopy across the cardiac function spectrum (p < 0.05). There was no difference in ventricular ectopy. Four DMD patients developed symptomatic atrial arrhythmias. Autopsy specimens from DMD patients demonstrated fibrofatty infiltration of both atrial and ventricular myocardium. DISCUSSION: The atrial myocardium in patients with DMD is unique. Autopsy specimens reveal fibofatty replacement of the atrial myocardium, which may be a nidus for both ectopy and arrhythmias in DMD patients.

Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV.

Background: Glycogen Storage disease type 4 (GSD4), a rare disease caused by glycogen branching enzyme 1 (GBE1) deficiency, affects multiple organ systems including the muscles, liver, heart, and central nervous system. Here we report a GSD4 patient, who presented with severe hepatosplenomegaly and cardiac ventricular hypertrophy. GBE1 sequencing identified two variants: a known pathogenic missense variant, c.1544G>A (p.Arg515His), and a missense variant of unknown significance (VUS), c.2081T>A (p. Ile694Asn). As a liver transplant alone can exacerbate heart dysfunction in GSD4 patients, a precise diagnosis is essential for liver transplant indication. To characterize the disease-causing variant, we modeled patient-specific GBE1 deficiency using CRISPR/Cas9 genome-edited induced pluripotent stem cells (iPSCs). Methods: iPSCs from a healthy donor (iPSC-WT) were genome-edited by CRISPR/Cas9 to induce homozygous p.Ile694Asn in GBE1 (iPSC-GBE1-I694N) and differentiated into hepatocytes (iHep) or cardiomyocytes (iCM). GBE1 enzyme activity was measured, and PAS-D staining was performed to analyze polyglucosan deposition in these cells. Results: iPSCGBE1-I694N differentiated into iHep and iCM exhibited reduced GBE1 protein level and enzyme activity in both cell types compared to iPSCwt. Both iHepGBE1-I694N and iCMGBE1-I694N showed polyglucosan deposits correlating to the histologic patterns of the patient's biopsies. Conclusions: iPSC-based disease modeling supported a loss of function effect of p.Ile694Asn in GBE1. The modeling of GBE1 enzyme deficiency in iHep and iCM cell lines had multi-organ findings, demonstrating iPSC-based modeling usefulness in elucidating the effects of novel VUS in ultra-rare diseases.

Wireless Pulmonary Artery Pressure Monitor Implantation in a Patient with Duchenne Muscular Dystrophy.

Assessing heart failure progression in patients with Duchenne Muscular Dystrophy (DMD) is challenging given the multi-system nature of disease. Herein we describe the first case use of an implantable pulmonary artery pressure monitor and describe the potential clinical utility of this approach in patients with DMD.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Modifiable risk factor reduction for pediatric ventricular assist devices and the influence of persistent modifiable risk factors at transplant.

OBJECTIVES: Ventricular assist devices (VADs) are associated with a mortality benefit in children. Database-driven analyses have associated VADs with reduction of modifiable risk factors (MRFs), but validation with institutional data is required. The authors studied MRF reduction on VAD and the influence of persistent MRFs on survival after heart transplant. METHODS: All patients at the authors' institution requiring a VAD at transplant (2011-2022) were retrospectively identified. MRFs included renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2), hepatic dysfunction (total bilirubin ≥1.2 mg/dL), total parenteral nutrition dependence, sedatives, paralytics, inotropes, and mechanical ventilation. RESULTS: Thirty-nine patients were identified. At time of VAD implantation, 18 patients had ≥3 MRFs, 21 had 1 to 2 MRFs, and 0 had 0 MRFs. At time of transplant, 6 patients had ≥3 MRFs, 17 had 1 to 2 MRFs, and 16 had 0 MRFs. Hospital mortality occurred in 50% (3 out of 6) patients with ≥3 MRFs at transplant vs 0% of patients with 1 to 2 and 0 MRFs (P = .01 for ≥3 vs 1-2 and 0 MRFs). MRFs independently associated with hospital mortality included paralytics (1.76 [range, 1.32-2.30]), ventilator (1.59 [range, 1.28-1.97]), total parenteral nutrition dependence (1.49 [range, 1.07-2.07]), and renal dysfunction (1.31 [range, 1.02-1.67]). Two late mortalities occurred (3.6 and 5.7 y), both in patients with 1 to 2 MRFs at transplant. Overall posttransplant survival was significantly worse for ≥3 versus 0 MRFs (P = .006) but comparable between other cohorts (P > .1). CONCLUSIONS: VADs are associated with MRF reduction in children, yet those with persistent MRFs at transplant experience a high burden of mortality. Transplanting VAD patients with ≥3 MRFs may not be prudent. Time should be given on VAD support to achieve aggressive pre-transplant optimization of MRFs.

