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Atrial-selective drugs for treatment of atrial fibrillation

Vorhofselektive Antiarrhythmika für die Therapie von Vorhofflimmern

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Abstract

Atrial fibrillation (AF) is accompanied by a high risk of thromboembolic complications necessitating anticoagulation therapy. Arrhythmias have a high tendency to become persistent. Catheter ablation techniques are highly effective in the treatment of AF; however, these procedures are far too costly and time-consuming for the routine treatment of large numbers of AF patients. Moreover, many patients prefer drug treatment although conventional antiarrhythmic drugs are moderately effective and are burdened with severe cardiac and noncardiac side effects. New antifibrillatory drugs developed for the treatment of AF include multichannel blockers with a high degree of atrial selectivity. The rationale of this approach is to induce antiarrhythmic actions only in the atria without conferring proarrhythmic effects in the ventricles.

Atrial selective drug action is expected with ion channel blockers targeting ion channels that are expressed predominantly in the atria, i.e., Kv1.5 (IKur), or Kir 3.1 and Kir 3.4 (IK,ACh). Na+ channel blockers that dissociate rapidly may exert atrial selectivity because of subtle differences in atrial and ventricular action potentials. Finally, atrial-selective targets may evolve due to disease-specific processes (e.g., rate-dependent Na+ channel blockers, selective drugs against constitutively active IK,ACh channels).

Zusammenfassung

Vorhofflimmern geht mit einem hohen Risiko für thromboembolische Komplikationen einher, so dass eine Antikoagulationstherapie erforderlich ist. Charakteristisch für diese Arrhythmie ist die große Neigung zur Chronifizierung. Eine hoch effektive Therapieform ist die Katheterablation, allerdings sind die heute üblichen Verfahren viel zu teuer und zeitaufwendig, um damit die große Zahl der Vorhofflimmerpatienten routinemäßig zu versorgen. Trotz der geringeren Wirksamkeit und der hohen Inzidenz von kardialen und extrakardialen Nebenwirkungen konventioneller Antiarrhythmika wünschen viele Patienten zunächst einen medikamentösen Therapieversuch. Neue antifibrillatorische Substanzen mit der Indikation Vorhofflimmern umfassen Multikanalblocker mit einem hohen Ausmaß an Vorhofselektivität. Dieser Therapieansatz beruht auf der Vorstellung, dass beim Vorhofflimmern lediglich die Vorhöfe auf ein Antiarrhythmikum ansprechen sollen. Die Ventrikel benötigen keinen antiarhythmischen Effekt und sollen möglichst überhaupt nicht beeinflusst werden, um das Risiko pro-arrhythmischer Effekte zu vermeiden.

Eine vorhofselektive Wirkung kann von Ionenkanalblockern, die gegen nur im Vorhof exprimierte Kanäle gerichtet sind, erwartet werden, wie z. B. Kv1.5 (IKur), oder Kir 3.1 und Kir 3.4 (IK,ACh). Rasch dissoziierende Na+-Kanalblocker können wegen der elektrophysiologischen Unterschiede zwischen Ventrikel- und Vorhofgewebe ebenfalls eine vorhofselektive Wirkung haben. Und schließlich kann eine vorhofselektive Wirkung aufgrund krankheitsspezifischer Prozesse erzielt werden, z. B. mit frequenzabhängigen Na+-Kanalblockern oder – zumindest theoretisch denkbar – mit selektiven Blockern des konstitutiv aktiven IK,ACh.

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Acknowledgments

The authors receive financial support from Fondation Leducq (07 CVD 03, “Leducq European–North American Atrial Fibrillation Research Alliance”), the German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network, member of the steering committee; New Antiarrhythmic Drugs, Research project 03FPB00226), and the EU FP7-Health-2010-single-stage “EUTRAF”.

Conflict of interest

UR has received grants and honoraria for consulting and lecturing for Cardiome, Merck, Sharp, and Dohme.

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  1. Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstr. 74, 01307, Dresden, Deutschland

    U. Ravens & T. Christ

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Correspondence to U. Ravens.

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Ravens, U., Christ, T. Atrial-selective drugs for treatment of atrial fibrillation. Herzschr. Elektrophys. 21, 217–221 (2010). https://doi.org/10.1007/s00399-010-0088-8

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