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.

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.

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.

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.

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.

SynCardia Temporary Total Artificial Heart: Single-Center Experience at a Children's Hospital.

The SynCardia temporary total artificial heart (TAH-t) is a pneumatically driven pulsatile device that replaces a patient's ventricles and all four valves. It is now available in two sizes and can be used in patients with sufficient chest size as a bridge to transplant or destination therapy. We describe our experience at a children's hospital with the TAH-t. Seven patients implanted with a TAH-t at Cincinnati Children's Hospital Medical Center from November 2012 to March 2021 were included. Duration of support ranged from 10 to 414 days with a median of 27 days. There was a trend toward decreased time to extubation and intensive care unit (ICU) length of stay, with the three most recent patients being extubated on postoperative day 1. Seventy-one percent of the patients were successfully transplanted following their TAH-t placement. Children and young adults with transplant graft failure requiring durable, biventricular support with a TAH-t had superior outcomes (75% survival to retransplant) than previously described.

Racial and socioeconomic disparities in pediatric heart transplant outcomes in the era of anti-thymocyte globulin induction.

BACKGROUND: Black race is associated with worse outcomes across solid organ transplantation. Augmenting immunosuppression through antithymocyte globulin (ATG) induction may mitigate organ rejection and graft loss. We investigated whether racial and socioeconomic outcome disparities persist in children receiving ATG induction. METHODS: Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children who underwent heart transplant with ATG induction between 2000 and 2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant). We explored the association of these outcomes with race and socioeconomic disparity, assessed using a neighborhood deprivation index [NDI] score at 1-year post-transplant (high NDI score implies more socioeconomic disadvantage). RESULTS: The study cohort included 1,719 ATG-induced pediatric heart transplant recipients (22% Black, 78% White). There was no difference in first year treated rejection (Black 24.5%, White 28.1%, p = 0.2). During 10 year follow up, the risk of treated rejection was similar; however, Black recipients were at higher risk of HC rejection (p = 0.009) and graft loss (p = 0.02). Black recipients had a higher mean NDI score (p < 0.001). Graft loss conditional on 1-year survival was associated with high NDI score in both White and Black recipients (p < 0.0001). In a multivariable Cox model, both high NDI score (HR 1.97, 95% CI 1.23-3.17) and Black race (HR 2.22, 95% CI 1.40-3.53) were associated with graft loss. CONCLUSION: Black race and socioeconomic disadvantage remain associated with late HC rejection and graft loss in children with ATG induction. These disparities represent important opportunities to improve long term transplant outcomes.

Decreased Risk of Strokes in Children with Ventricular Assist Devices Within ACTION.

We sought to characterize strokes in children with ventricular assist devices. Of 407 patients in the ACTION registry (4/1/18-5/3/2021), 45 (11%) experienced 52 strokes (45 ischemic and 7 hemorrhagic). Median time to stroke was 23.5 days and 19/52 (37%) occurred ≤ 10 days. Stroke rate was 0.09 and 0.63 strokes per patient-year for implantable continuous and paracorporeal devices, respectively. Patients with stroke were younger, more likely to have congenital heart disease and have been on extracorporeal membrane oxygenation at time of VAD. Based on these data, ACTION is now focused on decreasing strokes in these higher-risk patients with particular attention to the peri-implant period.

Abdominal CT and MRI Findings of Portal Hypertension in Children and Adults with Fontan Circulation.

