La corrente tardiva del Na come nuovo target di terapia antiischemica: ruolo della ranolazina

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1 1 La corrente tardiva del Na come nuovo target di terapia antiischemica: ruolo della ranolazina Alessandro Mugelli* Department of Preclinical and Clinical Pharmacology University of Florence Florence (Italy) * Disclosures: recipient of research funding by Gilead and Menarini.

2 2 Chronic stable angina Many patients remain symptomatic and at risk of major cardiac events despite optimal medical therapy and myocardial revascularization procedures 1 At 1 year ~10 25% of patients still have angina and 60 80% require antianginal therapy 2 In patients with comorbidities (HTA, DM, HF) it may be difficult to uptitrate the dose of traditional antianginal drugs Dose-limiting adverse effects (i.e., hypotension, bradycardia, AVB) or associated intolerance before angina relief is achieved (1) Gibbons RJ et al. J Am Coll Cardiol. 2003;41: (2) Scirica, Morrow. Curr Cardiol Rep 2007; 9:

3 3 Chronic stable angina We need new antianginal drugs with a different (and complementary) mechanism of action and without these limitations

4 4 The late sodium current (late INa ): A new therapeutic target in angina 1. The role of late I Na under physiological conditions 2. Pathological conditions associated with an increase in late I Na 3. The role of the late I Na in the ischemic myocardium A Pathological Paradigm 4. Ranolazine, a novel antianginal and anti-ischemic agent with a new mechanism of action, the inhibition of the late I Na

5 5 Cardiac Na + channels Na + Phase 0 Excitability Cond. Velocity QRS Peak I Na 85 mv

6 6 Tetrodotoxin, a selective blocker of Na + channels, prolongs APD in Purkinje fibers at concentrations lower than those at which it inhibits the peak I Na Late I Na 1: control. 2: TTX (0.03 µm) The shortening was due to a TTX-sensitive Na + current flowing during the plateau of the action potential This current flows through a small proportion of Na+ channels with no inactivation mechanism (or inactivation different from normal), e.g. the late I Na Coraboeuf et al. Am J Physiol 1979;236:H561-H567

7 7 Late Na current in guinea pig ventricular myocytes Two types of Na + channel activity: brief openings (PEAK) and sustained openings with rapid interruptions (burst type) (LATE) Channels that either do not close, or close and then reopen 0 Late Peak Late Late I Na I Na Slowly Slowly inactivating inactivating Late Late reopenings reopenings Bursting Bursting behaviour behaviour Kiyosue and Arita. Circ Res 1989;64:389-97

8 8 A Pathological Paradigm: Sodium Channelopathy Pathological Conditions Acquired Congenital VG VG: voltage-gated Na Ch inactivation failure Enhanced late I Na Adapted from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006.

9 Role of I NaT and I NaL on AP I NaT : source of charges for conduction 0 mv I NaL : contributes to the plateau phase 0 pa I NaL 100 ms I NaT

10 When I NaL increases. APD (QT) Na + influx

11 If I NaL increases.. Na + entry into the cell increases..

12 EXTRACELLULAR INTRACELLULAR CYTOSOL SR LUMEN Ca 2+ NCX Na + RyR Ca 2+ Na + NHE NaV Na/K H + Na + Ca 2+ SERCA Ca 2+ Ca 2+ ATPase K + SERCA/RyR Na + in/out

13 If I NaL increases.. Ca 2+ and H + homeostasis is altered

14 L aumento di I NaL rallenta il rilassamento 14 0 Sodium Current Peak Normal Late I Na 1 2 (Plateau) 0 Abnormal Peak Late I Na P (mmhg) Ao LV 0 (Upstroke) Phasic 3 4 Phasic Tonic coronary flow (ml/min) Twitch Belardinelli, L. 2007

15 15 Diastolic relaxation failure increases O 2 consumption and reduces O 2 supply Na + and Ca 2+ overload Increased wall tension during diastole: Increases MVO 2 Compresses intramural small vessels Reduces myocardial blood flow (subendocardium) Worsens ischemia and angina

16 L'aumento di [Na + ] cit altera il bilancio energetico

17 Oxygen Supply / Demand Ischemia (Hypoxia, Ischemic metabolites, acidosis, and ROS) 17 O 2 Consumption O 2 Supply Contracture ( LVEDP) Vicious Cycle Late I Na [Na + ] i NCX NHE Modified from: Belardinelli L, et al. Eur Heart. 2006;8 (Suppl. A):A10-A13. Ca 2+ & H + Overload arrhythmias stunning

