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New drugs vs. old concepts: a fresh look at antiarrhythmics
Authors:Thireau Jérôme  Pasquié Jean-Luc  Martel Eric  Le Guennec Jean-Yves  Richard Sylvain
Affiliation:aInserm U1046 Physiologie & Médecine Expérimentale du Cœur et des Muscles, Université Montpellier-1, Université Montpellier-2, 371 avenue du doyen Gaston Giraud, 34295 Montpellier Cedex 5, France;bCentre de Recherches Biologiques (CERB), chemin de Montifault, 18800 Baugy, France
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.
Keywords:Abbreviations: AA, antiarrhythmic   ACE, angiotensin-converting enzyme   AF, atrial fibrillation   ANS, autonomic nervous system   AP, action potential   AT-1, angiotensin-1   CAMKII, Ca2+/calmodulin kinase type II   CatB, cysteine cathepsin B   CatL, cysteine cathepsin L   CatS, cysteine cathepsin S   CAVB, chronic atrio-ventricular block   CPVT, catecholaminergic polymorphic ventricular tachycardia   DAD, delayed afterdepolarization   DHA, docosahexaenoic acid   EAD, early afterdepolarization   ECG, electrocardiogram   EPA, eicosapentaenoic acid   hERG, human ether-a-go-go-related gene   ICD, implantable cardioverter defibrillator   HF, heart failure   HRV, heart rate variability   ICaL, L-type calcium current   If, funny current (hyperpolarization-activated current)   IKAch, potassium current activated by acetylcholine   IKR, rapid component of potassium current   IKS, slow component of potassium current   IKUR, ultra-rapid potassium current   INa, sodium current   INaP, persistent sodium current   ITO, transient outward current   LQT, long QT syndrome   LV, left ventricle   MAPK, mitogen-activated protein kinase   MI, myocardial infarction   MMP, matrix metalloproteinase   mPTP, mitochondrial permeability transition pore   n-3 LC-PUFA, n-3 long-chain polyunsaturated fatty acid   NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase   NCX, sodium&ndash  calcium exchanger   NOS, nitric oxide synthase   PF, Purkinje fiber   PKA, protein kinase A   PKC, protein kinase C   PLN, phospholamban   QTc, Q-T interval corrected for heart rate   ROS, reactive oxygen species   RP, refractory period   RyR1, ryanodine receptor type 1   RyR2, ryanodine receptor type 2   SCD, sudden cardiac death   SERCA2, sarco/endoplasmic reticulum Ca2+ ATPase type 2   SR, sarcoplasmic reticulum   TdP, Torsades de pointes   TGF, transforming growth factor   TNF, tumor necrosis factor   TRPM4, transient receptor potential type M4   TTX, tetrodotoxin   VA, ventricular arrhythmia   VF, ventricular fibrillation   VT, ventricular tachycardia   VW, Vaughan Williams
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