Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP binding.

The inwardly rectifying potassium current of the cardiomyocyte (I) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.

Augmentation of myocardial I dysregulates calcium homeostasis and causes adverse cardiac remodeling.

HCN channels underlie the depolarizing funny current (I) that contributes importantly to cardiac pacemaking. I is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4) to assess functional consequences of HCN4 overexpression-mediated I increase in cardiomyocytes to levels observed in human heart failure.

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes.

Background/aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity.

Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells.

Background: Human induced pluripotent stem cells (hiPSC) harbor the potential to differentiate into diverse cardiac cell types. Previous experimental efforts were primarily directed at the generation of hiPSC-derived cells with ventricular cardiomyocyte characteristics. Aiming at a straightforward approach for pacemaker cell modeling and replacement, we sought to selectively differentiate cells with nodal-type properties.

TranslatiOnal Registry for CardiomyopatHies (TORCH) - rationale and first results.

Aims: Non-ischemic cardiomyopathies (CMPs) comprise heart muscle disorders of different causes with high variability in disease phenotypes and clinical progression. The lack of national structures for the efficient recruitment, clinical and molecular classification, and follow-up of patients with non-ischemic CMPs limit the thorough analysis of disease mechanisms and the evaluation of novel diagnostic and therapeutic strategies. This paper describes a national, prospective, multicenter registry for patients with non-ischemic CMPs.

Data privacy management and data quality monitoring in the German Centre for Cardiovascular Research's multicentre TranslatiOnal Registry for CardiomyopatHies (DZHK-TORCH).

Aims: The multicentric TranslatiOnal Registry for CardiomyopatHies (TORCH) of the German Centre for Cardiovascular Research aims to recruit 2300 patients with non-ischemic cardiomyopthies.

Methods And Results: The investigations were performed after standard operating procedures. The data are collected in standardized electronic case report forms provided by the data holding of the central data management of the German Centre for Cardiovascular Research using secuTrial (interActive Systems GmbH, Berlin, Germany).

Inhibition of inwardly rectifying Kir2.x channels by the novel anti-cancer agent gambogic acid depends on both pore block and PIP interference.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels.

Role of plasma membrane-associated AKAPs for the regulation of cardiac I current by protein kinase A.

The cardiac I current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of I current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet.

Dual Mechanism for Inhibition of Inwardly Rectifying Kir2.x Channels by Quinidine Involving Direct Pore Block and PIP-interference.

Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.

TREK-1 (K2.1) K channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2.

Efficacy, High Procedural Safety And Rapid Optimization Of Cryoballoon Atrial Fibrillation Ablation In The Hands Of A New Operator.

Background: Cryoballoon (CB) ablation is successful in eliminating atrial fibrillation (AF).

Purpose: The purpose of this study was to assess procedural efficacy and safety of CB ablation performed by a newly trained operator.

Methods: Forty patients with documented paroxysmal AF (58 ± 11 years, 26 male) undergoing CB catheter ablation were prospectively enrolled.

miR-19b Regulates Ventricular Action Potential Duration in Zebrafish.

Sudden cardiac death due to ventricular arrhythmias often caused by action potential duration (APD) prolongation is a common mode of death in heart failure (HF). microRNAs, noncoding RNAs that fine tune gene expression, are frequently dysregulated during HF, suggesting a potential involvement in the electrical remodeling process accompanying HF progression. Here, we identified miR-19b as an important regulator of heart function.

Inhibition of Cardiac Kir Current (IK1) by Protein Kinase C Critically Depends on PKCβ and Kir2.2.

Background: Cardiac inwardly rectifying Kir current (IK1) mediates terminal repolarisation and is critical for the stabilization of the diastolic membrane potential. Its predominant molecular basis in mammalian ventricle is heterotetrameric assembly of Kir2.1 and Kir2.

Therapeutic targeting of two-pore-domain potassium (K(2P)) channels in the cardiovascular system.

The improvement of treatment strategies in cardiovascular medicine is an ongoing process that requires constant optimization. The ability of a therapeutic intervention to prevent cardiovascular pathology largely depends on its capacity to suppress the underlying mechanisms. Attenuation or reversal of disease-specific pathways has emerged as a promising paradigm, providing a mechanistic rationale for patient-tailored therapy.

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action.

Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-à-go-go-related gene (hERG) channels have not been analyzed.

Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action.

Midazolam is a short-acting benzodiazepine that is widely used in anesthesia. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking. Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1.

Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224.

Dronedarone is a novel class III antiarrhythmic drug that is widely used in atrial fibrillation. It has been shown in native cardiomyocytes that dronedarone inhibits cardiac inwardly rectifying current IK1 at high concentrations, which may contribute both its antifibrillatory efficacy and its potential proarrhythmic side effects. However, the underlying mechanism has not been studied in further detail to date.

The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.

Background: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM).

Objectives: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis.

Vernakalant activates human cardiac K(2P)17.1 background K(+) channels.

Atrial fibrillation (AF) contributes significantly to cardiovascular morbidity and mortality. The growing epidemic is associated with cardiac repolarization abnormalities and requires the development of more effective antiarrhythmic strategies. Two-pore-domain K(+) channels stabilize the resting membrane potential and repolarize action potentials.

Isoenzyme-specific regulation of cardiac Kv1.5/Kvβ1.2 ion channel complex by protein kinase C: central role of PKCβII.

The ultrarapidly activating delayed rectifier current, I(Kur), is a main determinant of atrial repolarization in humans. I(Kur) and the underlying ion channel complex Kv1.5/Kvβ1.

Inhibition of cardiac two-pore-domain K+ (K2P) channels by the antiarrhythmic drug vernakalant--comparison with flecainide.

The mixed ion channel blocker, vernakalant (RSD1235), is effective in rapid conversion of atrial fibrillation (AF) to sinus rhythm (SR). Suppression of cardiac two-pore-domain potassium (K2P) channels causes action potential prolongation and has recently been proposed as a novel antiarrhythmic strategy. The objective of this study was to investigate acute effects of vernakalant on human K2P2.

Provocation of an autoimmune response to cardiac voltage-gated sodium channel NaV1.5 induces cardiac conduction defects in rats.

Objectives: This study sought to test the hypothesis that inducing an autoimmune response against the cardiac sodium channel (NaV1.5) induces arrhythmias.

Background: Sporadic evidence supports the concept that autoantibodies may cause cardiac arrhythmias but substantial experimental investigations using in vivo models have been lacking to date.

Anti-KCNQ1 K⁺ channel autoantibodies increase IKs current and are associated with QT interval shortening in dilated cardiomyopathy.

Aims: Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel.

Inhibition of cardiac Kir2.1-2.3 channels by beta3 adrenoreceptor antagonist SR 59230A.

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists.

Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapy-dependent modulation of atrial electrophysiology may provide a more specific alternative to pharmacological and ablative treatment strategies.

Objective: We hypothesized that genetic inactivation of atrial repolarizing ether-a-go-go-related gene (ERG) K(+) currents using a dominant-negative mutant would provide rhythm control in AF.