Human Fibrinogen for Maintenance and Differentiation of Induced Pluripotent Stem Cells in Two Dimensions and Three Dimensions.

Human fibrin hydrogels are a popular choice for use as a biomaterial within tissue engineered constructs because they are biocompatible, nonxenogenic, autologous use compatible, and biodegradable. We have recently demonstrated the ability to culture induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium on fibrin hydrogels. However, iPSCs themselves have relatively few substrate options (e.

Exercise testing oversights underlie missed and delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia in young sudden cardiac arrest survivors.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by adrenergically induced ventricular tachycardia, syncope, and sudden cardiac arrest (SCA). In the absence of structural disease, exercise-provoked premature ventricular contractions in bigeminy or couplets and nonsustained ventricular tachycardia are highly predictive of CPVT.

Objective: The purpose of this study was to determine the number of missed or delayed CPVT diagnoses attributable to exercise testing oversights in a cohort of young SCA survivors.

Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young.

Objectives: This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY).

Background: Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling.

International Triadin Knockout Syndrome Registry.

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.

Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations.

Cost Efficacy of α-Galactosidase A Enzyme Screening for Fabry Disease.

The prevalence of Fabry disease (FD) in adult patients with suspected hypertrophic cardiomyopathy (HCM) has been reported between 0.3% and 4%. Fabry disease-specific therapy necessitates early diagnosis; however, the optimal screening strategy and cost efficacy of routine α-galactosidase A (α-gal A) vs comprehensive galactosidase alpha gene (GLA) testing remain poorly understood.

Long QT syndrome caveolin-3 mutations differentially modulate K 4 and Ca 1.2 channels to contribute to action potential prolongation.

Key Points: Mutations in the caveolae scaffolding protein, caveolin-3 (Cav3), have been linked to the long QT type 9 inherited arrhythmia syndrome (LQT9) and the cause of underlying action potential duration prolongation is incompletely understood. In the present study, we show that LQT9 Cav3 mutations, F97C and S141R, cause mutation-specific gain of function effects on Ca 1.2-encoded L-type Ca channels responsible for I and also cause loss of function effects on heterologously expressed K 4.

Safety of Sports for Young Patients With Implantable Cardioverter-Defibrillators: Long-Term Results of the Multinational ICD Sports Registry.

Background: Despite safety concerns, many young patients with implantable cardioverter-defibrillators (ICDs) participate in sports. We undertook a prospective, multinational registry to determine the incidence of serious adverse events because of sports participation. The primary end points were death or resuscitated arrest during sports or injury during sports because of arrhythmia or shock.

Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases.

Background: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation.

Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation.

Purpose: There is a significant variation in the clinical approach of initiation and dose adjustment of dofetilide in atrial fibrillation (AF). Excessive QT prolongation could predispose patients to torsades de pointes (TdP), which can be fatal.

Methods: We performed a retrospective case-control study at Mayo Clinic Rochester (January 1, 2003 to December 31, 2016).

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.

Objective: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus.

Study Design: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies.

Clinical Significance of Early Repolarization in Long QT Syndrome.

Objectives: This study sought to determine the prevalence of early repolarization pattern (ERP) within a large cohort of patients with long QT syndrome (LQTS) and examine the correlation and clinical significance of ERP with symptomatic status and subsequent risk of breakthrough cardiac events (BCEs).

Background: The electrocardiographic ERP is associated with an increased risk of arrhythmic events and sudden cardiac death.

Methods: ERP was defined as an end-QRS notch or slur on the downslope of a prominent R-wave with a J point ≥0.

Prevalence and clinical phenotype of concomitant long QT syndrome and arrhythmogenic bileaflet mitral valve prolapse.

Background: Mitral valve prolapse (MVP), including the recently described arrhythmogenic bileaflet MVP syndrome (ABiMVPS), is associated with repolarization abnormalities and may represent an underestimated cause of sudden cardiac death. The impact of concomitant MVP or ABiMVPS on long QT syndrome (LQTS) clinical severity is unknown.

Methods And Results: Retrospective review of 754 LQTS patients [445 females (58%) and mean QTc 471 ± 41 ms] with available echocardiographic data was performed to identify LQTS patients with not only MVP, but also a pro-arrhythmic ABiMVPS phenotype defined as bileaflet MVP, inferolateral T-wave inversions, and frequent complex ventricular ectopy/arrhythmia.

A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.

Background: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Ca1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain.

Noncardiac genetic predisposition in sudden infant death syndrome.

Purpose: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.

Methods: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.

Noninvasive assessment of dofetilide plasma concentration using a deep learning (neural network) analysis of the surface electrocardiogram: A proof of concept study.

Background: Dofetilide is an effective antiarrhythmic medication for rhythm control in atrial fibrillation, but carries a significant risk of pro-arrhythmia and requires meticulous dosing and monitoring. The cornerstone of this monitoring, measurement of the QT/QTc interval, is an imperfect surrogate for plasma concentration, efficacy, and risk of pro-arrhythmic potential.

Objective: The aim of our study was to test the application of a deep learning approach (using a convolutional neural network) to assess morphological changes on the surface ECG (beyond the QT interval) in relation to dofetilide plasma concentrations.

Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter International Study of a Rare Disorder.

Objectives: The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations.

Background: TS is an extremely rare genetic disorder of the L-type cardiac channel Ca1.2 encoded by CACNA1C.

Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: A systematic review.

Background: The implantable cardioverter-defibrillator (ICD) may be associated with a high risk of complications in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). However, ICDs in this population have not been systematically evaluated.

Objective: The purpose of this study was to characterize the use and outcomes of ICDs in CPVT.

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.

Methods And Results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis.