Constitutive deletion of the obscurin-Ig58/59 domains induces atrial remodeling and Ca2+-based arrhythmogenesis.

Obscurin is a giant protein that coordinates diverse aspects of striated muscle physiology. Obscurin immunoglobulin domains 58/59 (Ig58/59) associate with essential sarcomeric and Ca2+ cycling proteins. To explore the pathophysiological significance of Ig58/59, we generated the Obscn-ΔIg58/59 mouse model, expressing obscurin constitutively lacking Ig58/59.

Ryanodine receptor stabilization therapy suppresses Ca- based arrhythmias in a novel model of metabolic HFpEF.

Heart Failure with preserved ejection fraction (HFpEF) has a high rate of sudden cardiac death (SCD) and empirical treatment is ineffective. We developed a novel preclinical model of metabolic HFpEF that presents with stress-induced ventricular tachycardia (VT). Mechanistically, we discovered arrhythmogenic changes in intracellular Ca handling distinct from the changes pathognomonic for heart failure with reduced ejection fraction.

Ryanodine Receptor Stabilization Therapy Suppresses Ca -Based Arrhythmias in a Novel Model of Metabolic HFpEF.

Heart Failure with preserved ejection fraction (HFpEF) is the most prevalent form of heart failure worldwide and its significant mortality is associated with a high rate of sudden cardiac death (SCD; 30% - 40%). Chronic metabolic stress is an important driver of HFpEF, and clinical data show metabolic stress as a significant risk factor for ventricular arrhythmias in HFpEF patients. The mechanisms of SCD and ventricular arrhythmia in HFpEF remain critically understudied and empirical treatment is ineffective.

Na /K ATPase-Ca 1.2 nanodomain differentially regulates intracellular [Na ], [Ca ] and local adrenergic signaling in cardiac myocytes.

Background: The intracellular Na concentration ([Na ] ) is a crucial but understudied regulator of cardiac myocyte function. The Na /K ATPase (NKA) controls the steady-state [Na ] and thereby determines the set-point for intracellular Ca . Here, we investigate the nanoscopic organization and local adrenergic regulation of the NKA macromolecular complex and how it differentially regulates the intracellular Na and Ca homeostases in atrial and ventricular myocytes.

Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.

Mitochondrial ATP production in ventricular cardiomyocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca ([Ca]) and blood flow that is tuned by local cardiomyocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed.

Camera-based Measurements of Intracellular [Na+] in Murine Atrial Myocytes.

Intracellular sodium concentration ([Na]i) is an important regulator of intracellular Ca. Its study provides insight into the activation of the sarcolemmal Na/Ca exchanger, the behavior of voltage-gated Na channels and the Na,K-ATPase. Intracellular Ca signaling is altered in atrial diseases such as atrial fibrillation.

Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown.

Calcium Signaling Silencing in Atrial Fibrillation: Implications for Atrial Sodium Homeostasis.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF's incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets.

Calcium influx through the mitochondrial calcium uniporter holocomplex, MCU.

Ca flux into the mitochondrial matrix through the MCU holocomplex (MCU) has recently been measured quantitatively and with milliseconds resolution for the first time under physiological conditions in both heart and skeletal muscle. Additionally, the dynamic levels of Ca in the mitochondrial matrix ([Ca]) of cardiomyocytes were measured as it was controlled by the balance between influx of Ca into the mitochondrial matrix through MCU and efflux through the mitochondrial Na / Ca exchanger (NCLX). Under these conditions [Ca] was shown to regulate ATP production by the mitochondria at only a few critical sites.

The surprising complexity of KATP channel biology and of genetic diseases.

The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.

Dynamics of the mitochondrial permeability transition pore: Transient and permanent opening events.

A gentle optical examination of the mitochondrial permeability transition pore (mPTP) opening events was carried out in isolated quiescent ventricular myocytes by tracking the inner membrane potential (ΔΨ) using TMRM (tetramethylrhodamine methyl ester). Zeiss Airyscan 880 ″super-resolution" or "high-resolution" imaging was done with very low levels of illumination (0.009% laser power).

