Untersuchungen zu den elektrophysiologischen Mechanismen verschiedener neuer antiarrhythmischer Substanzen an einem experimentellen Vorhofmodell

Vorhofflimmern (VHF) ist die häufigste Herzrhythmusstörung weltweit. Durch die medikamentöse Verlängerung der Aktionspotentialdauer und Refraktärzeit sowie der Leitungszeit, welche durch die Blockade von Natrium- und Kaliumkanälen des Vorhofmyokards verursacht wird, kann effektiv auf das Auftreten von Vorhofflimmerepisoden Einfluss genommen werden. Auch das Erzeugen einer Postrepolarisations-Refraktärität scheint einen wichtigen Einfluss auf die Unterdrückung von VHF zu haben. Bei der vorliegenden Studie wurden Messungen der oben genannten elektrophysiologischen Eigenschaften an gesunden isolierten Kaninchenherzen am Langendorff-Apparat durchgeführt. Dabei wurden Flecainid, Sotalol und Amiodaron als Kontrollmedikamente verwendet. Die Medikamente Ranolazin, Dronedaron, Simvastatin, DHA und SEA0400 wurden experimentell untersucht. Die effektivsten Medikamente dieser Studie sind Flecainid, Ranolazin und Amiodaron, welche eine erhebliche Verlängerung dieser Eigenschaften verursacht haben

Investigational antiarrhythmic agents:promising drugs in early clinical development

Introduction: 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. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy.Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K+-channels, the late Na+-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca2+-activated K+-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development.Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy

Calcium Handling Abnormalities as a Target for Atrial Fibrillation Therapeutics: How Close to Clinical Implementation?

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a substantial impact on morbidity and mortality. Antiarrhythmic drugs play a major role in rhythm-control therapy of AF. However, currently available agents exhibit limited efficacy and pronounced adverse effects, notably drug-induced proarrhythmia. Recent experimental studies have identified that Ca handling abnormalities are critical elements in AF pathophysiology with central roles in atrial ectopic activity, reentry, and atrial remodeling suggesting that Ca handling abnormalities could be promising targets for novel AF therapeutics. Here, we summarize key aspects of AF-related Ca-handling abnormalities, describe currently available compounds targeting atrial Ca handling, and highlight potential novel targets and experimental drugs currently under investigation. Finally, we assess how close AF therapeutics based on Ca-handling abnormalities are to clinical implementation

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. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions