Rational Approach to Improving Cardiac Arrhythmia Therapy Rational Approach to Improving Cardiac Arrhythmia Therapy Stanley Nattel, MD Stanley Nattel, MD DEDICATED TO THE MASTER OF RATIONAL THERAPEUTICS SN.23 SENAC: Cinchona bark for palpitations (1749) FREY: On atrial fibrillation in humans and Its Elimination by Quinidine (1918) Ventricular fibrillation as an electrical accident Lidocaine to treat ventricular ectopy post-mi A B PVC's PRE-LIDOCAINE C 2 sec. POST-LIDOCAINE VT LIDOCAINE IV WIGGERS CJ, Am Heart J 2:399-412, 194 GIANELLY R et al, NEJM 277:1215-1219, 1967
Total suppression of ventricular arrhythmias by encainide Oral flecainide acetate for the treatment of ventricular arrhythmias RODEN DM et al, NEJM 32 :877-882, 198 ANDERSON JL et al, NEJM 35 :473-477, 1981 Odds ratio for total mortality 1-48 hr post-mi Effects of class 1C antiarrhythmias on post-mi mortality CAST MACMAHON S et al, JAMA 26:191-1916, 1988 NEJM 321:46-412, 1989 Effects of class 1C antiarrhythmias on post-mi mortality Effects of class 1C antiarrhythmias on post-mi mortality CAST CAST II CAST CAST II NEJM 321:46-412, 1989 CAST II Investigators, NEJM 327 :227-233, 1992 NEJM 321:46-412, 1989 CAST II Investigators, NEJM 327 :227-233, 1992
Meta-analysis of quinidine effects on mortality in AF patients OK, Class I drugs are bad. Class III is the future. From first class to third class: recent upheaval in antiarrhythmic therapy lessons from clinical trials. Lazzara R. COPLEN et al, Circulation 82 :116-1116, 199 LAZZARA R, AJC 78(4A):28-33, 1996 Effects of a pure class III drug on post-mi mortality Something doesn t fit! WALDO AL et al, Lancet 348:7-12, 1996 Something doesn t fit! Focus on a specific arrhythmia Look for the finding that doesn t fit. THAT is the clue to great discoveries!! Prevalence % 18 16 14 12 1 8 6 4 2 Age-Related Prevalence of AF Framingham CHS Rochester Western Australia 4 5 6 7 8 9 Age FEINBERG WM ET AL, Arch Intern Med 1995; 155:469-473
New antiarrhythmic drug development approaches for AF Problem of ventricular proarrhythmia I Kur I Ks Atrium Novel ion channel targets Ventricle I Ks Agrandissement des 3 dérivations synchrones montrant en D III les torsades de pointes. DESSERTENNE, Arch. des Mal.du Cœur 1966; 59:263-272. and strategy of atrial-selective therapies I Kur I Ks Atrium K + channel blockers with atrial selectivity I Ks Ventricle Agrandissement des 3 dérivations synchrones montrant en D III les torsades de pointes. DESSERTENNE, Arch. des Mal.du Cœur 1966; 59:263-272 Atrial-selective therapies I Kur I Kur (ultrarapid delayed rectifier) is Atrial-specific in Man Atrial cell Ventricular cell XX Atrium I Kur I Ks I Ks Ventricle Agrandissement des 3 dérivations synchrones montrant en D III les torsades de pointes. DESSERTENNE, Arch. des Mal.du Cœur 1966; 59:263-272 LI ET AL, Circ Res. 1996; 78:689-696
I Kur (ultrarapid delayed rectifier) is Atrial-specific in Man Atrial cell Ventricular cell HUMAN ATRIAL MUSCLE 3 µm XEN-D11 5 mv 5 mv 1 µm XEN-D11 1 ms 1 µm XEN-D11 3 µm XEN-D11 VARRO ET AL, 27 ERP (ms) 12 RAA 1 8 6 4 1 2 3 4 BCL (ms) ERP 3 (ms) 2 RV Efficacy of an I Kur blocker (Xen-D11) on atrial and ventricular ERPs in AT-remodeled dogs ERP (ms) ERP (ms).3mg/kg 12 1mg/kg 3mg/kg 12 1 1 15 1 5 8 6 4 1 2 3 4 BCL (ms) ERP 5 (ms) 2 15 1 5 8 6 4 1 2 3 4 BCL (ms) Post drug LI ET AL, Circ Res. 1996; 78:689-696 1 ms HUMAN VENTRICULAR MUSCLE.3mg/kg 1mg/kg 3mg/kg.3mg/kg 1mg/kg 3mg/kg Shiroshita-Takeshita et al, Heart Rhythm 3: S183, 26. DAF (s) 12 Efficacy of an I Kur blocker (Xen-D11) on AF in dogs with atrial tachycardia remodeling (%) 1 New antiarrhythmic drug development approaches for AF 1 8 6 8 6 4 2 4 2 Targeting the substrate.3mg/kg 1mg/kg 3mg/kg.3mg/kg 1mg/kg 3mg/kg :p<.5, :p<.1vs baseline Shiroshita-Takeshita et al, Heart Rhythm 3: S183, 26. Determinants of Arrhythmia Mechanisms in AF: Role of Remodeling Determinants of Arrhythmia Mechanisms in AF: Prevention of Remodeling Substrate Trigger Ectopic activity Substrate Trigger Ectopic activity XX XX Remodeling Remodeling Reentry Atrial Fibrillation Reentry Atrial Fibrillation
