De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 “trios” (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10−4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C. Both RYR2 mutations are pathogenic (P = 1.7 × 10−7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10−7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

Are SIDS, SUDC and SUDEP the different masks of the same great mystery?

The cases of sudden, unexpected child death against the background of relative clinical well-being, i.e., in the absence of apparent reasons take a special place in the structure of infant mortality. Sudden Infant Death Syndrome (SIDS), which is recognized as one of the leading causes of postnatal infant mortality in most developed countries, is the most common cause of unexpected out-ofhospital death of a child. Today SIDS remains one of the most mysterious problems in medicine. The lack of identifiable mechanisms causing SIDS has led to a large number of theories about the mechanisms responsible for death due to this syndrome. Also, sudden unexplained death in childhood (SUDC), which is the unexplained death of children over one- year-old, is currently distinguished among cases of unexpected death. The main clinical features of SUDC include: more common in boys; death occurs at night time, children are found in the early morning in a prone position, face down; children often have convulsions, including febrile ones in the clinical symptom complex during life. Several authors have noted that in some cases, the death due to SUDC resembles Sudden Death in Epilepsy (SUDEP), which is the leading cause of death in epilepsy. To date, it has already been shown that SUDEP is one of the forms of canalopathies characteristic of young children and it is associated with a high risk of sudden death. The mechanisms of thanatogenesis in SUDEP remain unknown. SIDS, SUDC, and SUDEP are a series of fatal syndromes united by multifactorial pathophysiological mechanisms, the causes of which are not fully understood. In fact, these syndromes represent a catastrophic multisystem failure, which is caused by an extremely unfavorable combination of autonomic, respiratory and cardiogenic disorders.

Unearthing the evidence: post-mortem interrogation of cardiac implantable electronic devices

Background The diagnostic yield of post-mortem interrogation of cardiac implantable electronic devices (CIEDs) including pacemakers, defibrillators and implantable loop recorders has not been well described. Methods We reviewed all post-mortem CIED interrogations performed by our statewide Institute of Forensic Medicine between 2005–2020 for investigation of sudden or unexplained death. Results 260 patients (68.8% male, median age 72.8 years [IQR 62.7–82.2]) underwent post-mortem CIED interrogation (202 pacemakers, 56 defibrillators and 2 loop recorders). CIEDs were implanted for a median of 2.0 [IQR 0.75–5] years, with 19 devices requiring replacement (and 5 end of life). Post-mortem interrogation was successful in 256 (98.5%) cases. Potential CIED malfunction was identified in 21 (8.1%) cases: untreated ventricular arrhythmias (n=13), lead failures (n=3) and battery depletion (n=5). CIED interrogation directly informed cause of death in 130 (50.0%) cases, with fatal ventricular arrhythmias identified in 121 patients (46.5%). In retrospect, 72 (27.7%) patients had abnormalities recorded by their device in the 30 days preceding death: non-sustained ventricular tachycardia (n=26), rapid atrial fibrillation (n=17), longevity concerns (n=22), intrathoracic impedance alarms (n=3), lead issues (n=3) or therapy delivered (n=1). In 6 cases where the patient was found deceased after a prolonged time, CIED interrogation accurately determined time of death. In one case, CIED interrogation was the primary method of patient identification. Conclusion Post-mortem CIED interrogation frequently contributes important information regarding critical device malfunction, pre-mortem abnormalities, cause and time of death or patient identity. Device interrogation should be considered for select patients with CIEDs undergoing autopsy. FUNDunding Acknowledgement Type of funding sources: None.

AMPLATZER™ AMULET™ LEFT ATRIAL APPENDAGE OCCLUDER VERSUS WATCHMAN™ DEVICE FOR STROKE PROPHYLAXIS (AMULET IDE): A RANDOMIZED CONTROLLED TRIAL

Background: Percutaneous closure of the left atrial appendage (LAA) is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with non-valvular atrial fibrillation (NVAF). The Amplatzer™ Amulet™ LAA Occluder IDE Trial (Amulet IDE Trial) was designed to evaluate the safety and effectiveness of the dual-seal mechanism of the Amulet LAA occluder compared with the Watchman™ device. Methods: Patients with NVAF at increased risk of stroke were randomly assigned (1:1) to undergo percutaneous implantation of a LAA occluder with the Amulet occluder or Watchman device. The primary endpoints included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months) and effectiveness (composite of ischemic stroke or systemic embolism at 18 months) and the rate of LAA occlusion at 45 days. Pre-specified secondary endpoints included a composite of all stroke, systemic embolism, or cardiovascular/unexplained death at 18 months, major bleeding at 18 months, and superiority test of the three primary endpoints. Results: A total of 1878 patients were enrolled. The Amulet occluder was noninferior to the Watchman device for the primary safety endpoint (14.5% vs. 14.7%; difference=-0.14, 95% CI, -3.42-3.13; p<0.001 for noninferiority). Major bleeding and all-cause death were similar between groups (10.6% vs 10.0% and 3.9% vs 5.1%, respectively). Procedure-related complications were higher for the Amulet occluder (4.5% vs. 2.5%), largely related to more frequent pericardial effusion and device embolization. The Amulet occluder was noninferior to the Watchman device for the primary effectiveness endpoint (2.8% vs. 2.8%; difference=0.00, 95% CI, -1.55-1.55; p<0.001 for non-inferiority), and the composite of stroke, systemic embolism or cardiovascular/unexplained death (5.6% vs 7.7%, difference=-2.12, 95% CI, -4.45-0.21; p<0.001 for noninferiority). The rate of major bleeding was similar between groups (11.6% vs. 12.3%; difference=-0.71, 95% CI -3.72-2.31; p=0.32 for superiority). LAA occlusion was higher for the Amulet occluder compared with the Watchman device (98.9% vs. 96.8%; difference=2.03, 95% confidence interval [CI], 0.41-3.66; p<0.001 for noninferiority; p=0.003 for superiority). Conclusions: The Amulet occluder was non-inferior for safety and effectiveness of stroke prevention for NVAF compared with the Watchman device, and superior for LAA occlusion. Procedure-related complications were higher with the Amulet device and decreased with operator experience. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02879448

ATP1A3 ‐Encoded Sodium‐Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia

Background Pathogenic variation in the ATP1A3 ‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status ( P <0.001) than in patients with genotype‐negative status, and significantly shorter in patients with the ATP1A3‐D801N variant than patients with other variants ( P <0.001). The mean QTc for ATP1A3‐D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.