School age and adolescent heart failure following the Norwood procedure.

BACKGROUND: Heart failure results in significant morbidity and mortality for young children with hypoplastic left heart syndrome (HLHS) following the Norwood procedure. The trajectory in later childhood is not well described. METHODS: We studied the outcome into adolescence of participants enrolled in the Single Ventricle Reconstruction trial who underwent the Fontan procedure or survived to 6 years without having undergone Fontan procedure. The primary outcome was heart failure events, defined as heart transplant listing or death attributable to heart failure. Symptomatic heart failure for participants surviving 10 or more years was also assessed utilizing the Pediatric Quality of Life Inventory (PedsQL). RESULTS: Of the 345 participants who underwent a Fontan operation or survived to 6 years without Fontan, 25 (7.2%) had a heart failure event before the age of 12 years. Among these, 21 were listed for heart transplant, and 4 died from heart failure. Nineteen participants underwent heart transplant, all of whom survived to age 12 years. Factors associated with a heart failure event included longer Norwood hospital length of stay, aortic atresia, and no Fontan operation by age 6 years. Assessment of heart failure symptoms at 12 years of age revealed that 24 (12.2%) of 196 PedsQL respondents "often" or "almost always" had difficulty walking more than one block. CONCLUSIONS: Heart failure events occur in over 5% of children with palliated HLHS between preschool age and adolescence. Outcomes for children listed for transplant are excellent. However, a substantial portion of palliated HLHS children have significant symptoms of heart failure at 12 years of age.

Left Atrial Phasic Function via Cardiac Magnetic Resonance Imaging in Patients with Duchenne Muscular Dystrophy.

Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). Left atrial (LA) function is a poorly understood concept in this patient population, and research suggests underlying structural changes that could affect atrial function. Cardiac magnetic resonance (CMR) imaging may provide an important non-invasive approach to evaluating LA function. This study was a single center retrospective review of consecutive CMR studies over a 1 year period comparing LA phasic function within a cohort of DMD patients, and to those with structurally and functionally normal hearts. LA strain measurements including global reservoir, conduit, boost-pump strain, and LA volumes were obtained retrospectively. Spearman correlation analyses were performed on atrial strain measurements. 107 DMD and 79 normal CMR studies were included. The DMD cohort had worse systolic function (p < 0.001), smaller indexed max LA and left ventricular (LV) volumes (p < 0.001), and greater LA emptying fraction (p < 0.001). In the DMD cohort, emptying fraction decreased with advanced patient age (p < 0.001) and diminishing systolic function (p < 0.001). DMD patients with moderate or severe LV dysfunction demonstrated lower LA emptying fraction (p = 0.002), more impaired 2-chamber LA reservoir (p = 0.003), and LA pump (p = 0.006) and conduit strain (p = 0.018). DMD patients with preserved function have lower indexed LA volumes with higher LA emptying fractions than controls. Progression of disease and age is associated with decreased LA emptying fraction with early manifestations in reservoir and conduit strain. These findings suggest that strain markers of LA compliance and early left ventricular relaxation are associated with worsening cardiomyopathy in the DMD population.

In the era of outpatient ventricular assist devices, is it time to reconsider the practice of bridging older children to transplant on outpatient inotropes?