Calcium signalling silencing in atrial fibrillation.

Subcellular calcium signalling silencing is a novel and distinct cellular and molecular adaptive response to rapid cardiac activation. Calcium signalling silencing develops during short-term sustained rapid atrial activation as seen clinically during paroxysmal atrial fibrillation (AF). It is the first 'anti-arrhythmic' adaptive response in the setting of AF and appears to counteract the maladaptive changes that lead to intracellular Ca signalling instability and Ca -based arrhythmogenicity.

Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes.

Atrial fibrillation (AF) is characterized by sustained high atrial activation rates and arrhythmogenic cellular Ca2+ signaling instability; however, it is not clear how a high atrial rate and Ca2+ instability may be related. Here, we characterized subcellular Ca2+ signaling after 5 days of high atrial rates in a rabbit model. While some changes were similar to those in persistent AF, we identified a distinct pattern of stabilized subcellular Ca2+ signaling.

Dynamic remodeling of intracellular Ca²⁺ signaling during atrial fibrillation.

During atrial fibrillation (AF) intracellular Ca(2+) signaling in atrial myocytes changes substantially. This 'remodeled' intracellular Ca(2+) homeostasis plays an important role in the development of the contractile dysfunction and the changes in atrial electrophysiology (contractile and electrical remodeling) that are characteristic of AF. Recent studies also show that unstable intracellular Ca(2+) signaling (i.

Alterations of atrial Ca(2+) handling as cause and consequence of atrial fibrillation.

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia. As the most important risk factor for embolic stroke, AF is associated with a high morbidity and mortality. Despite decades of research, successful (pharmacological and interventional) 'ablation' of the arrhythmia remains challenging.

Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation.

Atrial dilatation is an independent risk factor for thromboembolism in patients with and without atrial fibrillation (AF). In many patients, atrial dilatation goes along with depressed contractile function of the dilated atria. While some mechanisms causing atrial contractile dysfunction in fibrillating atria have been addressed previously, the cellular and molecular mechanisms of atrial contractile remodeling in dilated atria are unknown.

Pharmacological evidence for altered src kinase regulation of I (Ca,L) in patients with chronic atrial fibrillation.

A reduction in L-type Ca(2+) current (I (Ca,L)) contributes to electrical remodeling in chronic atrial fibrillation (AF). Whether the decrease in I (Ca,L) is solely due to a reduction in channel proteins remains controversial. Protein tyrosine kinases (PTK) have been described as potent modulators of I (Ca,L) in cardiomyocytes.

Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange.

Background: AVE0118 (2'-{[2-(4-Methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide) blocks atrial ultrarapid delayed rectifier currents (I(Kur)) and prolongs the atrial action potential (AP) plateau without affecting ventricular repolarisation. In patients with atrial contractile dysfunction due to atrial tachyarrhythmias, this response might increase atrial contractility without risk of ventricular proarrhythmia. This study was designed to evaluate the inotropic mechanisms of AVE0118.

AVE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat.

Background: The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF.

The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation.

Objective: Electrical remodeling as well as atrial contractile dysfunction after the conversion of atrial fibrillation (AF) to sinus rhythm (SR) are mainly caused by a reduction of the inward L-type Ca(2+) current (I(CaL)). We investigated whether the expression of L-type Ca2+-channel subunits was reduced in atrial myocardium of AF patients.

Methods: Right atrial appendages were obtained from patients undergoing coronary artery bypass graft surgery (CAD, n = 35) or mitral valve surgery (MVD, n = 37).

Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort.

Objective: Although AF-induced atrial contractile dysfunction has significant clinical implications the underlying intracellular mechanisms are poorly understood.

Methods: From the right atrial appendages of 59 consecutive patients undergoing mitral valve surgery (31 in SR, 28 in chronic AF) thin muscle preparations (diameter<0.7 mm) were isolated.