Blocking the Late Sodium Current

Transcription

1 Non-classical Targets in Antiarrhythmic Therapy Blocking the Late Sodium Current Luiz Belardinelli, MD SVP, Cardiovascular Therapeutics Gilead Sciences, CA, USA Madrid June 28, 2011 Disclosures: Full time employee of Gilead Sciences, Inc.

2 Blocking the Late Sodium Current 2 OUTLINE General Role of Enhanced I Na,L in Arrhythmogenesis Is inhibiting (blocking) I Na,L Anti-arrhythmic? Specific Normal Physiological vs. Enhanced Pathological A Highly Arrhythmogenic Current Enhancers and Inhibitors Pre-Clinical and Clinical Evidence

3 Cardiac Sodium Channel Current 3 Normal (Physiologic) Single NaCh Current Na + Na + Impaired Inactivation Abnormal (Pathologic) mv 4 pa mv 100 msec 100 msec 4 pa Whole Cell NaCh Current Late I Na 0 [Na + ] i 0 Sodium Current Late I Na (30 to 60 pa) NCX Late I Na Peak [Ca 2+ ] i Peak Tracings Modified from: Kiyosue, T & Arita, M. Circ Res 64: , Belardinelli L et al. Eur Heart J Suppl. 6(suppl I):I3-7, 2004

4 Pathology of Enhanced late I Na from Channel to Organ Phenotype 4 Channel Cell Organ 1. Increased Na i + and Ca i 2+ normal enhanced late I Na 2. AP EAD DAD Electrical instability (arrhythmias) peak I Na 3. Twitch MVO2 Microvasc. Flow Contractile dysfunction (delayed relaxation, diastolic tension)

5 5 Pathological & Pharmacological Conditions Associated with Increased Late Na + -current (I Na ) 1. Pathological Conditions A. Acquired Hypoxia Ischemic metabolites (amphiphiles) Reactive Oxygen and Nitrogen Species Heart failure (human and dog myocytes) Post-MI remodeled myocytes 2. Pharmacological Ang-II or ouabain Toxins: ATX-II, AP-A, β - PMTX, Pyrethroids Drugs: (NaCh - modulators): DPI , BDF 9148 B. Congenital (Inherited) Cardiac: SCN5A (LQT3) CAV3 (LQT-9) ChiPs SCN4B (LQT-10) SNTA1 (LQT-12) Increase in Late I Na, [Na + ] i and [Ca ++ ] I Electrical Instability ChiPs=channel interacting proteins Reference available in Belardinelli L, et al. Heart;92 (Suppl. IV):IV6-IV14, 2006 and Zaza, Belardinelli, Shryock Pharm Ther 119:326-39, 2008

6 Role of Late I Na in the Genesis of Tachyarrhythmias 6 Increased late I Na ( Na i ) NCX, NHE Slow Ventricular Repolarization ( AP Duration) Ca ++ - overload Acidosis Electrical Instability Afterpotentials (EADs and DADs) Diastol. Depol. ( Rep. Firing) Beat-to-beat ΔAPD T-wave Alternans Disp. Vent. Repol Belardinelli et al. 2007

7 Pathological Partnership between Late Na + current and CaMKII 7 Diseases and pathological conditions Na + Late I Na VGSC P Late I Na APD ( Ca 2+ i ) APD [Na + ] i NCX Automaticity Afterpotentials Arrhythmias I Ti [Ca 2+ ] i pryr2 SR Ca 2+ leak pcamkii Yao L et al, AJP-Cell, in press 2011

8 8 Modulators of Late I Na Enhancers Pharmacological Agents: Drugs, Toxins (ATX-II) Acquired Pathological Conditions (ROS, ANG-II) and Diseases (IHD, HF, Afib) Congenital: NaCh mutations/chips mutations (Gain-of-Function NaCh) Blockers (Inhibitors) Sodium channel blockers (I Na,L inhibitors) Lidocaine, Mexiletine, Flecainide Ranolazine, PF-15845, GS Toxin: Tetrodotoxin (TTX) Saxitoxin (STX) ChiPs: channel interacting proteins Belardinelli et al. 2007