Effects of electrically maintained AF on spontaneous AF maintenance when stimulation stopped Atrial Myocyte Adaptation to Ca 2+ Loading Sinus rhythm (6/min) 1-fold rate increase AF (4-6/min) Cellular Ca 2+ loading Threat to cell viability WIJFFELS MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968 SN.22 Atrial Myocyte Adaptation to Ca 2+ Loading Atrial Myocyte Adaptation to Ca 2+ Loading Sinus rhythm (6/min) 1-fold rate increase AF (4-6/min) Sinus rhythm (6/min) 1-fold rate increase AF (4-6/min) Cellular Ca 2+ loading Cellular Ca 2+ loading Threat to cell viability minutes Threat to cell viability minutes hours - days mrna inactivation inactivation protein SN.22 SN.22 Atrial Myocyte Adaptation to Ca 2+ Loading Sinus rhythm (6/min) 1-fold rate increase AF (4-6/min) Cellular Ca 2+ loading Threat to cell viability minutes inactivation + hours - days mrna protein Patients without Recurrence (%) 1 8 6 4 2 Superiority of Amiodarone in AF Amiodarone (n = 21) Propafenone (n = 11) Sotalol (n = 11) 1 2 3 4 5 6 Days of Follow-up SN.22 APD RP SN.23 ROY et al, N Engl J Med 2; 342: 913-92 KOCHIADAKIS et al, Heart 2; 84: 1-7
Effects of Antiarrhythmic Drugs on AF Effects of Antiarrhythmic Drugs on AF (s) 14 12 1 8 6 4 2 14 12 1 8 6 4 2 14 12 1 8 6 4 2 (s) 14 12 1 8 6 4 2 14 12 1 8 6 4 2 14 12 1 8 6 4 2 Vulnerability (%) 1 5 1 5 1 5 Vulnerability (%) 1 5 1 5 1 5 SN.23 P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: 144-1446, 23 SN.23 P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: 144-1446, 23 Effects of Antiarrhythmic Drugs on AF Effects of Remodeling on α 1c Subunit Expression (s) Vulnerability (%) 14 12 1 8 6 4 2 1 5 SN.23 14 12 1 8 6 4 2 1 5 14 12 1 8 6 4 2 1 5 P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: 144-1446, 23 A B C D Pace Amio Amio + Pace Dof Dof + Pace Flec Flec + Pace E Area x OD normalized ND = no drug F = flecainide 1.2 1. NS NS NS.8.6.4.2. A = amiodarone D = dofetilide NS Pacing SHINAGAWA et al, Circulation, 17: 144-1446, 23 Effects of Remodeling on α 1c Subunit Expression Effects of Remodeling on α 1c Subunit Expression A Pace E 1.2 ND = no drug F = flecainide A = amiodarone D = dofetilide A Pace E 1.2 ND = no drug F = flecainide A = amiodarone D = dofetilide B C Amio Amio + Pace Dof Dof + Pace Area x OD normalized 1..8.6.4.2 NS NS NS NS B C Amio Amio + Pace Dof Dof + Pace Area x OD normalized 1..8.6.4.2 NS NS NS NS D Flec Flec + Pace. Pacing D Flec Flec + Pace. Pacing SHINAGAWA et al, Circulation, 17: 144-1446, 23 SHINAGAWA et al, Circulation, 17: 144-1446, 23
Effects of Various Agents on Ca v 1.2 Expression Effects of Various Agents on Ca v 1.2 Expression (AU) 1.5 (AU) 1.5 Ca v 1.2 GAPDH NP ATP SIM OXY PRO VitC VitC&E 1..5 Ca v 1.2 GAPDH NP ATP SIM OXY PRO VitC VitC&E 1..5 NP ATP SIM OXY PRO VitCVitC&E NP ATP SIM OXY PRO VitCVitC&E :p<.5 vs ATP, :p<.1 vs ATP :p<.5 vs ATP, :p<.1 vs ATP Can we identify new antiarrhythmic approaches that work by preventing atrial-tachycardia remodeling? Can we identify new antiarrhythmic approaches that work by preventing atrial-tachycardia remodeling? 3 DAF (s) 1 (%) 3 DAF (s) 1 (%) Sinus rhythm maintenance 1 1 1 5 1 5 1 1 1 NP ATP SIM NP ATP SIM 1 NP ATP SIM NP ATP SIM Shiroshita-Takeshita et al, Circulation 24;11: 2313-2319. Shiroshita-Takeshita et al, Circulation 24;11: 2313-2319. Siu et al, Am J Cardiol 23;92:1343-1345 Remodeling Induces Two Clinically Relevant AF Substrates: Atrial-tachycardia Remodeling and Structural Remodeling Atrial tachycardia remodeling -induced remodeling produces a structural substrate for AF Histology Epicardial maps LI et al, Circulation 1999; 1:87-95 AF-induced remodeling Heart disease-induced remodeling LI et al, ENG et al, Res. 1997;8:572-579 Circulation 1999; 1:87-95
Can Inhibiting Ang-II Formation Prevent Development of the Substrate for AF? Can Inhibiting Ang-II Formation Prevent Development of the Substrate for AF? % Connective tissue (s) % Connective tissue (s) 9 8 9 8 7 7 6 6 5 5 4 4 3 2 # 3 2 # 1 1 E = enalapril; HI=hydralazine/isosorbide induces fibrosis and increases CTL +E +HI LI D et al, Circulation 14: 268-2614, 21 E = enalapril; HI=hydralazine/isosorbide Enalapril attenuates fibrosis and increases CTL +E +HI LI D et al, Circulation 14: 268-2614, 21 Can Inhibiting Ang-II Formation Prevent Development of the Substrate for AF? ACE antagonism and clinical AF in LV dysfunction % Connective tissue (s) AF in post-mi patients with LVD AF in SOLVD patients 9 8 enalapril 7 6 5 AF occurrence SR maintenance placebo 4 3 2 # 1 E = enalapril; HI=hydralazine/isosorbide Vasodilator therapy does not mimic enalapril effects CTL +E +HI LI D et al, Circulation 14: 268-2614, 21 Pedersen et al, Circulation 1999; 1: 376-38 Vermes et al, Circulation 23; 17: 2926-2931 Atrial tachycardia remodeling: AF Begets AF New antiarrhythmic drug development approaches for AF Normal AP Substrate-selective ion channels AT AP SN.21 Wijffels MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968
Atrial tachycardia remodeling: AF Begets AF Constitutive that is enhanced by atrial tachycardia? Changes in outward currents Pre-TQ CONTROL AT Normal AP AT AP Tertiapin-Q (Specific blocker) TQ-sens SN.21 Wijffels MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968 Cha TJ et al, Circulation. 26;113:173-7. Effects of block on APD and tachyarrhythmia Effects of block on APD and tachyarrhythmia CONTROL AT CONTROL AT Cha TJ et al, Circulation. 26;113:173-7. Cha TJ et al, Circulation. 26;113:173-7. Atrial-selective therapies Effects of an -selective blocker (NIP 151) on AF in two canine models XX Atrium I Kur I Ks Vagal AF compound AF termination dose prevention of NO. Time plasma conc. (μg/kg/min) terminated sec AF reinduction (ng/ml) vehicle 1/12 - - /1 2 2/3 83 13 - NIP-151 5 4/5 5± 22±6 1/4 1 5/5 372±38 16±4 4/5 dofetilide 3 1/3 558 n.d /1 1 /3 - - - Agrandissement des 3 dérivations synchrones montrant en D III les torsades de pointes. DESSERTENNE, Arch. des Mal.du Cœur 1966; 59:263-272 Ventricle I Ks Aconitine-induced AF AF termination dose compound NO. Time (mg/kg) terminated sec vehicle /3 -.1 /3 -.3 2/3 67 NIP-151.1 3/3 61.3 3/3 55 Hashimoto N et al. Circulation. ;112:II-191.
Vagal AF Effects of an -selective blocker (NIP 151) on AF in two canine models compound AF termination dose prevention of NO. Time plasma conc. (μg/kg/min) terminated sec AF reinduction (ng/ml) vehicle 1/12 - - /1 2 2/3 83 13 - NIP-151 5 4/5 5± 22±6 1/4 1 5/5 372±38 16±4 4/5 Collateral effects on extra-atrial (SAN) and 3 1/3 558 n.d /1 dofetilide 1 /3 - - - extracardiac (GI and GU systems) need to be avoided Aconitine-induced AF AF termination dose compound NO. Time (mg/kg) terminated sec vehicle /3 -.1 /3 -.3 2/3 67 NIP-151.1 3/3 61.3 3/3 55 Hashimoto N et al. Circulation. ;112:II-191. We have come a long way We have come a long way But we do hope to get there! There is still a considerable way to go 5 mv 9 1 µm XEN-D11 8 HUMAN ATRIAL MUSCLE 7 3 µm XEN-D11 3 µm XEN-D11 6 5 1 µm XEN-D11 VARRO ET AL, 27 4 3 2 1 1 ms HUMAN VENTRICULAR MUSCLE 5 mv CTL # +E +H/I MGH McGill MGH McGill Thank You St. Paul s Dalhousie St. Paul s Dalhousie