1. Current anti-anginal therapy

2. Current antianginal strategies Current anti-anginal strategies Non pharmacologic Pharmacologic Trimetazidine Fasudil Nicorandil Ivabradine Ranolazine Exercise training EECPChelationtherapy SCS TMR

3. Exercise Training Exercise Training Enhanced external counterpulsation (EECP) Enhanced external counterpulsation (EECP)  Endothelial function  Endothelial function Promotes coronary collateral formation Promotes coronary collateral formation  Peripheral vascular resistance  Peripheral vascular resistance  Ventricular function  Ventricular function Placebo effect Placebo effect Chelation therapy Chelation therapy Current nonpharmacologic antianginal strategies Transmyocardial revascularization (TMR) Sympathetic denervation Angiogenesis Spinal cord stimulation (SCS)  Neurotransmission of painful stimuli  Release of endogenous opiates Redistributes myocardial blood flow to ischemic areas Allen KB et al. N Engl J Med. 1999;341:1029-36. Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25. Murray S et al. Heart. 2000;83:217-20.

4. Potential cardioprotective benefits of exercise Domenech R. Circulation. 2006;113:e1-3. Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72. NO production ROS generation ROS scavenging Other mechanisms VasculatureThrombosisMyocardium

5. EECP - Enhanced External CounterPulsation External, pneumatic compression of lower extremities in diastole. External, pneumatic compression of lower extremities in diastole.

6. EECP - Enhanced External CounterPulsation

7. Sequential inflation of cuffs Retrograde aortic pressure wave Retrograde aortic pressure wave Increased Coronary perfusion pressure Increased Coronary perfusion pressure Increased Venous Return Increased Venous Return Increased Preload Increased Preload Increased Cardiac Output Increased Cardiac Output Simultaneous deflation of cuffs in late Diastole Lowers Systemic Vascular Resistance Lowers Systemic Vascular Resistance Reduced Preload Reduced Preload Decreased Cardiac workload Decreased Cardiac workload Decreased Oxygen Consumption Decreased Oxygen Consumption

8. EECP - Enhanced External CounterPulsation 35 total treatments 35 total treatments 5 days per week x 7 weeks 5 days per week x 7 weeks 1 hour per day 1 hour per day Appears to reduce severity of Angina Appears to reduce severity of Angina Not shown to improve survival or reduce myocardial infarctions Not shown to improve survival or reduce myocardial infarctions Indicated for CAD not amenable to revascularization Indicated for CAD not amenable to revascularization Anatomy not amenable to procedures Anatomy not amenable to procedures High risk co-morbidities with excessive risk High risk co-morbidities with excessive risk May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication. May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication.

9. EECP – Contraindications & Precautions Arrhythmias that interfere with machine triggering Arrhythmias that interfere with machine triggering Bleeding diathesis Bleeding diathesis Active thrombophlebitis & severe lower extremity vaso-occlusive disease Active thrombophlebitis & severe lower extremity vaso-occlusive disease Presence of significant AAA Presence of significant AAA Pregnancy Pregnancy

10. TMLR - Transmyocardial Laser Revascularization High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow Possible explanations for effect Possible explanations for effect Myocardial angiogenesis Myocardial angiogenesis Myocardial denervation Myocardial denervation Myocardial fibrosis with secondary favorable remodeling Myocardial fibrosis with secondary favorable remodeling

11. TMLR – Direct Trial Only major blinded study Only major blinded study 298 pts with low dose, high dose, or no laser channels 298 pts with low dose, high dose, or no laser channels No benefit to TMLR vs Med therapy to No benefit to TMLR vs Med therapy to Patient survival Patient survival Angina class Angina class Quality of life assessment Quality of life assessment Exercise duration Exercise duration Nuclear perfusion imaging Nuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812 Leon MB, et al. JACC 2005; 46:1812 High Surgical Risk (Mortality 5%) High Surgical Risk (Mortality 5%) Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed. Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed.

