Mary E. Moya-Mendez

Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na ⁺ /K ⁺ -ATPase function, causing Ca ²⁺ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMs ^D801N ), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca ²⁺ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca² ⁺ influx via the Na ⁺ /Ca ²⁺ exchanger (NCX1) during depolarization was observed in iPSC-CMs ^D801N . Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca ²⁺ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca ²⁺ -mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.

BACKGROUND: Trauma remains the leading cause of death in all age groups of children, yet the role of extracorporeal membrane oxygenation (ECMO) in pediatric trauma remains unclear. The goal of this study was to evaluate contemporary ECMO practice patterns for pediatric trauma in both acute (p = 0.04). In the Traumatic Injury Population, overall survival was 67% (28/42) with 63% of children cannulated acutely surviving compared with 69% of children cannulated subacutely ( p = 0.53). Children cannulated after FBA, cold-water drowning, and airway injury had 100% survival rate while those cannulated after penetrating thoracic or blunt abdominal injury, cardiac arrest, and cardiogenic shock had the worst survival (50%, 0%, 50%, 63%, respectively). CONCLUSION: This is the largest multicenter study to date using contemporary data of children who received ECMO for a trauma indication. Compared with national nontraumatic ECMO cannulations, our overall cohort, and sub-cohort of children with traumatic injuries, had comparable survival. Children cannulated after FBA, cold-water drowning, and airway injury benefitted the most from ECMO support. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is one of the leading causes of sudden cardiac death in children, young adults, and athletes and is characterized by the fibro-fatty replacement of the myocardium, predominantly of the right ventricle. Sixty percent of patients with ACM have a known genetic cause, but for the remainder, the pathogenesis is unknown. This lack of mechanistic understanding has slowed the development of disease-modifying therapies, and children with ACM have a high degree of morbidity and mortality. METHODS: Induced pluripotent stem cells (iPSCs) from 3 family members were differentiated into cardiac myocytes (CMs). Calcium imaging was conducted by labeling calcium with CAL-520 and confocal imaging to capture calcium sparks after iPSC-CMs were electrically paced. A cardiac-specific, inducible knockout mouse ( Tax1bp3 ^−/− ) was made and intracardiac electrophysiology studies conducted to observe arrhythmia inducibility following pacing. RESULTS: We identified a kindred with multiple members affected by ACM cosegregating with biallelic variants in the gene TAX1BP3 , which encodes the protein TAX1BP3 (Tax1-binding protein 3). iPSC-CMs derived from this kindred demonstrated increased intracellular lipid droplets, induction of TRPV4 (transient receptor potential vanilloid type 4) expression, and inducible TRPV4 current. This was associated with depletion of the intracellular sarcoplasmic reticulum Ca ²⁺ store and increased RyR2 (ryanodine receptor 2)-mediated store Ca ²⁺ leak and delayed afterdepolarizations, a known mechanism of Ca ²⁺ -mediated arrhythmogenesis. Similarly, Tax1bp3 cardiac-specific knockout mice had increased Ca ²⁺ leak and were predisposed to ventricular arrhythmias compared with wild-type mice. Ca ²⁺ leak in both the iPSC-CMs and mouse ventricular myocytes was rescued by small molecule TRPV4 inhibition. This strategy also effectively reduced Ca ²⁺ leak in a PKP2 (plakophilin 2) p.His773AlafsX8 iPSC-CM model of ACM. CONCLUSIONS: We conclude that TAX1BP3 is associated with rare autosomal recessive ACM through TRPV4-mediated Ca ²⁺ leak from RyR2. Further, TRPV4 current inhibition has the potential to be a new therapeutic target for ACM.

Retained ballistic fragments from gunshot wounds pose diagnostic and management challenges for radiologists and surgeons alike. Imaging and clinical decision-making regarding removal warrant comprehensive risk/benefit discussions, considering anatomic location, complexity of surgical removal, and risk of long-term complications of bullet migration and potential lead toxicity. Herein, we describe a 9-year-old with a retained intra-thoracic para-aortic ballistic fragment causing elevated lead levels. Photon-counting detector computed tomography (PCD-CT) was used to create a 3D-printed anatomic model, critical for multidisciplinary pre-operative planning and as an educational tool with the patient and family, ultimately leading to successful surgical bullet removal. Since spectral CT imaging offers superior metal artifact reduction capabilities than conventional CT, cutting-edge technologies such as PCD-CT and 3D-printing should be considered in anatomically challenging cases.

People with alternating hemiplegia of childhood undergoing general anesthesia are at risk for severe complications including critical bradycardia and hemiplegic incidents. We performed a 10-year historical cohort study and completed a subgroup analysis of patients who specifically underwent general anesthesia. Patients with ATP1A3 positive variants were compared with those without such variants. The 14 patients reviewed underwent general anesthesia a combined total of 39 times. Two patients had a short QTc documented prior to anesthesia and presented with bradycardia in the recovery room. Two other patients experienced a suspected seizure and hemiplegic incident; one of those patients received no facility-administered medications prior to experiencing a hemiplegic incident, and the other experienced a hemiplegic incident on emergence from anesthesia with subsequent cardiac arrest and successful resuscitation. No apparent association was identified between type of anesthesia and the development of bradycardia or hemiplegic incidences. Of the four patients experiencing critical events, three had the ATP1A3-D801N variant. Although additional research is necessary to confirm such associations, patients with alternating hemiplegia of childhood, specifically the ATP1A3-D801N variant, appear to be at elevated risk for complications associated with general anesthesia, suggesting the need for an increased anticipation of complications for this population.

Background: Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. Methods: We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. Results: The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 – 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 – 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (PATP1A3 -related phenotypes and baseline QTc 4 seconds. Conclusions: Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. Clinical Perspective: What is Known: Individuals with ATP1A3-D801N have a short baseline QTc. Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.