Background Portal hypertension in the Fontan circulation is a function of elevated systemic venous pressure and liver fibrosis. Purpose To quantify the prevalence of radiologic evidence of portal hypertension and elevated VAST score (one point each for varices, ascites, splenomegaly, and thrombocytopenia) of 2 or greater in children and adults with Fontan circulation and to determine the association with hemodynamics and adverse outcomes. Materials and Methods This was a retrospective study of individuals with Fontan circulation who underwent abdominal MRI or CT for focal liver lesion surveillance between January 2012 and December 2019. Portal hypertension was defined as the presence of at least two of the following: varices, ascites, or splenomegaly. Fontan deterioration was defined as a composite of heart failure signs or symptoms requiring diuretic escalation, placement of a ventricular assist device, heart transplant, or death. Relationships between variables and the composite end point were assessed using univariable and multivariable logistic regression. Results A total of 123 patients (age range, 9-55 years; 32 children) were evaluated (median age, 23 years; IQR, 17-30 years; 63 male patients). Median time since diagnosis of Fontan circulation was 16 years (IQR, 12-23 years). Twenty-five of the 123 patients (20%) had radiologic evidence of portal hypertension, and 34 (28%) had a VAST score of 2 or greater. Fontan deterioration occurred in 25 of the 123 patients (20%); median follow-up duration was 0.4 year (IQR, 0.1-3.1 years). Compared with patients who had Fontan circulation without deterioration, patients with Fontan deterioration were more likely to have moderate or severe ventricular systolic dysfunction (P < .01), moderate or severe atrioventricular valve regurgitation (P < .01), higher Fontan pressure (P = .01), radiologic evidence of portal hypertension (P < .01), and VAST score of 2 or greater (P < .01). Conclusion Radiologic evidence of portal hypertension at abdominal imaging in children and adults with Fontan circulation was associated with higher venous pressures and an increased risk for Fontan deterioration. These characteristics may be used to identify patients who warrant comprehensive hemodynamic evaluation. © RSNA, 2022.

Diversity of Dystrophin Gene Mutations and Disease Progression in a Contemporary Cohort of Duchenne Muscular Dystrophy.

Abnormal dystrophin production due to mutations in the dystrophin gene causes Duchenne Muscular Dystrophy (DMD). Cases demonstrate considerable genetic and disease progression variability. It is unclear if specific gene mutations are prognostic of outcomes in this population. We conducted a retrospective cohort study of DMD patients followed at 17 centers across the USA and Canada from 2005 to 2015 with goal of understanding the genetic variability of DMD and its impact on clinical outcomes. Cumulative incidence of clinically relevant outcomes was stratified by genetic mutation type, exon mutation location, and extent of exon deletion. Of 436 males with DMD, 324 (74.3%) underwent genetic testing. Deletions were the most common mutation type (256, 79%), followed by point mutations (45, 13.9%) and duplications (23, 7.1%). There were 131 combinations of mutations with most mutations located along exons 45 to 52. The number of exons deleted varied between 1 and 52 with a median of 3 exons deleted (IQR 1-6). Subjects with mutations starting at exon positions 40-54 had a later onset of arrhythmias occurring at median age 25 years (95% CI 18-∞), p = 0.01. Loss of ambulation occurred later at median age of 13 years (95% CI 12-15) in subjects with mutations that started between exons 55-79, p = 0.01. There was no association between mutation type or location and onset of cardiac dysfunction. We report the genetic variability in DMD and its association with timing of clinical outcomes. Genetic modifiers may explain some phenotypic variability.

Chronic Ventricular Assist Device Support in Adult Congenital Heart Disease Patients: A Children's Hospital Perspective.

With improvement in early surgical outcomes in patients with complex congenital heart disease, most patients are now expected to survive to adulthood. As adult congenital heart disease (ACHD) patients age, they are at risk of heart failure, which has become the leading cause of mortality in ACHD. Some who develop advanced heart failure may not be candidates for transplant, and chronic ventricular assist device (VAD) therapy may be the only means of survival. There is limited experience with chronic VAD therapy in ACHD patients, and the outcomes are not well delineated. We describe our center's experience with chronic VAD therapy in ACHD patients receiving care exclusively within our children's hospital.

Ventricular Assist Device Therapy in the Fontan Circulation.

The number of Fontan patients with circulatory failure and systolic dysfunction is growing rapidly. The last decade has demonstrated that ventricular assist device (VAD) is an effective therapy in properly selected patients. Herein, we discuss the current approach to patient selection, implantation, and patient management.

Cardiac medication management in Duchenne muscular dystrophy.

There have been significant improvements in the skeletal muscle and respiratory care for patients with Duchenne muscular dystrophy (DMD) over the last two decades. This has resulted in longer expected survival as many patients will live into their 20s and 30s. This timeline has resulted in a greater proportion of patients experiencing heart failure and cardiac-related mortality. Herein, we describe the current indications for medical therapy for patients with DMD.

Ventricular Assist Device Therapy and Fontan: A Story of Supply and Demand.