9 Outward Inward Potencies of Tetrodotoxin, Ranolazine and GS to Inhibit Cardiac Ion Currents 9 Therapeutic range for ranolazine (2-8μM) Potencies (IC 50 Values in μm) Currents TTX Ranolazine GS I Na (peak) * >10 ** I Na (late) I Ca (peak) I Ca (late) I NCX - 91 TBD I Kr I Ks - >30 - I Kur TBD - - I K I KAch,Ado TBD - - I To TBD - - I KATP TBD - - Note: The IC 50 values for I Na (peak and late) and I Kr are from heterologous expression of SCN5A (human heart Na + channel) and HERG (K + channels) in HEK 293 cells. - No effect or 10% inhibition at 10μM I Ca is L-type (TBD on T-type I Ca ) * Potency dependent on Vm, f(hz), NaCh isoform, Exp. Conditions **Limited by solubility Approx. 20% inhibition at 5μM <20% at 30μM

10 10 Summary of pathological conditions, pharmacological agents, toxins known to elicit ventricular arrhythmias* that are suppressed by ranolazine 1. Reactive Oxygen Species Class III antiarrhythmic agents (e.g., dofetilide, sotalol, amiodarone) Non-cardiovascular drugs that cause TdP in pre-clinical models (e.g., moxifloxacin, cisapride, etc.) 12,13 4. Late I Na agonists (toxins) 1,5,6,11,14,15 5. Pharmacological agents (e.g., BayK 8644, Ouabain, Angiotensin II) High Co 2 (i.e., acidosis) LQT2 ips cell Ventricular myocytes from failing hearts (ischemia- or tachycardia-induced Primary: I Na,L (7μM) HF) Ischemic heart (pre-clinical) 24, Ischemic and non-ischemic heart (clinical) Concentration Range: 3 to 10μM Ranolazine suppresses H 2 O 2 -induced EADs, VT and VF Mechanism Secondary: I Kr (14μM) Possible: I Na *Includes ventricular ectopic beats and tachycardia, beat-to-beat variability of ventricular repolarization, abnormal automaticity, and triggered activity caused by early and delayed afterdepolarizations. peak I Na dependent on rate and membrane potential References available upon request; modified from Antzelevitch and Belardinelli et al HR 2011 (in press)

11 APD 50 (% of control) Suppression by Ranolazine of Hydrogen Peroxideinduced EADs in a Guinea Pig Ventricular Myocyte 11 mv mv msec 60 A. Control A. Control B. H 2 O 2 ( msec mv C. H 2 O 2 + Ranolazine (10 μm) mv msec C. H 2 O 2 + Ranolazine (10 D. H 2 O 2 (wash Ranolazine) H 2 O 2 (Time/min) B. H 2 O 2 (200 μm) D. H 2 O 2 Ranolazine Washout msec Song Y. et al. J Pharmacol Exp Ther 318: , 2006.

12 Ranolazine Reduces the Increase in Late I Na, Intracellular Sodium and Calcium Caused by H 2 O 2 in Ventricular Myocytes 12 A. Intracellular Sodium ([Na + ] i ) B. Intracellular Calcium ([Ca 2+ ] i ) [Na]i (mm) Baseline H 2 O 2 H 2 O 2 + RAN * [Ca 2+ ] i (nm) Baseline H 2 O 2 H 2 O 2 + RAN * Song Y. et al. J Pharmacol Exp Ther 318: , 2006.

