Preface [Hot topic: Anti-arrhythmic Drugs (Guest Editors: Uwe Gerlach & Heinrich C. Englert)]

Arrhythmias are considered to be an important risk factor, which significantly contributes to mortality and morbidity of cardiovascular patients. However, presently available antiarrhythmic drugs are not generally accepted as a means for risk reduction, mainly due to proarrhythmic side effects intrinsically associated with their mode of action. This was the disappointing result of several clinical studies carried out more than 10 years ago using class I and class III antiarrhythmics. Consequently, antiarrhythmic therapy mainly focussed on electrical device such as the implantable cardioverter defribrillator, where it was believed that no proarrhythmic potential was given. Thus, there was some time left for medicinal chemists to think about failure and possible improvement of existing antiarrhythmics. In addition, they had the opportunity to explore interesting novel antiarrhythmic targets amply provided by new techniques in electrophysiology and molecular biology during the last decade. Of course, the questions “do we really need new antiarrhythmics” and “can they really compete with electrical device” will continuously accompany these efforts. Looking at cost benefit ratios, we think that an effective and safe antiarrhythmic agent has a good chance to compete. In the present issue of Current Medicinal Chemistry - Cardiovascular & Hematological Agents K. Lee starts with a review on existing IKr channel (HERG) blockers, the main representatives of class III agents. In particular, he highlights the efforts to improve the reverse frequency dependence profile of the IKr blockers by optimizing the onset and recovery time constant of the IKr or the balance between the block of IKr and Ca++ channels in the heart to eliminate the proarrhythmic risk. In this context the HERG channel is one of the best-explored ion channel target regarding our structural knowledge of ligand binding. On the other hand for safety reasons it is a prerequisite from the drug administration authorities, that non-cardiovascular drugs are free of a cardiac side effect such as HERG blockade, not taylored for arrhythmias. A. Zolotoy et al. use the knowledge obtained by the intense exploration of HERG blockers to create a model, based on physicochemical determinants, how to avoid this unwanted and dangerous sideeffect. Class III properties, however, are not restricted to IKr blockade alone. A fascinating discovery made by means of detailed patch clamp technique showed that besides IKr another potassium channel, IKs, contributes to repolarization of the cardiac action potential. Could blockers of this channel differ from existing IKr blockers regarding their antiarrhythmic and safety profile? In his contribution, U. Gerlach highlights the efforts and available blockers in this field. A potassium channel that is silent under normal conditions but opens and subsequently shortens the cardiac action potential in myocardial ischemia is the cardiac ATP sensitive potassium channel SUR2A / Kir6.2. Blockers of this channel have no proarrhythmic side effects under normal conditions but are highly effective against ischemically induced arrhythmias. H. Englert et al. review the target, existing blockers and recent efforts to design selective compounds aiming at the prevention of sudden cardiac death. Another, therapeutically attractive target is represented by the voltage-gated potassium channel Kv1.5, which differs from other cardiac potassium channels since it is functional only in the atria. J. Brendel and colleagues focus on this new concept and review blockers of Kv1.5 as a promising new strategy to treat and prevent atrial arrhythmias without the risk of inducing potentially lethal proarrhythmic side effects in the ventricles. We would like to thank all authors for their excellent and timely reviews.