Rachel E. Harris

Cardiac disease has become the primary cause of death among individuals with Duchenne Muscular Dystrophy. There are currently no published data on the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with dystrophin deficient cardiomyopathy. The purpose of this study was to analyze the use of SGLT2i in patients with dystrophin deficient cardiomyopathy and describe indications for therapy, effects on cardiac function, and adverse effects. We utilized the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) dystrophinopathy registry to review patients on SGLT2i. 80 patients were initiated on an SGLT2i. The median age at initiation was 19.6 years and median weight was 66.8 kg. Most patients were already prescribed three other cardiac medications classes. At initiation, the median ejection fraction (EF) was 37% (IQR 30.0-42.3%) by echocardiogram and 37% (IQR 31.5–41.0%) by cardiac magnetic resonance imaging (cMRI). Follow-up data was collected for 55 patients with a median follow-up time of 1.4 years. At follow-up, the median EF was 40% (IQR 32-47.8%) by echocardiogram and 39% (IQR 33-40.2%) by cMRI. There were 14 adverse events which included bone fracture (5%), acute kidney injury (5%), urinary tract infection (2.5%), genitourinary infection (1.3%) and others (3.8%). Seven patients (8.8%) required permanent discontinuation. This medication appears well tolerated with a low incidence of adverse effects. Longer term follow-up data is needed. However, SGLT2i may represent an additional therapy for slowing the progression of cardiac disease.

Background: Duchenne muscular dystrophy (DMD) is marked by cardiac and skeletal myopathy with disparate onset and progression suggesting distinct pathophysiologies. Nontargeted proteomics may elucidate the different disease pathways underlying skeletal muscle and cardiomyopathy progression and identify proteins that improve DMD risk stratification. Methods and results: Sixty subjects were enrolled; 56 underwent cardiac magnetic resonance to determine left ventricular ejection fraction, late gadolinium enhancement, and myocardial circumferential strain. Of the 60 patients enrolled, 51 underwent quantitative muscle testing and 33 underwent actigraphy. Aptamer-based technology (SomaScan) evaluated 1128 proteins in plasma. The correlations between serum protein levels and cardiac or skeletal muscle indices were tested using a Spearman correlation test followed by multiple testing correction yielding q -values. The median age was 15.0 years (12.7–17.9 interquartile range). Of 1128 proteins analyzed, 208 correlated with only cardiac indices; 14 correlated with only skeletal muscle indices; 10 proteins correlated strongly with both indices. Protein functions included (1) calcium regulation, (2) cardiac remodeling, (3) cell homeostasis, (4) fibrosis, (5) inflammation, (6) lipid regulation, and (7) other. Conclusion: Our nontargeted proteomics study identified serum biomarkers correlating with skeletal and cardiac progression in DMD. Candidate proteins—some uniquely associated with skeletal or cardiac indices and others overlapping—offer promising leads for studies to improve risk stratification and guide targeted therapies in DMD.

Cobalamin C (Cbl‐C) disease, the most common inborn error of cobalamin metabolism caused by biallelic pathogenic MMACHC variants, leads to multisystem involvement from methylmalonic acid and homocysteine accumulation. When diagnosed early, it is treatable. Rapid genome sequencing (GS) is becoming increasingly accessible and enables timely diagnosis and prompt treatment. We report a neonate who had severely decreased prenatal and postnatal biventricular function requiring inotropic support. Given the critically ill condition and unclear etiology, rapid GS was obtained and revealed homozygous pathogenic MMACHC variants, confirming a diagnosis of Cbl‐C disease. This prompted the early initiation of treatment with high‐dose hydroxocobalamin, betaine, levocarnitine, and folic acid. His cardiac function gradually improved, and he was discharged at 28 days of life. Critical care providers should suspect treatable inherited metabolic disorders in patients with unexplained presentations and recognize rapid GS as a powerful tool for early identification and treatment in critically ill patients.