18 18 Late I Na is involved in the Long QTS KPQ: deletion of residues 1505 to 1507 in III-IV IV linker of NaCh (inactivation gating process) K = lysine, P = proline, Q = glutamine LQT1 LQT2 LQT3 LQT4 LQT5 LQT6 LQT7* LQT8** LQT9 LQT10 LQT11 LQT12 Gene KCNQ1, KvLQT1 KCNH2, HERG KCNQ1, KvLQT1 KCNH2, HERG KCNE1, mink KCN2, MiRP1 KCNJ2, Kir2.1 Channel I Ks I Kr Late I Na Ca i, Late I Na? I Ks I Kr I K1 CACNA1C, Ca 1.2 I v Ca CAV3, Caveolin-3 SCN4B, NavB4 AKAP9, Yotiao SNTA1, α-1 Syntrophin * Andersen Tawil Syndrome ** Timothy Syndrome Late I Na Late I Na I Ks Late I Na

19 0 mv -120 mv Normal vs. Enhanced Late Sodium Current Normal Enhanced ( KPQ) 5 pa 50 ms 50 ms Late openings of individual channels lead to increased whole cell macroscopic late I Na Ranolazine I NaL I NaL Modified from Bennet, P. et al. Nature 376:683, 1995 and Belardinelli, et al. Eur. Heart. 6 (Suppl. I):13-17, 2004.

20 LQT3 syndrome is a monogenetic disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Pathogenetic pathway Belardinelli L., 2007 I II III IV Genotype Mutant SCN5A Δ KPQ Late I Na Peak I Na control Molecular phenotype Increased late I Na Sudden death mutant EAD Cellular phenotype Prolonged action potential; early afterdepolarizations; delayed relaxation TdP Organ phenotype Prolonged QT interval; torsade de pointes delayed relaxation (not shown) Syncope Sudden death Clinical phenotype Syncope Sudden death

21 Effect of Ranolazine in the Congenital Long-QT Syndrome Type 3 Patients LQT3 syndrome is a monogenetic disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Pathogenetic pathway Belardinelli L., 2007 I II III IV Genotype Mutant SCN5A Δ KPQ Late I Na Peak I Na control Molecular phenotype Increased late I Na Sudden death mutant EAD Cellular phenotype Prolonged action potential; early afterdepolarizations; delayed relaxation TdP Organ phenotype Prolonged QT interval; torsade de pointes delayed relaxation (not shown) Syncope Sudden death Clinical phenotype Syncope Sudden death

22 22 Effect of Ranolazine in the Congenital Long-QT Syndrome Type 3 Patients

23 23 Ranolazine Is a Selective Late I Na Inhibitor in Human Heart of LQT3 Patients [Ranolazine] (ng/ml) Change in QTc (msec) On Ranolazine, IV Off 45 mg/hr 90 mg/hr * * * * * HR = 55 ± 9 bpm Inhibition of Late I QT cf = 560 ± 23 msec Na (2 pts w/qtc > 610 msec) 250 PR/QRS interval (msec) 200 PR = 200 msec Lack of effect on In humans ranolazine at therapeutic plasma QRS = 90 peak levels I ± 8 msec Na (and I Ca ) 0inhibits late I Na ( QTc) but does not inhibit I Ca,L or peak I Na (no effect on P-R P R or QRS intervals) Values are mean SEM from 5 patients 1 QTc (Fridericia) change from baseline 2 KPQ Time (hrs) Modified from Moss AJ et al. JCE 2008

24 24 Role of the late I Na in ischemia

25 Myocardial ischemia causes enhanced late I Na 0 Sodium Current Peak Late Ischemia Na + Impaired Inactivation 0 Sodium Current Peak Late Na + Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

26 26 A Pathological Paradigm: Sodium Channelopathy Pathological Conditions Acquired Hypoxia/ROS Ischemia Heart failure VG Ca 2+ H + Overload VG: voltage-gated Na Ch inactivation failure Enhanced late I Na Na + i Adapted from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006.