12. Chelation Therapy IV EDTA infusions IV EDTA infusions 30 treatments over about 3 months 30 treatments over about 3 months Cost – about $3,000 Cost – about $3,000 Aggressive marketing by 500 to 1000 physicians offering this treatment Aggressive marketing by 500 to 1000 physicians offering this treatment PLACEBO effect only PLACEBO effect only Claimed pathophysiologic effects Claimed pathophysiologic effects Liberation of Calcium in plaque Liberation of Calcium in plaque Lower LDL, VLDL, and Iron stores Lower LDL, VLDL, and Iron stores Inhibit platelet aggregation Inhibit platelet aggregation Relax vasomotor tone Relax vasomotor tone Scavenge “free radicals” Scavenge “free radicals”

13. Spinal Cord Stimulation power sourceconducting wires electrodes at stimulation site Stimulation typically administered for 1-2 hrs tid Therapeutic mechanism appears to be alteration of anginal pain perception

14. Long-term Outcomes Following SCS Prospective Italian Registry: 104 Patients, Follow-up 13.2 Mo Episodes/wk * p<0.0001 * * * ** * * (DiPede, et al. AJC 2003;91:951)

15. Randomized Trial of SCS vs. CABG For Patients with Refractory Angina Spinal cord stimulation (n=53) CABG (n=51) *P < 0.0001 **** (Mannheimer, et al. Circulation 1998;97:1157) 104 Patients with refractory angina, not suitable for PCI and high risk for re-op (3.2% of patients accepted for CABG) No difference in symptom relief between SCS and CABG

16. Current pharmacologic antianginal strategies New mechanistic approaches to angina New mechanistic approaches to angina Rho kinase inhibition (fasudil) Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) Preconditioning (nicorandil) Sinus node inhibition (ivabradine) Sinus node inhibition (ivabradine) Late Na+ current inhibition (ranolazine) Late Na+ current inhibition (ranolazine)

17. Rho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8. Ca 2+ PLC SR Ca 2+ Receptor Agonist Myosin Myosin-P Myosin phosphatase PIP 2 IP 3 MLCK VOCROC Ca 2+ Calmodulin Rho Rho kinase Fasudil

18. Metabolic modulation (pFOX): Trimetazidine O2 requirement of glucose pathway is lower than FFA pathway O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway FFA Glucose Acyl-CoA Acetyl-CoA Pyruvate Energy for contraction Myocytes β-oxidation Trimetazidine MacInnes A et al. Circ Res. 2003;93:e26-32. Lopaschuk GD et al. Circ Res. 2003;93:e33-7. Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45. pFOX = partial fatty acid oxidation FFA = free fatty acid

19. Preconditioning: Nicorandil Nitrate-associated effects Vasodilation of coronary epicardial arteries Activation of ATP-sensitive K + channels Ischemic preconditioning Dilation of coronary resistance arterioles IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J. 2004;6:e34. N O O NO 2 HN

20. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial

21. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial SA node AV node Common bundle Bundle branches Purkinje fibers

22. Sinus node inhibition: Ivabradine I f current is an inward Na+/K+ current that activates pacemaker cells of the SA node I f current is an inward Na+/K+ current that activates pacemaker cells of the SA node Ivabradine Ivabradine Selectively blocks I f in a current-dependent fashion Selectively blocks I f in a current-dependent fashion Reduces slope of diastolic depolarization, slowing HR Reduces slope of diastolic depolarization, slowing HR DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. 40 20 0 –20 –40 –60 0.5 Potential (mV) ControlIvabradine 0.3 µM Time (seconds) SA = sinoatrial

23. Sodium Current 0 Late Peak 0 Late Peak Sodium Current Na + ImpairedInactivationImpairedInactivation Ischemia Myocardial ischemia causes enhanced late INa Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

24. Late Na+ current inhibition: Ranolazine Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7. Myocardial ischemia  Late I Na Na + Overload Ca 2+ Overload Mechanical dysfunction  LV diastolic tension  Contractility Electrical dysfunction Arrhythmias Ranolazine

25. Understanding Angina at the Cellular Level Ischemia impairs cardiomyocyte sodium channel function Ischemia impairs cardiomyocyte sodium channel function Impaired sodium channel function leads to: Impaired sodium channel function leads to: Pathologic increased late sodium current Pathologic increased late sodium current Sodium overload Sodium overload Sodium-induced calcium overload Sodium-induced calcium overload Calcium overload causes diastolic relaxation failure, which: Calcium overload causes diastolic relaxation failure, which: Increases myocardial oxygen consumption Increases myocardial oxygen consumption Reduces myocardial blood flow and oxygen supply Reduces myocardial blood flow and oxygen supply Worsens ischemia and angina Worsens ischemia and angina Ranolazine Ischemia ↑ Late I Na Na + Overload Diastolic relaxation failure Extravascular compression Ca ++ Overload Chaitman BR. Circulation. 2006;113:2462-2472

26. Na+/Ca2+ overload and ischemia Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.  Late Na + current  Diastolic wall tension (stiffness) Intramural small vessel compression (  O 2 supply)  O 2 demand Na + overload Ca 2+ overload Myocardial ischemia

