Phase 2 Re-Entry Without I: Role of Sodium Channel Kinetics in Brugada Syndrome Arrhythmias.

Background: In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (I) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations.

Objectives: The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of I.

Methods: Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.

Cardiac Alternans: From Bedside to Bench and Back.

Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms.

The Extraordinarily Rare Ciliate Legendrea loyezae Fauré-Fremiet, 1908 (Haptoria, Ciliophora).

Diverse and dynamic communities of ciliates and other microbes thrive in the natural environment, driving the functioning of aquatic ecosystems. Many microbes are present in very low numbers or are dormant in the 'seedbank', escaping detection in environmental surveys and, consequently, remaining underexplored. Here, we report an extraordinarily rare ciliate that was discovered after persistent exploration of freshwater anoxic sediments - Legendrea loyezae Fauré-Fremiet, 1908, a member of the Family Spathidiidae, Order Haptorida.

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation.

Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T () Variant I79N.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and often results in cardiac remodeling and an increased incidence of sudden cardiac arrest (SCA) and death, especially in youth and young adults. Among thousands of different variants found in HCM patients, variants of (cardiac troponin T-TNNT2) are linked to increased risk of ventricular arrhythmogenesis and sudden death despite causing little to no cardiac hypertrophy. Therefore, studying the effect of variants on cardiac propensity for arrhythmogenesis can pave the way for characterizing HCM in susceptible patients before sudden cardiac arrest occurs.

Why Is Only Type 1 Electrocardiogram Diagnostic of Brugada Syndrome? Mechanistic Insights From Computer Modeling.

Background: Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered.

Methods: Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (I), sodium current, and L-type calcium current (I) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R).

Trans*Forming Access and Care in Rural Areas: A Community-Engaged Approach.

Research indicates that rural transgender and gender diverse (TGD) populations have a greater need for health services when compared with their urban counterparts, face unique barriers to accessing services, and have health disparities that are less researched than urban TGD populations. Therefore, the primary aim of this mixed-methods study ( = 24) was to increase research on the health care needs of TGD people in a rural Appalachian American context. This study was guided by a community-engaged model utilizing a community advisory board of TGD people and supportive parents of TGD children.

Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.

Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of ICa,L, compromising inotropy.

Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles.

Background: Concomitant apamin-sensitive small conductance calcium-activated potassium current (I) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong.

Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates I and causes JWS in the presence of ajmaline.

Stabilizer Cell Gene Therapy: A Less-Is-More Strategy to Prevent Cardiac Arrhythmias.

Background: In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia.

Methods: Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations.

Sex-specific I activation in rabbit ventricles with drug-induced QT prolongation.

Background: Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca-activated K current (I) activation during β-adrenergic stimulation.

Objective: The purpose of this study was to test the hypothesis that there is a sex difference in I in the rabbit models of diLQTS.

Small-conductance Ca-activated K channels promote J-wave syndrome and phase 2 reentry.

Background: Small-conductance Ca-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown.

Objective: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca channels in promoting J-wave syndrome and ventricular arrhythmias.

[Concretism as a Correlate of the Acuteness of Schizophrenic Symptomatology].

Formal thought disorders are common in people diagnosed with schizophrenia. Among them, concretism stands for deficiencies in the understanding of idiomatic expressions, metaphors and proverbs. However, little is known as to whether concretism is a correlate of the acuteness or severity of schizophrenia within patients.

A Spatiotemporal Ventricular Myocyte Model Incorporating Mitochondrial Calcium Cycling.

Intracellular calcium (Ca) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca release units that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca cycling components into our previously developed ventricular myocyte model consisting of a three-dimensional Ca release unit network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca cycling, mitochondrial permeability transition pore stochastic opening and closing, intracellular reactive oxygen species signaling, and oxidized Ca/calmodulin-dependent protein kinase II signaling were incorporated into the model.

Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease.

Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb).

Small-conductance calcium-activated potassium current modulates the ventricular escape rhythm in normal rabbit hearts.

Background: The apamin-sensitive small-conductance calcium-activated K (SK) current I modulates automaticity of the sinus node. I blockade by apamin causes sinus bradycardia.

Objective: The purpose of this study was to test the hypothesis that I modulates ventricular automaticity.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade.

Background: The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (I) blockade.

Method And Results: High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting.

The Ca transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations.

Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca transient without any constraint on the action potential.

Sex-specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles.

Key Points: It is unknown if a sex difference exists in cardiac apamin-sensitive small conductance Ca -activated K (SK) current (I ). There is no sex difference in I in the basal condition. However, there is larger I in female rabbit ventricles than in male during isoproterenol infusion.

Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits.

Background: Apamin-sensitive small conductance calcium-activated K current (I) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM).

Objective: The purpose of this study was to determine the role of I in long-term CM.

Methods: CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing.