Disclosures & Acknowledgments California Heart Rhythm Symposium San Francisco, CA September 8, 2012 Gilead Sciences - Research Support and Consultantship AstraZeneca - Research Support and Consultantship Cardiome - Research Support Merck - Research Support “ J Wave Syndromes. Population Council - Research Support Mechanisms” Buchang Group - Research Support Charles Antzelevitch NIH - Research Support NYSTEM - Research Support Masonic Medical Research Laboratory AHA - Research Support Utica, NY 13501 New York State &Florida Masons - Research Support Voltage Clamp Studies Voltage Clamp Studies Action Potential Studies Action Potential Studies Silvio Litovsky Silvio Litovsky Andrew Zygmunt Andrew Zygmunt Characteristics of the J Wave Anton Lukas Anton Lukas Jonathan Cordeiro Jonathan Cordeiro S. Krishnan S. Krishnan Helen Diana (Dan Hu) Helen Diana (Dan Hu) Perfused Wedge Studies Perfused Wedge Studies Hector Barajas-Martinez Hector Barajas-Martinez Janire Urrutia Janire Urrutia • Also referred to as an Osborn wave Gan-Xin Yan Gan-Xin Yan Yoshiyasu Aizawa Yoshiyasu Aizawa Serge Sicouri Serge Sicouri Stem Cell & Molecular Biology Stem Cell & Molecular Biology Wataru Shimizu Wataru Shimizu • A distinct J wave is commonly Jose Di Diego Jose Di Diego Xavier Michael Jesudoss Xavier Michael Jesudoss A. Burashnikov A. Burashnikov Bobby Cherian Kallukalam Bobby Cherian Kallukalam observed in the baseline ECG of Jeffrey Fish Jeffrey Fish Yuesheng Wu Yuesheng Wu Gi-Byoung Nam Gi-Byoung Nam Mayurika Desai Mayurika Desai some animal species, including baboons and dogs. Tetsuro Emori Tetsuro Emori Jackie Treat Jackie Treat Masahiko Kondo Masahiko Kondo Molecular Genetics Molecular Genetics • A distinct J wave is rarely observed in humans under Masato Tsuboi Masato Tsuboi Fabrice Extramiana Fabrice Extramiana Guido Pollevick Guido Pollevick Chinmay Patel Chinmay Patel normal conditions, although an elevated J point is Alejandra Guerchicoff Alejandra Guerchicoff Eyal Nof Eyal Nof Ryan Pfeiffer Ryan Pfeiffer Yoshino Minoura Yoshino Minoura commonly encountered Elena Burashnikov Elena Burashnikov István Koncz István Koncz Gabriel Caceres Gabriel Caceres In Vivo and Modeling Studies In Vivo and Modeling Studies • In humans and animals, the appearance of a prominent Colleen Puleo Colleen Puleo Vladislav V. Nesterenko Vladislav V. Nesterenko J wave in the ECG is considered pathognomonic of Collaborators Collaborators Sami Viskin, Michel Haissaguerre, Mel Scheinman, Minoru Horie , Yoshifusa Aizawa, Arthur Sami Viskin, Michel Haissaguerre, Mel Scheinman, Minoru Horie , Yoshifusa Aizawa, Arthur hypothermia, hypercalcemia, the Brugada syndrome, Wilde, Andras Varro, Michael Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Jon Wilde, Andras Varro, Michael Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Jon early repolarization pattern or other arrhythmogenic Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Giustetto, Martin Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike Giustetto, Martin Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike syndromes Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Lior Gepstein Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Lior Gepstein 1
Lead II ECG (dog) Hypothermia (24.5 C) Yan and Antzelevitch. Circulation 93:372-379, 1996 2
Restitution of J wave parallels that of action potential notch Yan and Antzelevitch. Circulation 93:372-379, 1996 Early Repolarization Patterns Cellular Basis for the J Wave Transmural distribution of the I to - mediated action potential notch is responsible for the inscription of the electrocardiographic J wave Modified from Antzelevitch et al, JACC, 2011 Yan and Antzelevitch. Circulation 93:372-379, 1996 3
Brugada Syndrome Type 1 Antzelevitch C.. J Cardiovasc Electrophys 12:268, 2001 Genetic Basis for Brugada Syndrome Ventricular Arrhythmias in Brugada Syndrome Causative Genes Locus Ion Channel Gene/Protein % of Probands V1 V4 BrS1 SCN5A, Na v 1.5 3p21 I Na 11-28% BrS2 GPD1L 3p24 I Na Rare BrS3 CACNA1C, Ca v 1.2 12p13.3 I Ca 6.6% BrS4 CACNB2b, Ca v β 2b 10p12.33 I Ca 4.8% V2 V5 BrS5 SCN1B , Na v β 1 19q13.1 I Na 1.1% BrS6 KCNE3, MiRP2 11q13-14 I to Rare BrS7 SCN3B, Na v β 3 11q23.3 I Na Rare BrS8 KCNJ8, Kir6.1 12p11.23 I K-ATP 2% V3 V6 BrS9 CACNA2D1 , Ca v α 2 δ 7q21.11 I Ca 1.8% BrS10 KCND3 , K v 4.3 1p13.2 I to Rare BrS11 MOG1 17p13.1 I Na Rare 4
Drug-induced Brugada Syndrome Genetic Basis for Brugada Syndrome I. Antiarrhythmic drugs Modulatory Genes Na + channel blockers Class IC drugs (Flecainide, Pilsicainide, Propafenone) Class IA drugs (Ajmaline, Procainamide, Disopyramide, Cibenzoline) Ca 2+ channel blockers (Verapamil) Locus Ion Channel Gene/Protein Beta Blockers (Propranolol intoxication) II. Antianginal drugs HCN4 15q24-q25 I f Ca 2+ channel blockers (Nifedipine, Diltiazem) Nitrates (Isosorbide dinitrate, Nitroglycerine) KCNH2, HERG I Kr K+ channel openers (Nicorandil) 7q35 III. Psychotropic drugs KCNE5 (KCNE1-like) Xq22.3 I to Tricyclic antidepressants (Amitriptyline, Nortriptyline, Desipramine, Clomipramine) Tetracyclic antidepressants (Maprotiline) Phenothiazine (Perphenazine, Cyamemazine) Selective serotonin reuptake inhibitors (Fluoxetine) Lithium Anticonvulsants (clonazepam) Antipsychotics (Trifluoperazine, Loxapine) IV. Other drugs Histaminic H1 receptor antagonists Dimenhydrinate Diphenhydramine Cocaine intoxication Alcohol Intoxication Modified from Antzelevitch. PACE 29:1130-1159, 2006 and Shimizu, J Electrocardiol, 2005 Brugada Syndrome Amitriptyline-induced Epi M Endo Intrinsic Heterogeneity Intrinsic Heterogeneity 0 0 0 Brugada Syndrome 50 mV Accentuate Notch & Accentuate Notch & I Na, I Ca I Na, I Ca Cause Loss of APD Cause Loss of APD I to , I Kr , I Ks, I K-ATP , I to , I Kr , I Ks, I K-ATP , Dome in Epicardium Dome in Epicardium 200 msec I Cl(Ca) I Cl(Ca) 0 3 Dispersion of Repolarization Dispersion of Repolarization 4 1 2 Transmural Dispersion Transmural Dispersion 4 of Repolarization of Repolarization Transmural Transmural Epicardial Epicardial 0 3 Phase 2 Reentry in Phase 2 Reentry in 0 RV Epicardium RV Epicardium QT interval QT interval Phase 2 reentry Phase 2 reentry 2 Phase 2 Reentry-induced Phase 2 Reentry-induced 0 50 ST Segment ST Segment VT/VF VT/VF mV 1 200 msec (Vulnerable Window) (Vulnerable Window) Epi 1 50 mV Extrasystole Extrasystole 50 Epi 2 mV 0.5 ECG VT/VF (Reentry) VT/VF (Reentry) mV Minoura et al. 500 msec J Cardiovasc Electrophysiol 23:423-32, 2012 Antzelevitch. Am J Physiol 293:H2024-38, 2007 5
Therapy - Brugada Syndrome Devices or Ablative Devices or Ablative ICD ICD � � ? Pacemaker ? Pacemaker ? Ablation or Cryosurgery ? Ablation or Cryosurgery Pharmacologic Pharmacologic Amiodarone - does not protect Amiodarone - does not protect (Brugada et al. Circulation, 1998) (Brugada et al. Circulation, 1998) Χ Χ β Blockers - β Blockers - do not protect do not protect (Brugada et al, 1998, Nademanee et al) (Brugada et al, 1998, Nademanee et al) Χ Χ β Adrenergic agonists – Isoproterenol (Miyazaki et al, 1996; Shimizu et al, ) β Adrenergic agonists – Isoproterenol (Miyazaki et al, 1996; Shimizu et al, ) � � ↑ I Ca Phosphodiesterase Inhibitors-cilostazol (Tsuchiya et al., JCE 13: 698, 2002) Phosphodiesterase Inhibitors-cilostazol (Tsuchiya et al., JCE 13: 698, 2002) � � Class IC antiarrhythmics – Flecainide, Propafenone - contraindicated Class IC antiarrhythmics – Flecainide, Propafenone - contraindicated Χ Χ Class IA antiarrhythmics Class IA antiarrhythmics Χ Χ Χ Procainamide, Disopyramide - contraindicated Χ Procainamide, Disopyramide - contraindicated � Quinidine (Yan and Antzelevitch, 1999; Alings et al, 2001; Belhassan et al, 1999) � Quinidine (Yan and Antzelevitch, 1999; Alings et al, 2001; Belhassan et al, 1999) ? Tedisamil ? Tedisamil ↓ I to ? AVE0118 ? AVE0118 Anti-androgen therapy Anti-androgen therapy � � I to Blocker - cardioselective and ion channel specific I to Blocker - cardioselective and ion channel specific � � ? ? Journal of Molecular and Cellular Cardiology 49 (2010) 543–553 Late I Na agonist – dmLSB (Danshen derivative) Late I Na agonist – dmLSB (Danshen derivative) Early Repolarization Early Pattern Predisposes to Repolarization Development of Pattern Polymorphic VT/VF via a and SCD Brugada Syndrome-like 31% of IVF Mechanism vs. 5% of Controls ER was defined as QRS-ST junction elevation of > 0.1 mV manifested as QRS slurring or Yan an Antzelevitch, Circulation, 1999 notching Gussak and Antzelevitch, J Electrocardiol, 2000 Haïssaguerre et al., N Engl J Med 358:2016-23, 2008 Antzelevitch and Yan, Heart Rhythm 7:549-58, 2010 6
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