New drugs vs. old concepts: a fresh look at antiarrhythmics |
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Authors: | Thireau Jérôme Pasquié Jean-Luc Martel Eric Le Guennec Jean-Yves Richard Sylvain |
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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 |
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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. |
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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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