Rational Approach to Improving Cardiac Arrhythmia Therapy. Rational Approach to Improving Cardiac Arrhythmia Therapy

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1 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: , 194 GIANELLY R et al, NEJM 277: , 1967

2 Total suppression of ventricular arrhythmias by encainide Oral flecainide acetate for the treatment of ventricular arrhythmias RODEN DM et al, NEJM 32 : , 198 ANDERSON JL et al, NEJM 35 : , 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: , 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 : , 1992 NEJM 321:46-412, 1989 CAST II Investigators, NEJM 327 : , 1992

3 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 : , 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 % Age-Related Prevalence of AF Framingham CHS Rochester Western Australia Age FEINBERG WM ET AL, Arch Intern Med 1995; 155:

4 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: 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: 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: LI ET AL, Circ Res. 1996; 78:

5 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 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 BCL (ms) ERP 5 (ms) BCL (ms) Post drug LI ET AL, Circ Res. 1996; 78: 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 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

6 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: 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 (%) Superiority of Amiodarone in AF Amiodarone (n = 21) Propafenone (n = 11) Sotalol (n = 11) Days of Follow-up SN.22 APD RP SN.23 ROY et al, N Engl J Med 2; 342: KOCHIADAKIS et al, Heart 2; 84: 1-7

7 Effects of Antiarrhythmic Drugs on AF Effects of Antiarrhythmic Drugs on AF (s) (s) Vulnerability (%) Vulnerability (%) SN.23 P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: , 23 SN.23 P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: , 23 Effects of Antiarrhythmic Drugs on AF Effects of Remodeling on α 1c Subunit Expression (s) Vulnerability (%) SN P<.5, P<.1 vs CTL SHINAGAWA et al, Circulation, 17: , 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 NS NS NS A = amiodarone D = dofetilide NS Pacing SHINAGAWA et al, Circulation, 17: , 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 NS NS NS NS B C Amio Amio + Pace Dof Dof + Pace Area x OD normalized NS NS NS NS D Flec Flec + Pace. Pacing D Flec Flec + Pace. Pacing SHINAGAWA et al, Circulation, 17: , 23 SHINAGAWA et al, Circulation, 17: , 23

8 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 NP ATP SIM NP ATP SIM 1 NP ATP SIM NP ATP SIM Shiroshita-Takeshita et al, Circulation 24;11: Shiroshita-Takeshita et al, Circulation 24;11: Siu et al, Am J Cardiol 23;92: 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: Circulation 1999; 1:87-95

9 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) # 3 2 # 1 1 E = enalapril; HI=hydralazine/isosorbide induces fibrosis and increases CTL +E +HI LI D et al, Circulation 14: , 21 E = enalapril; HI=hydralazine/isosorbide Enalapril attenuates fibrosis and increases CTL +E +HI LI D et al, Circulation 14: , 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 AF occurrence SR maintenance placebo # 1 E = enalapril; HI=hydralazine/isosorbide Vasodilator therapy does not mimic enalapril effects CTL +E +HI LI D et al, Circulation 14: , 21 Pedersen et al, Circulation 1999; 1: Vermes et al, Circulation 23; 17: 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:

10 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: Cha TJ et al, Circulation. 26;113: 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: Cha TJ et al, Circulation. 26;113: 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/ /1 2 2/ NIP /5 5± 22±6 1/4 1 5/5 372±38 16±4 4/5 dofetilide 3 1/3 558 n.d /1 1 / Agrandissement des 3 dérivations synchrones montrant en D III les torsades de pointes. DESSERTENNE, Arch. des Mal.du Cœur 1966; 59: Ventricle I Ks Aconitine-induced AF AF termination dose compound NO. Time (mg/kg) terminated sec vehicle /3 -.1 / /3 67 NIP / /3 55 Hashimoto N et al. Circulation. ;112:II-191.

11 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/ /1 2 2/ NIP /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 / 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 67 NIP / /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-D µm XEN-D11 VARRO ET AL, ms HUMAN VENTRICULAR MUSCLE 5 mv CTL # +E +H/I MGH McGill MGH McGill Thank You St. Paul s Dalhousie St. Paul s Dalhousie