Investigational antiarrhythmic agents: promising drugs in early clinical development.

Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias.

Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation.

Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies.

Calcium Signaling and Cardiac Arrhythmias.

There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease.

The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models.

Background And Purpose: The density of the inward rectifier current (I ) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re-entry. The synthetic compound pentamidine analogue 6 (PA-6) is a selective and potent I inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, using established models in large animals.

Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity.

Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias.

Calcium-mediated cellular triggered activity in atrial fibrillation.

Although atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia, the basic mechanisms underlying this disorder remain incompletely understood. During the past decade or so, it has become clear that alterations in intracellular Ca handling may play a role in the pathogenesis of AF. Studies in small and large animal models, as well as atrial samples from patients with different forms of AF, have implicated ryanodine receptor type 2 (RyR2) dysfunction and enhanced spontaneous Ca release events from the sarcoplasmic reticulum (SR) as a potential cause of proarrhythmic cellular ectopic (triggered) activity in AF.

JAK-STAT signalling and the atrial fibrillation promoting fibrotic substrate.

Aims: Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis.

Serine/Threonine Phosphatases in Atrial Fibrillation.

Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins.

Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy.

Aims: Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K2P3.

Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure.

Background: Chronic heart failure (HF) is associated with altered signal transduction via β-adrenoceptors and G proteins and with reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of patients with end-stage HF, but the functional consequences of this are largely unknown, particularly for NDPK-C. Here, we investigated the potential role of NDPK-C in cardiac cAMP formation and contractility.

Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome.

Reversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more nonspecific in their function.

Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation.

Atrial fibrillation (AF) is an extremely prevalent arrhythmia that presents a wide range of therapeutic challenges. AF usually begins in a self-terminating paroxysmal form (pAF). With time, the AF pattern often evolves to become persistent (nonterminating within 7 days).

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis.

A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca(2+) handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabolic and electrophysiological features, but whether interventricular differences promote differential remodeling leading to arrhythmias is not well understood.

Atrial-Selective Potassium Channel Blockers.

Atrial fibrillation (AF) is associated with increased morbidity and mortality. Atrial-selective potassium (K(+)) channel blockers may represent a novel therapeutic target. The best validated atrial-specific ion currents are the acetylcholine-activated inward-rectifier K(+) current IK,ACh and ultrarapidly activating delayed-rectifier K(+) current IKur.