OBJECTIVE: Ventricular assist devices (VADs) and inotropes are feasible modalities to bridge children to heart transplant (HT) in outpatient settings. However, it is unclear which modality yields superior clinical status at HT and posttransplant survival. METHODS: The United Network for Organ Sharing was used to identify patients aged 18 years or younger, weighing >25 kg, from 2012 to 2022 who were outpatients at HT (n = 835). Patients were grouped by bridging modality at HT: VAD (n = 235 [28%]), inotropes (n = 176 [21%]), or neither (no support) (n = 424 [50%]). RESULTS: VAD patients were of similar age (P = .260) but heavier (P = .007) and more likely to have dilated cardiomyopathy (P < .001) than their inotrope counterparts. VAD patients had similar clinical status at HT but superior functional status (performance scale >70%) (59% vs 31%) (P < .001). Overall posttransplant survival in VAD patients (1-year and 5-year survival, 97% and 88%, respectively) was comparable to patients with no support (93% and 87%, respectively) (P = .090) and those on inotropes (98% and 83%, respectively) (P = .089). One-year conditional survival was superior for VAD vs inotrope (2-year and 6-year survival, 96% and 91%, respectively vs 97% and 79%, respectively) (P = .030) and 5-year conditional survival for VAD patients was superior to inotrope (7-year and 10-year survival, 100% and 100%, respectively vs 100% and 88%, respectively) (P = .022) and no support (100% and 83%, respectively) (P = .011). CONCLUSIONS: Consistent with prior studies, short-term outcomes for pediatric patients bridged to HT in the outpatient setting with VAD or inotropes is excellent. However, compared with outpatients bridged to HT on inotropes, outpatient VAD support allowed for better functional status at HT and superior late posttransplant survival.

Single Center Experience With Durable Continuous Flow Single Ventricle Assist Device: A Viable Option in Fontan Circulatory Failure.

Ventricular assist devices are increasingly used for patients with single ventricle physiology. We describe the use of durable, continuous flow, single ventricular assist device (SVAD) therapy in Fontan circulatory failure patients. Retrospective, single-center review of patients with Fontan circulation implanted with a SVAD between 2017 and 2022. Patient characteristics and outcomes were obtained by chart review. Nine patients underwent SVAD implantation (median age 24 years). Most patients had a total cavopulmonary connection; one had an atriopulmonary Fontan. Five patients had a systemic right ventricle. SVAD was most often utilized as bridge to candidacy (67%). Eight patients had at least moderate systemic ventricular systolic dysfunction. SVAD support continued for a median of 65 days (longest duration, 1,105 days) and one patient remains on support at time of submission. Of five patients discharged home, median length of stay after SVAD was 24 days. Six patients were transplanted (median 96 days from SVAD). Two patients died from pretransplant multisystem organ failure before transplant. All transplanted patients remain alive (median time since transplant 593 days). Continuous flow SVAD therapy can be effective for patients with Fontan circulatory failure and systolic dysfunction. Further studies should investigate feasibility and optimal SVAD timing with more advanced Fontan associated end-organ dysfunction.

Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy.

BACKGROUND: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. OBJECTIVES: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. METHODS: In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RESULTS: RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. CONCLUSIONS: RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.

Racial disparity exists in the utilization and post-transplant survival benefit of ventricular assist device support in children.