13 H 2 O 2 -induced [Na + ] i accumulation is abolished in CaMKIId KO mice 13 [Na + ] i (F 340 /F 380 ) s WT 12 min 6 min 0 min [Na + ] i (F 340 /F 380 ) s CaMKIId -/- 12 min 6 min 0 min [Na + ] i (mmol/l) WT, N=12 H 2 O 2 * CaMKIId -/-, N= Time (min) Wagner, Maier et al., unpublished

14 14 Suppression and Termination of EAD-mediated Triggered Activity and VF by Ranolazine in Hearts Exposed to H A. Baseline H 2 O 2 + Ran (1.2 min) ECG H 2 O 2 (8 min) H 2 O 2 + Ran (40 min) H 2 O 2 (10 min) H 2 O 2 + Ran Wash (40 min) H 2 O 2 (12 min) H 2 O 2 + Ran Wash (65 min) 1s Morita N, Karagueuzian H, et al. JACC 57: , 2011

15 Clinical Evidence for the Anti-arrhythmic Role of I Na,L 15 Ranolazine (Therapeutic Range: 2-8μM) Peak I Na : 428μM* Late I Na : 6μM I Kr : 14μM 1. Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due To Type-3 Long QT Syndrome Moss et al. J Cardiovasc Electrophysiol. 19(12): , 2008 QTc vs. [Ran] μm 24 msec per 1,000ng/ml: r= (p=0.033) 2. Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non ST-Segment Elevation Acute Coronary Syndrome Scirica et al. Circulation 116: , Relationship Between Nonsustained Ventricular Tachycardia After Non ST- Elevation Acute Coronary Syndrome and Sudden Cardiac Death Scirica et al. Circulation 122: , 2010 *Vm, f, NaCh isoform, tissue

16 Sudden Cardiac Death (%) Ventricular Ectopic Beats as a Risk Factor for Sudden Cardiac Death Risk vs. No Triplets or VT Triplets HR* 1.1 ( ), p=0.74 VT 4-7bts HR* 2.3 ( ), p<0.001 VT 8bts HR* 2.8 ( ), p=0.001 VT 8 beats (n=431) 4.3% VT 4-7 beats (n=1171) 2.9% Days from Randomization Triplets (VT=3 beats) (n=1978) 1.4% No Triplets or VT (n=2764) 1.2% * Adjusted for TIMI Risk Score, Prior MI, Prior HF, CrCl, revasc during index hospitalization Scirica BM et al. J Am Coll Cardiol. 2009;53(10, Suppl.1):A121

17 Ranolazine Reduces Incidence of Non- Sustained Ventricular Tachycardia 17 80% 60% p < % 52% Placebo Ranolazine Incidence 40% 20% 0% p < % 21% p < % 5% p < % 3% p < p = % 1% 1% 1% >= 3 >= 4 >= 8 >= 10 >= 15 >= Ventricular Ventricular Ectopic Ectopic Beats Beats Wang W et al. Circulation 120(18): S661, 2562, 2009 Modified from Scirica B et al, Circulation 122:455, 2010 Given the statistically neutral primary efficacy analysis of the MERLIN TIMI-36 trial, this analysis should be regarded as inherently exploratory.

18 Relationship Between Number of Consecutive Ventricular Ectopic Beats and SCD 18 Incidence of Sudden Cardiac Death 10% 8% 6% 4% 2% 0% Cochran-Armitage test for trend: p < % 8.3% 1.4% 1.3% 3.1% 3.5% 3.8% 1.4% 1.5% 3.0% 1.4% 1.8% No VT Triplet > 20 No VT Triplet > 20 n = Placebo Treatment by VEB interaction p = 0.36 Wang W et al. Circulation 120(18): S661, 2562, 2009 Modified from Scirica B et al, Circulation 122:455, 2010 Cochran-Armitage test for trend: p = % 3.7% Ranolazine Given the statistically neutral primary efficacy analysis of the MERLIN TIMI-36 trial, this analysis should be regarded as inherently exploratory.

