title: New drugs vs. old concepts: a fresh look at antiarrhythmics.
abstract: Common arrhythmias, particularly atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are a major public health concern. Classic antiarrhythmic (AA) drugs for AF are of limited effectiveness, and pose the risk of life-threatening VT/VF. For VT/VF, implantable cardiac defibrillators appear to be the unique, yet unsatisfactory, solution. Very few AA drugs have been successful in the last few decades, due to safety concerns or limited benefits in comparison to existing therapy. The Vaughan-Williams classification (one drug for one molecular target) appears too restrictive in light of current knowledge of molecular and cellular mechanisms. New AA drugs such as atrial-specific and/or multichannel blockers, upstream therapy and anti-remodeling drugs, are emerging. We focus on the cellular mechanisms related to abnormal Na⁺ and Ca²⁺ handling in AF, heart failure, and inherited arrhythmias, and on novel strategies aimed at normalizing ionic homeostasis. Drugs that prevent excessive Na⁺ entry (ranolazine) and aberrant diastolic Ca²⁺ release via the ryanodine receptor RyR2 (rycals, dantrolene, and flecainide) exhibit very interesting antiarrhythmic properties. These drugs act by normalizing, rather than blocking, channel activity. Ranolazine preferentially blocks abnormal persistent (vs. normal peak) Na⁺ currents, with minimal effects on normal channel function (cell excitability, and conduction). A similar "normalization" concept also applies to RyR2 stabilizers, which only prevent aberrant opening and diastolic Ca²⁺ leakage in diseased tissues, with no effect on normal function during systole. The different mechanisms of action of AA drugs may increase the therapeutic options available for the safe treatment of arrhythmias in a wide variety of pathophysiological situations.
authors.affiliation: Inserm U1046 Physiologie & Médecine Expérimentale du Cœur et des Muscles, Université Montpellier-1, Université Montpellier-2, 34295 Montpellier Cedex 5, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pasquié
authors.forename: Eric
authors.initials: E
authors.lastname: Martel
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D007473:Ion Channels