Duchenne muscular dystrophy (DMD) is an X‐linked genetic neuromuscular disorder that is caused by a mutation in the dystrophin gene. The disease is characterized by progressive weakness of skeletal muscle, resulting in loss of ambulation and eventually respiratory insufficiency. Cardiac muscle is also involved, and cardiomyopathy is a prominent feature of DMD. The care of patients with DMD has changed in important ways over the past 15 years, with the use of chronic steroid therapy combined with noninvasive respiratory support such as continuous positive airway pressure for home use. More recently, therapies targeting specific genetic mutations in DMD have been approved, using gene‐skipping oligonucleotides, and many other novel therapies are being evaluated in clinical trials, including mini‐dystrophin genes delivered by viral vectors. In view of this new era in care and outcomes, it is appropriate to review the role of advanced cardiac therapies such as ventricular assist devices and heart transplantation in the care of this population. In September 2024, a group of healthcare professionals with expertise in DMD and heart failure convened to review this topic; the consensus opinion of this group (DMD Cardiac Care Consortium) is presented in this manuscript.

Background: In 2020, the Organ Procurement and Transplantation Network authorized the creation of a National Heart Review Board for Pediatrics along with a guidance document. The purpose of this study was to evaluate the utilization of exception requests and approval rates after the implementation of the new review board. Methods: This was a retrospective review of 1A and 1B exception requests between June 2021 and January 2023. Exception request narratives were reviewed to determine if the request followed guidance and then analyzed the frequency of those approved by diagnosis. Results: There were 591 exception requests submitted for 419 candidates with an overall approval rate of 91%. Only 55% of the exceptions followed the guidance, but of those, 97% were approved. Exceptions submitted that did not follow the guidance had a lower approval rate of 85%. 1A exception requests that followed the guidance were significantly more likely to be approved than those that did not (97% vs. 62%, respectively, p < 0.05). For 1B requests, approval rates did not differ between requests that followed the guidance and those that did not (98% vs. 95%, respectively, p = 0.15). Candidates with single ventricle congenital heart disease made up 59% of 1B exception requests. There is no 1B exception guidance for candidates with dilated or hypertrophic cardiomyopathy; however, requests were still submitted and 95% were approved. Conclusion: Most status 1A exceptions being granted followed the guidance document from OPTN. While the greatest number of requests for 1B exceptions were for single ventricle physiology candidates, many exceptions outside the guidance are being sought and granted.

Background In patients requiring mechanical circulatory support (MCS), the incidence of acute kidney injury (AKI) is between 37 and 63%. In this study, we performed an exploratory analysis evaluating the relationship of multiple urine biomarkers with AKI development in pediatric MCS patients. Methods This is a single center retrospective study in a pediatric cohort receiving MCS from August 2014 to November 2020. We measured 14 urine biomarkers of kidney injury on day 1 following MCS initiation and analyzed their association with development of AKI in the first 7 days of MCS initiation. Results Sixty patients met inclusion criteria. Patients with AKI were more likely to be supported by venoarterial extracorporeal membrane oxygenation (65% vs. 8.3%, p < 0.001), compared to the no AKI group and less likely to have ventricular assist devices (10% vs. 50%, p < 0.001). There was a significant increase in the median urine albumin and urine osteoactivin in the AKI group, compared to the no AKI group (p = 0.020 and p = 0.018, respectively). When normalized to urine creatinine (UCr), an increased log osteoactivin/UCr was associated with higher odds of AKI development (OR: 2.05; 95% CI: 1.07, 4.44; p = 0.028), and higher log epidermal growth factor (EGF)/UCr (OR: 0.41; 95% CI: 0.15, 0.96) was associated with decreased odds of AKI. Conclusions Early increase in urine osteoactivin is associated with AKI development within 7 days of MCS initiation in pediatric patients. Contrary, an increased urine EGF is associated with kidney protection. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information