The last 10 years have seen an increase in the number of Fontan patients with heart failure. There has been a coincident rapid evolution in the field of pediatric and congenital heart disease ventricular assist device therapy. Herein, we describe the existing body of literature regarding the use of ventricular assist device therapy in the Fontan circulation as well as the current approach to clinical decision-making and device implantation within the field.

The Creation of a Pediatric Health Care Learning Network: The ACTION Quality Improvement Collaborative.

Improving the outcomes of pediatric patients with congenital heart disease with end-stage heart failure depends on the collaboration of all stakeholders; this includes providers, patients and families, and industry representatives. Because of the rarity of this condition and the heterogeneity of heart failure etiologies that occur at pediatric centers, learnings must be shared between institutions and all disciplines to move the field forward. To foster collaboration, excel discovery, and bring data to the bedside, a new, collaborative quality improvement science network-ACTION (Advanced Cardiac Therapies Improving Outcomes Network)-was developed to meet the needs of the field. Existing gaps in care and the methods of improvement that will be used are described, along with the mission and vision, utility of real-world data for regulatory purposes, and the organizational structure of ACTION is described.

The total artificial heart in pediatrics: outcomes in an evolving field.

BACKGROUND: The use of the SynCardia temporary total artificial heart (TAH-t) in adults has increased with time. The development of the smaller, 50 cc TAH-t has expanded the potential applications of the device in children. We sought to describe the evolving use of the TAH-t over time and describe outcomes in the current era. METHODS: The SynCardia database was queried to identify all pediatric patients ≤18 years of age implanted with the device between December 1985 and October 2019. Patient demographics, clinical outcome and support characteristics collected. RESULTS: Fifty-one children were supported, 36 with the 70 cc TAH-t and 15 with the 50 cc TAH-t with a total support time of 6,243 days. The number of implants has increased with time (19 between 2015 and 2019). A total of 13 patients have been converted to Freedom Driver support, seven 50 cc TAH-t and six 70 cc TAH-t. The majority of implants in the last 5 years (15/19, 79%) have been with the 50 cc TAH-t. The most common diagnosis was dilated cardiomyopathy [24 (47%)] and the average age at the time of implant was 16±2 years old. Overall survival for the patient cohort was 71%. CONCLUSIONS: The use of the SynCardia TAH-t to support children with end-stage heart failure has increased over time. Clinical outcomes with both the 50 cc and 70 cc TAH-t are similar to reported outcomes in adults who require TAH-t or other methods of biventricular support.

Implantable Cardioverter Defibrillator Use in Males with Duchenne Muscular Dystrophy and Severe Left Ventricular Dysfunction.

Duchenne muscular dystrophy (DMD) is characterized by myocardial fibrosis and left ventricular (LV) dysfunction. Implantable cardioverter defibrillator (ICD) use has not been characterized in this population but is considered for symptomatic patients with severe LV dysfunction (SLVD) receiving guideline-directed medical therapy (GDMT). We evaluated ICD utilization and efficacy in patients with DMD. Retrospective cohort study of DMD patients from 17 centers across North America between January 2, 2005 and December 31, 2015. ICD use and its effect on survival were evaluated in patients with SLVD defined as ejection fraction (EF) < 35% and/ or shortening fraction (SF) < 16% on final echocardiogram. SLVD was present in 57/436 (13.1%) patients, of which 12 (21.1%) died during the study period. Of these 12, (mean EF 20.9 ± 6.2% and SF 13.7 ± 7.2%), 8 received GDMT, 5 received steroids, and none received an ICD. ICDs were placed in 9/57 (15.8%) patients with SLVD (mean EF 31.2 ± 8.5% and SF 10.3 ± 4.9%) at a mean age of 20.4 ± 6.3 years; 8/9 received GDMT, 7 received steroids, and all were alive at study end; mean ICD duration was 36.1 ± 26.2 months. Nine ICDs were implanted at six different institutions, associated with two appropriate shocks for ventricular tachycardia in two patients, no inappropriate shocks, and one lead fracture. ICD use may be associated with improved survival and minimal complications in DMD cardiomyopathy with SLVD. However, inconsistent GDMT utilization may be a significant confounder. Future studies should define optimal indications for ICD implantation in patients with DMD cardiomyopathy.