27 27 MVO 2 O 2 Supply Contracture ( LVEDP) Oxygen Supply: Demand Ischemia Hypoxia, Ischemic metabolites, Ischemia begets Ischemia acidosis, and ROS Ischemia begets Ischemia Deleterious Positive Late I Na Feedback Cycle Contracture Ischemia Ca ++ - overload Late I Na [Na + ] i NCX 27 Arrhythmias Ca ++ Overload Modified from: Belardinelli et al. Eur Heart 8 (Suppl. A):A10-A13, 2006.

28 28 Positive feedback during ischaemia increases the imbalance between myocardial O 2 supply and demand Ischemia O 2 supply/ MVO 2 extravascular compression ( O 2 supply) Contracture ( LVEDP) Deleterious Positive Feedback Cycle X Late I Na [Na + ] i Ca 2+ overload

29 29 Ranolazine First SELECTIVE Late cardiac sodium current (I Na ) inhibitor A NEW CLASS OF ANTI-ANGINAL ANGINAL AGENTS CH 3 H N OH N N O OCH 3 O CH 3 Film-coated prolonged release tablets containing 375 mg, 500 mg or 750 mg

30 30 Ranolazine: mechanism of action Ischemia Late I Na Ranolazine Na + overload NCX Ca ++ overload Electrical dysfunction Arrhythmias Mechanical dysfunction Diastolic tension Contractility O2 supply & demand ATP consumption ATP formation Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97: Maier LS. Cardiol Clin 2008;26: NCX: sodium-calcium exchanger

31 31 Ranolazine reduces the effects of ischemia on [Ca 2+ ], Ca 2+ i transients, LV function and coronary flow Ca 2+ transient Diastolic [Ca 2+ ] i Fraser H et al. J Mol Cell Cardiol. 2006;41:

32 32 Ranolazine reduces the increase in diastolic tension in LV trabeculae from human failing heart Sossalla S et al. J Mol Cell Cardiol 2008; 45:

33 Effetti del blocco di I NaL (RILEVANTI PER ISCHEMIA) positivizzazione del bilancio fra apporto e consumo di O 2 in condizioni di aumento di I NaL Ciò consegue a normalizzazione di: 1) rilassamento diastolico; 2) efficienza contrattile (lavoro/mvo 2 ); 3) controllo del ph intracellulare; Quindi, blocco I NaL NON: 1) cambia la frequenza cardiaca 2) cambia le resistenze periferiche (post- carico) 3) deprime la contrattilità miocardica 4) intereferisce con il controllo nervoso

34 34 Selective Inhibition of Late Sodium Current by Ranolazine A. Normal Late Sodium Current Therapeutic Range 2 to 8 µm C. Human Cardiac NaCh in HEK293 Cells Peak I Na Late I NaL I Na Late I Na B. Enhanced Late Sodium Current % Inhibition 100 Peak IC 50 = 428 µm Na + i 50 late IC 50 = 6.9 µm IC 50 Ca 2+ i Δ IC 50 = 62-fold Ranolazine ILate NaL I Na 0 1E C i f i ( ) Concentration of Ranolazine (mm) Peak I Na Belardinelli, et al. Eur. Heart. 6 (Suppl. I):13-17, Rajamani, S., et al., Eur Heart J. 28(1): 400 (abstract) 2007.

35 E questione di selettività. BLOCCO RELATIVO I NaL /I NaT Ranolazine 62 SELETTIVO Amiodarone 13 Flecainide NON SELETTIVO

36 36 A new and complementary mechanism Nitrates Beta-blockers CaCBs SNI O 2 supply Ischemia O 2 demand Heart rate Contractility Preload Afterload Coronary supply MVO 2 Ranolazine Na + -induced Ca 2+ overload Mechanical dysfunction Electrical instability Decreased ATP formation

37 37 Late Na + current inhibition - A new antianginal approach 1. The enhanced late I Na plays a critical role in Na + -induced Ca 2+ overload in the ischemic myocardium Contributes to electrical, mechanical and metabolic dysfunction It represents a new therapeutic target in patients with Chronic Stable Angina

38 38 Late Na + current inhibition - A new antianginal approach 2. Ranolazine,, a selective late I Na inhibitor, blocks Na + - dependent Ca 2+ overload It improves LV function, decreasing diastolic tension Unlike other antianginal drugs, it has no significant effects on Coronary blood flow, heart rate, blood pressure or venous return

39 39 Late Na + current inhibition - A new antianginal approach This distinct and complementary mechanism represents an alternative approach in patients with Chronic Stable Angina who are not controlled by conventional antianginal drugs or who do not tolerate those drugs