PURPOSE: Children of minority race and ethnicity experience inferior outcomes postheart transplantation (HTx). Studies have associated ventricular assist device (VAD) bridge-to-transplant (BTT) with similar-to-superior post-transplant-survival (PTS) compared to no mechanical circulatory support. It is unclear whether racial and ethnic discrepancies exist in VAD utilization and outcomes. METHODS: The United Network for Organ Sharing (UNOS) database was used to identify 6,121 children (<18 years) listed for HTx between 2006 and 2021: black (B-22% of cohort), Hispanic (H-21%), and white (W-57%). VAD utilization, outcomes, and PTS were compared between race/ethnicity groups. Multivariable Cox proportional analyses were used to study the association of race and ethnicity on PTS with VAD BTT, using backward selection for covariates. RESULTS: Black children were most ill at listing, with greater proportions of UNOS status 1A/1 (p < 0.001 vs H & W), severe functional limitation (p < 0.001 vs H & W), and greater inotrope requirements (p < 0.05 vs H). Non-white children had higher proportions of public insurance. VAD utilization at listing was: B-11%, H-8%, W-8% (p = 0.001 for B vs H & W). VAD at transplant was: B-24%, H-21%, W-19% (p = 0.001 for B vs H). At transplant, all VAD patients had comparable clinical status (functional limitation, renal/hepatic dysfunction, inotropes, mechanical ventilation; all p > 0.05 between groups). Following VAD, hospital outcomes and one-year PTS were equivalent but long-term PTS was significantly worse among non-whites-(p < 0.01 for W vs B & H). On multivariable analysis, black race independently predicted mortality (hazard ratio 1.67 [95% confidence interval 1.22-2.28]) while white race was protective (0.54 [0.40-0.74]). CONCLUSIONS: Pediatric VAD use is, seemingly, equitable; the most ill patients receive the most VADs. Despite similar pretransplant and early post-transplant benefits, non-white children experience inferior overall PTS after VAD BTT.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Initial multicenter experience with ventricular assist devices in children and young adults with muscular dystrophy: An ACTION registry analysis.

PURPOSE: Cardiac disease results in significant morbidity and mortality in patients with muscular dystrophy (MD). Single centers have reported their ventricular assist device (VAD) experience in specific MDs and in limited numbers. This study sought to describe the outcomes associated with VAD therapy in an unselected population across multiple centers. METHODS: We examined outcomes of patients with MD and dilated cardiomyopathy implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers from 9/2012 to 9/2020. RESULTS: A total of 19 VADs were implanted in 18 patients across 12 sites. The majority of patients had dystrophinopathy (66%) and the median age at implant was 17.2 years (range 11.7-29.5). Eleven patients were non-ambulatory (61%) and 6 (33%) were on respiratory support pre-VAD. Five (28%) patients were implanted as a bridge to transplant, 4 of whom survived to transplant. Of 13 patients implanted as bridge to decision or destination therapy, 77% were alive at 1 year and 69% at 2 years. The overall frequencies of positive outcome (transplanted or alive on device) at 1 year and 2 years were 84% and 78%, respectively. Two patients suffered a stroke, 2 developed sepsis, 1 required tracheostomy, and 1 experienced severe right heart failure requiring right-sided VAD. CONCLUSIONS: This study demonstrates the potential utility of VAD therapies in patients with muscular dystrophy. Further research is needed to further improve outcomes and better determine which patients may benefit most from VAD therapy in terms of survival and quality of life.

Obesity and loss of ambulation are associated with lower extremity oedema in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy have multiple risk factors for lower extremity oedema. This study sought to define the frequency and predictors of oedema. Patients aged 15 years and older were screened by patient questionnaire, and the presence of oedema was confirmed by subsequent physical exam. Twenty-four of 52 patients (46%) had oedema, 12 of whom had swelling extending above the foot and two with sores/skin breakdown. There was no significant difference in age, frequency, or duration of glucocorticoid use, non-invasive respiratory support use, forced vital capacity, cardiac medication use, or ejection fraction between patients with and without oedema (all p > 0.2). Those with oedema had a greater time since the loss of ambulation (8.4 years versus 3.5 years; p = 0.004), higher body mass index (28.3 versus 24.8; p = 0.014), and lower frequency of deflazacort use (67% versus 89%; p = 0.008). Multivariate analysis revealed a longer duration of loss of ambulation (p = 0.02) and higher body mass index (p = 0.009) as predictors of oedema. Lower extremity oedema is common in Duchenne muscular dystrophy but independent of cardiac function. Interventions focused on minimising body mass index increases over time may be a therapeutic target.

