Common Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

Background: Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton.

Methods: Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of . After knockdown or overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy.

Beneficial Effect of Calcium Treatment for Hyperkalemia Is Not Due to "Membrane Stabilization".

Objectives: Hyperkalemia is a common life-threatening condition causing severe electrophysiologic derangements and arrhythmias. The beneficial effects of calcium (Ca 2+ ) treatment for hyperkalemia have been attributed to "membrane stabilization," by restoration of resting membrane potential (RMP). However, the underlying mechanisms remain poorly understood.

Beneficial Effect of Calcium Treatment for Hyperkalemia Is Not Due to "Membrane Stabilization".

Objectives: Hyperkalemia is a common life-threatening condition causing severe electrophysiologic derangements and arrhythmias. The beneficial effects of calcium (Ca 2+ ) treatment for hyperkalemia have been attributed to "membrane stabilization," by restoration of resting membrane potential (RMP). However, the underlying mechanisms remain poorly understood.

Post-ROSC Atrial fibrillation is not associated with rearrest but is associated with stroke and mortality following out of hospital cardiac arrest.

Background: Atrial fibrillation (AF) in patients resuscitated from cardiac arrest (CA) is associated with increased short-term mortality. However, whether this is because AF adversely affects early resuscitation success, causes post-resuscitation morbidity, or because it is a marker for patient co-morbidities, remains unclear. We aimed to determine the prevalence of AF in patients with ROSC to test the hypothesis that AF is associated with increased risk of rearrest and to determine its impact on mortality and stroke risk.

Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.

Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca release from the sarcoplasmic reticulum through the ryanodine receptor/Ca-release channel RyR1. The RyR1 contains ∼100 Cys thiols of which ∼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood.

Spontaneous Repolarization Alternans Causes VT/VF Rearrest That Is Suppressed by Preserving Gap Junctions.

Background: Ventricular tachycardia (VT)/ventricular fibrillation (VF) rearrest after successful resuscitation is common, and survival is poor. A mechanism of VT/VF, as demonstrated in ex vivo studies, is when repolarization alternans becomes spatially discordant (DIS ALT), which can be enhanced by impaired gap junctions (GJs). However, in vivo spontaneous DIS ALT-induced VT/VF has never been demonstrated, and the effects of GJ on DIS ALT and VT/VF rearrest are unknown.

MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis.

Background: MicroRNA-1 (miR1), encoded by the genes and , is the most abundant microRNA in the heart and plays a critical role in heart development and physiology. Dysregulation of miR1 has been associated with various heart diseases, where a significant reduction (>75%) in miR1 expression has been observed in patient hearts with atrial fibrillation or acute myocardial infarction. However, it remains uncertain whether miR1-deficiency acts as a primary etiological factor of cardiac remodeling.

Automated analysis framework for cardiac ablation therapy monitoring with optical coherence tomography.

Radiofrequency ablation (RFA) is a minimally invasive procedure that is commonly used for the treatment of atrial fibrillation. However, it is associated with a significant risk of arrhythmia recurrence and complications owing to the lack of direct visualization of cardiac substrates and real-time feedback on ablation lesion transmurality. Within this manuscript, we present an automated deep learning framework for intracardiac optical coherence tomography (OCT) analysis of swine left atria.

Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin-dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC.

Elucidating arrhythmogenic right ventricular cardiomyopathy with stem cells.

Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that is associated with fatal arrhythmias often occurring in healthy young adults. Fibro-fatty infiltrate, a clinical hallmark, progresses with the disease and can develop across both ventricles.

Polarization-sensitive optical coherence tomography monitoring of percutaneous radiofrequency ablation in left atrium of living swine.

Radiofrequency ablation (RFA) is commonly used to treat atrial fibrillation (AF). However, the outcome is often compromised due to the lack of direct real-time feedback to assess lesion transmurality. In this work, we evaluated the ability of polarization-sensitive optical coherence tomography (PSOCT) to measure cardiac wall thickness and assess RF lesion transmurality during left atrium (LA) RFA procedures.

Ventricular arrhythmias in mouse models of diabetic kidney disease.

Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates.

Effect of Amiodarone and Hypothermia on Arrhythmia Substrates During Resuscitation.

Background Amiodarone is administered during resuscitation, but its antiarrhythmic effects during targeted temperature management are unknown. The purpose of this study was to determine the effect of both therapeutic hypothermia and amiodarone on arrhythmia substrates during resuscitation from cardiac arrest. Methods and Results We utilized 2 complementary models: (1) In vitro no-flow global ischemia canine left ventricular transmural wedge preparation.

MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel.

Background: MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis of the heart through noncanonical mechanisms.

Methods: We focused on the predominant miR of the heart (miR1) and investigated whether miR1 could physically bind with ion channels in cardiomyocytes by electrophoretic mobility shift assay, in situ proximity ligation assay, RNA pull down, and RNA immunoprecipitation assays.

Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

Background: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates.

Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine.

Background: Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca) cycling abnormalities. Late sodium current (I) is enhanced in HF and promotes Ca overload; however, mechanisms underlying an antiarrhythmic effect of I blockade in HF remain unclear.

Objective: The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca cycling.

Mutant voltage-gated Na channels can exert a dominant negative effect through coupled gating.

Mutations in voltage-gated Na channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na channel (Na)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel.

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming.

Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest.

Background: We designed an innovative porcine model of ischemia-induced arrest to determine dynamic arrhythmia substrates during focal infarct, global ischemia from ventricular tachycardia or fibrillation (VT/VF) and then reperfusion to determine the effect of therapeutic hypothermia (TH) on dynamic arrhythmia substrates and resuscitation outcomes.

Methods And Results: Anesthetized adult pigs underwent thoracotomy and regional plunge electrode placement in the left ventricle. Subjects were then maintained at either control (CT; 37°C, n=9) or TH (33°C, n=8).