19 Risk of Sudden Cardiac Death Associated with Ventricular Tachycardia Lasting 8 Beats 19 8% Sudden Cardiac Death NO VT Patients with No VT 8 beats HR 0.96 (95% CI 0.66, 1.42); p=0.85 8% VT Patients with VT 8 beats HR 0.36 (95% CI 0.10, 1.27); p=0.097 Sudden Cardiac Death 6% 4% 2% Placebo 6% 4% 2% Placebo Ranolazine Ranolazine 0% Days After Randomization Wang W et al. Circulation 120(18): S661, 2562, 2009 Modified from Scirica B et al, Circulation 122:455, % Days After Randomization Given the statistically neutral primary efficacy analysis of the MERLIN TIMI-36 trial, this analysis should be regarded as inherently exploratory.

20 20 In Summary 1. Late I Na (enhanced) is a potent arrhythmogenic mechanism (electrical instability, Na i & Ca i overload) 2. Late I Na appears to contribute to the arrhythmogenesis associated with a number of pathological conditions, toxins and drugs 3. Inhibition of Late I Na seems to be a plausible therapeutic target to suppress arrhythmias caused by enhanced automatic activity, triggered activity (afterpotentials) and unstable AP repolarization (disp. of repol. & APD)

21 Backup Slides 21

22 Summary of atrial tachyarrhythmias and bradyarrhythmias suppressed by ranolazine 22 Concentration Range: 3 to 10μM 1. Vagally-mediated AF in isolated canine atria and in pig in vivo 1, adrenergically-mediated AF in canine atria exposed to ischemia/reperfusion 1 3. DAD- and EAD-induced triggered activity in canine isolated PV 3 and human RA trabeculae 4 4. DAD and EAD activity as well as automaticity in isolated atrial guinea pig myocytes 5, 6 5. EAD-induced atrial arrhythmias in LQT3 mouse 7 6. Bradyarrhythmia in LQT3 mouse 8 7. Bradyarrhythmias (clinical) 9 8. Supraventricular tachycardia (clinical) 9 9. New onset of AF (clinical) Paroxysmal AF (clinical) 10, Post-operative AF (clinical) 12 Mechanism Peak I Na I Kr I Na,L ( Triggers) peak I Na dependent on rate and membrane potential References available upon request; modified from Antzelevitch and Belardinelli et al HR 2011 (in press)

23 Induction of Polymorphic Atrial Tachycardia in a Heart Treated with ATX-II (3 nm) a. RA MAP (spontaneous) (poly AT) 23 b. RAe S1 S1 S2 S1 S1 S1 S2 A A c. LAe S1 S1 S1 S2 A V A V d. LVe S1 V S1 V S1 V S2 S1 (irregular) 0.5 sec Wu L, Belardinelli L et al, 2011

24 EADs in Atria from SCN5A ΔKPQ Mice: Suppression by Ranolazine 24 Lemoine et al. Cardiovascular Research 2011

25 Reduction of Repolarization Reserve Unmasks Proarrhythmia Mediated by Endogenous Late INa 25 Decreased I Kr Unmasks Late Sodium Current (physiological, 30-60pA) Increases Dispersion of Repolarization Increases Beat - to - beat APD Tachyarrhythmias (TdP) Belardinelli, L. 2008

26 seconds seconds seconds seconds 26 VT-induced by I Kr Inhibition: suppression by TTX A. Control 3 pause B. E-4031 (60 nmol/l) Spontaneous TdP 3 pause-triggered TdP seconds seconds C. E-4031 (60 nmol/l) + TTX (0.6 µmol/l) seconds pause seconds Wu L, Shryock C, Song Y, Belardinelli L. JPET. 316: ,

27 Ranolazine and TTX Decrease Dispersion of Ventricular 1.00 B. BVR ( APD) repolarization, APD and Incidence of TdP BVR (ms) ** ** ** ** ** TTX or Ran Conc (µm) TDR (MAPD Endo-Epi ms) A. Dispersion (TDR) C. TdP E-4031+TTX E-4031+RAN * * ** ** ** TTX or Ran Conc (µm) Incidence of TdP (%) ** ** ** ** ** ** TTX or Ran Conc (µm) Wu L, Shryock C, Song Y, Belardinelli L. JPET. 316: , 2006.