Echocardiography Provides a Reliable Estimate of Total Cardiac Volume for Pediatric Heart Transplantation.

BACKGROUND: Donor-to-recipient size matching for heart transplantation typically involves comparing donor and recipient body weight; however, weight is not linearly related to cardiac size. Attention has shifted toward the use of computed tomography- (CT-) derived total cardiac volume (TCV), that is, CT-TCV, to compare donor and recipient heart organ size. At this time, TCV size matching is near impossible for most centers due to logistical limitations. To overcome this impediment, echocardiogram-derived TCV (ECHO-TCV) is an attractive, alternative option to estimate CT-TCV. The goal of this study is to test whether ECHO-TCV is an accurate and reliable surrogate for TCV measurement compared with the gold standard CT-TCV. METHODS: ECHO-TCV and CT-TCV were measured in a cohort spanning the neonatal to young adult age range with the intention to simulate the pediatric heart transplant donor pool. ECHO-TCV was measured using a modified Simpson's summation-of-discs method from the apical 4-chamber (A4C) view. The gold standard of CT-TCV was measured from CT scans using three-dimensional reconstruction software. The relationship between ECHO-TCV and CT-TCV was evaluated and compared with other anthropometric and image-based markers that may predict CT-TCV. Inter-rater reliability of ECHO-TCV was tested among 4 independent observers. Subanalyses were performed to identify imaging views and timing that enable greater accuracy of ECHO-TCV. RESULTS: Banked imaging data of 136 subjects with both echocardiogram and CT were identified. ECHO-TCV demonstrated a linear relationship to CT-TCV with a Pearson correlation coefficient of r = 0.96 (95% CI, 0.95-0.97; P < .0001) and mean absolute percent error of 8.6%. ECHO-TCV correlated most strongly with CT-TCV in the subset of subjects <4 years of age (n = 33; r = 0.98; 95% CI, 0.96-0.99; P < .0001). The single-score intraclass correlation coefficient across all 4 raters is 0.96 (interquartile range, 0.93-0.98). ECHO-TCV measured from a standard A4C view at end diastole with the atria in the plane of view had the strongest correlation to CT-TCV. CONCLUSIONS: ECHO-TCV by the A4C view was found to be both an accurate and reliable alternative measurement of CT-TCV and is derived from readily available donor ECHO images. The ECHO-TCV findings in this study make the ECHO method an attractive means of direct donor-to-recipient TCV size matching in pediatric heart transplantation.

Deep Learning for Automated Measurement of Total Cardiac Volume for Heart Transplantation Size Matching.

Background: Total Cardiac Volume (TCV) based size matching using Computed Tomography (CT) is a novel technique to compare donor and recipient heart size in pediatric heart transplant that may increase overall utilization of available grafts. TCV requires manual segmentation, which limits its widespread use due to time and specialized software and training needed for segmentation. Objective: This study aims to determine the accuracy of a Deep Learning (DL) approach using 3-dimensional Convolutional Neural Networks (3D-CNN) to calculate TCV, with the clinical aim of enabling fast and accurate TCV use at all transplant centers. Materials and Methods: Ground truth TCV was segmented on CT scans of subjects aged 0-30 years, identified retrospectively. Ground truth segmentation masks were used to train and test a custom 3D-CNN model consisting of a Dense-Net architecture in combination with residual blocks of ResNet architecture. Results: The model was trained on a cohort of 270 subjects and a validation cohort of 44 subjects (36 normal, 8 heart disease retained for model testing). The average Dice similarity coefficient of the validation cohort was 0.94 ± 0.03 (range 0.84-0.97). The mean absolute percent error of TCV estimation was 5.5%. There is no significant association between model accuracy and subject age, weight, or height. DL-TCV was on average more accurate for normal hearts than those listed for transplant (mean absolute percent error 4.5 ± 3.9 vs. 10.5 ± 8.5, p = 0.08). Conclusion: A deep learning based 3D-CNN model can provide accurate automatic measurement of TCV from CT images.