Elizabeth Irene Reiser, By And Through Her Guardian, Richard E. Reiser And Eleanor Reiser v. Richard Lohner And Howard Francis, Medical Doctors, And Provo Obstetrical And Gynecology Clinic, Inc., A Professional Corporation : Brief of Defendants-Respondents

Appeal from a Verdict of the Fourth Judicial District Court of Utah County, State of Utah Honorable James S. Sawaya, Presidin

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Electrophysiological patterning of the heart

The results in this thesis indicate that there is a direct relation between the spatio-temporal activity pattern of particular cardiac transcription factors and the electrophysiological characteristics of myocardial structures. Insight into the mechanisms that regulate the expression of these factors and their target regulatory sequences in ion channel encoding genes, could lead to the identification of new approaches and candidate markers for improved arrhythmogenic risk stratification

Lineages of the Cardiac Conduction System

The cardiac conduction system (CCS) initiates and coordinately propagates the electrical impulse to orchestrate the heartbeat. It consists of a set of interconnected components with shared properties. A better understanding of the origin and specification of CCS lineages has allowed us to better comprehend the etiology of CCS disease and has provided leads for development of therapies. A variety of technologies and approaches have been used to investigate CCS lineages, which will be summarized in this review. The findings imply that there is not a single CCS lineage. In contrast, early cell fate decisions segregate the lineages of the CCS components while they remain connected to each othe

Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias

Heterogeneous distribution of electrophysiological behavior across the heart is essential for normal cardiac function. If this heterogeneity becomes excessive it may contribute to arrhythmogenesis and sudden cardiac death. Controversy exists regarding the localization of activation and repolarization gradients in the diseased heart and how these heterogeneities contribute to arrhythmogenesis. In this review we focus on the genesis and existence of transmural heterogeneity in activation and repolarization. We will describe a possible embryonic origin of these heterogeneities and address the question how heterogeneities contribute to the genesis of the electrocardiogram and how they may cause reentrant arrhythmias. This review subsequently concentrates on several pathologies in which transmural heterogeneities are thought to play a rol

Atrial Fibrillation: Biophysics, Molecular Mechanisms, and Novel Therapies

Atrial fibrillation (AF) affects millions of people worldwide and is associated with increased morbidity and mortality [1]. The incidence of AF is expected to rise with aging of the population. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. Therefore, a comprehensive understanding of AF pathophysiology is needed to foster the development of improved diagnostic, pharmacological, and nonpharmacological therapeutic approaches to improve clinical management. The focus of this special issue of this journal is to capture most recent advances in the study of AF with the aim of directing further research. Conventional mechanisms linked to AF are diverse and expertly reviewed in various manuscripts [2, 3]. However, progression in the field of AF research may come from an unconventional view-angle. For example, M. Miragoli and A. V. Glukhov reviewed the role of myofibroblasts as novel targets for cardiac arrhythmias with the aim of describing and evaluating the implications of noncardiomyocyte view in the context of AF. B. Weil and C. Ozcan discussed the pathophysiological remodelling in AF in comparison with that occurring in hibernating myocardium, attempting to identify common molecular mechanisms and proposing possible future therapeutic implications of this emerging paradigm

Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract

In patients with Brugada syndrome, arrhythmias typically originate in the right ventricular outflow tract (RVOT). The RVOT develops from the slowly conducting embryonic outflow tract. We hypothesize that this embryonic phenotype is maintained in the fetal and adult RVOT and leads to conduction slowing, especially after sodium current reduction. We determined expression patterns in the embryonic myocardium and performed activation mapping in fetal and adult hearts, including hearts from adult mice heterozygous for a mutation associated with Brugada syndrome (Scn5a1798insD/+). The embryonic RVOT was characterized by expression of Tbx2, a repressor of differentiation, and absence of expression of both Hey2, a ventricular transcription factor, and Gja1, encoding the principal gap-junction subunit for ventricular fast conduction. Also, conduction velocity was lower in the RVOT than in the right ventricular free wall. Later in the development, Gja1 and Scn5a expression remained lower in the subepicardial myocardium of the RVOT than in RV myocardium. Nevertheless, conduction velocity in the adult RVOT was similar to that of the right ventricular free wall. However, in hearts of Scn5a1798insD/+ mice and in normal hearts treated with ajmaline, conduction was slower in the RVOT than in the right ventricular wall. The slowly conducting embryonic phenotype is maintained in the fetal and adult RVOT and is unmasked when cardiac sodium channel function is reduce

Neurokinin-3 receptor activation selectively prolongs atrial refractoriness by inhibition of a background K+ channel

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