27. Ischaemia (  oxygen supply/  Demand)  late Na + current  Na + /Ca ++ exchange pump activation [Ca 2+ ] overload  Diastolic wall tension (stiffness)  Vascular compression  [Na + ] i Ranolazine

28. Ranolazine – hemodynamic affects No affect of Blood Pressure or Heart Rate No affect of Blood Pressure or Heart Rate Can be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates. Can be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates. Ranolazine has twin pronged action. Ranolazine has twin pronged action. 1. pFOX 2. Late Na inward entry blockade

29. Metabolic modulation (pFOX) and ranolazine Clinical trials showed ranolazine SR 500– 1000 mg bid (~2–6 µmol/L) reduced angina Clinical trials showed ranolazine SR 500– 1000 mg bid (~2–6 µmol/L) reduced angina Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition Ranolazine does not inhibit pFOX substantially at clinically relevant doses Ranolazine does not inhibit pFOX substantially at clinically relevant doses Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine MacInnes A et al. Circ Res. 2003;93:e26-32. Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83. Antzelevitch C et al. Circulation. 2004;110:904-10. pFOX = partial fatty acid oxidation

30. Ranolazine: Key concepts Ischemia is associated with ↑ Na+ entry into cardiac cells Ischemia is associated with ↑ Na+ entry into cardiac cells Na+ efflux by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload Na+ efflux by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload Ca2+ overload may cause electrical and mechanical dysfunction Ca2+ overload may cause electrical and mechanical dysfunction ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload Ranolazine reduces late INa Ranolazine reduces late INa Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.

31. Na+ and Ca2+ during ischemia and reperfusion Tani M and Neely JR. Circ Res. 1989;65:1045-56. Na + (μmol/g dry) Ca 2+ (μmol/g dry) Time (minutes) Rat heart model IschemiaReperfusion 90 60 30 0 12 8 4 0 0102030405060 Intracellular levels

32. Medication Class Impact on HR Impact on BP Physiologic Mechanism Beta Blockers Decrease pump function Calc Channel Blockers Decrease Pump function + Vaso- dilitation NitratesVaso-dilitation RanolazineOO Reduced Cardiac Stiffness Pharmacologic Classes for Treatment of Angina

33. Late Na+ accumulation causes LV dysfunction Fraser H et al. Eur Heart J. 2006. Isolated rat hearts treated with ATX-II, an enhancer of late I Na LV dP/dt (mm Hg/sec, in thousands) LV-dP/dt LV+dP/dt (-) (+) Time (minutes) ATX-II 12 nM (n = 13) ATX-II Ranolazine 8.6 µM (n = 6) Ranolazine 1020304050 -4 -3 -2 0 1 2 3 4 5 6

34. LV end diastolic pressure Baseline15304560 0 10 20 30 40 50 60 70 Vehicle (n = 10) Ranolazine 10 µM (n = 7) * * Reperfusion time (minutes) mm Hg LV -dP/dt (Relaxation) Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7. Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7. *P < 0.05 Vehicle Ranolazine Baseline30607590 -1000 -800 -600 -400 -200 0 * * * * mm Hg/sec Reperfusion time (minutes) Vehicle (n = 12) Ranolazine 5.4 µM (n = 9) Isolated rabbit hearts Late INa blockade - blunts experimental ischemic LV damage

35. Myocardial ischemia: Sites of action of anti-ischemic medication Consequences of ischemia Ca 2+ overload Electrical instability Myocardial dysfunction (↓systolic function/ ↑diastolic stiffness) Ischemia ↑ O 2 Demand Heart rate Blood pressure Preload Contractility ↓ O 2 Supply Development of ischemia Traditional anti-ischemic medications: β-blockers Nitrates Ca 2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006. Ranolazine

36. Summary Ischemic heart disease is a prevalent clinical condition Ischemic heart disease is a prevalent clinical condition Improved understanding of ischemia has prompted new therapeutic approaches Improved understanding of ischemia has prompted new therapeutic approaches Rho kinase inhibition Rho kinase inhibition Metabolic modulation Metabolic modulation Preconditioning Preconditioning Inhibition of I f and late INa currents Inhibition of I f and late INa currents

37. Summary Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects Mechanisms of action is complementary to traditional agents Mechanisms of action is complementary to traditional agents

38. Stable CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

39. ECG R Q T U P S mV + - P Wave Space QRS ST T PQ