1. New Mechanistic Approaches to Myocardial Ischemia

2. New mechanistic approaches to myocardial ischemia Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) Sinus node inhibition (ivabradine) Late Na + current inhibition (ranolazine)

3. Rho kinase inhibition: Fasudil Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8. Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin 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

4. Metabolic modulation (pFOX): Trimetazidine O 2 requirement of glucose pathway is lower than FFA 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

5. Metabolic modulation (pFOX) and ranolazine 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 –Ranolazine does not inhibit pFOX at clinically relevant doses Inhibition of fatty acid oxidation does not appear to be 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

6. 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

7. Sinus node inhibition: Ivabradine I f current is an inward Na + /K + current that activates pacemaker cells of the SA node Ivabradine –Selectively blocks I f in a current-dependent fashion –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

8. 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

9. Na + and Ca 2+ 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

10. Sodium Current 0 Late Peak 0 Late Peak Sodium Current Na + ImpairedInactivationImpairedInactivation Ischemia Myocardial ischemia causes enhanced late I Na 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.

11. 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

12. Na + /Ca 2+ 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

13. 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 I Na blockade blunts experimental ischemic LV damage

14. Ranolazine: Key concepts Ischemia is associated with ↑ Na + entry into cardiac cells – Na + efflux in recovery by Na + /Ca 2+ exchange results in ↑ cellular [Ca 2+ ] i and eventual Ca 2+ overload – Ca 2+ overload may cause electrical and mechanical dysfunction ↑ Late I Na is an important contributor to the [Na + ] i - dependent Ca 2+ overload Ranolazine reduces late I Na 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.

15. 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

16. Summary Ischemic heart disease is a prevalent clinical condition Improved understanding of ischemia has prompted new therapeutic approaches –Rho kinase inhibition –Metabolic modulation –Preconditioning –Inhibition of I f and late I Na currents Late I Na inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects –Mechanisms of action are complementary to traditional agents