New Mechanistic Approaches to Myocardial Ischemia

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 Rho Fasudil Rho kinase Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Agonist Ca2+ Ca2+ Receptor PLC PIP2 VOC ROC IP3 SR Ca2+ Myosin Myosin phosphatase MLCK Ca2+ Myosin-P Calmodulin Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.

4. O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway Metabolic modulation (pFOX): Trimetazidine Myocytes Glucose FFA Acyl-CoA Pyruvate β-oxidation Trimetazidine Acetyl-CoA Energy for contraction 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 • Activation of ATP-sensitive K+ channels • Ischemic preconditioning • Dilation of coronary resistance arterioles O N HN NO2 O • Nitrate-associated effects • Vasodilation of coronary epicardial arteries IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J. 2004;6:e34.

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

8. Late Na+ current inhibition: Ranolazine Ranolazine Myocardial ischemia Late INa Na+ Overload Ca2+ Overload Mechanical dysfunctionLV diastolic tensionContractility Electrical dysfunctionArrhythmias 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.

9. Na+ and Ca2+ duringischemia and reperfusion Ischemia Reperfusion 90 60 30 0 12 8 4 0 0 10 20 30 40 50 60 Rat heart model Intracellular levels Na+ (μmol/g dry) Ca2+ (μmol/g dry) Time (minutes) Tani M and Neely JR. Circ Res. 1989;65:1045-56.

10. Myocardial ischemia causes enhanced late INa 0 SodiumCurrent Late Peak 0 Ischemia SodiumCurrent Late Na+ Peak Impaired Inactivation 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 10 20 30 40 50 Isolated rat hearts treated with ATX-II, an enhancer of late INa 6 LV+dP/dt 5 (+) Ranolazine 8.6 µM(n = 6) 4 3 LV dP/dt(mm Hg/sec, in thousands) 2 Ranolazine ATX-II 12 nM(n = 13) ATX-II 1 0 -1 -2 LV-dP/dt (-) -3 -4 Time (minutes) Fraser H et al. Eur Heart J. 2006.

12. Na+/Ca2+ overload and ischemia Myocardial ischemia Intramural small vessel compression( O2 supply) O2 demand Late Na+ current Na+ overload Diastolic wall tension (stiffness) Ca2+ overload Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.

13. Late INa blockade blunts experimental ischemic LV damage Isolated rabbit hearts LV -dP/dt (Relaxation) LV end diastolic pressure Baseline 30 60 75 90 70 0 60 -200 * 50 40 -400 mm Hg mm Hg/sec 30 * * -600 20 -800 * 10 * * -1000 0 Baseline 15 30 45 60 Reperfusion time (minutes) Reperfusion time (minutes) Vehicle (n = 12) Vehicle (n = 10) Ranolazine 5.4 µM (n = 9) Ranolazine 10 µM (n = 7) Vehicle Ranolazine 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

14. Ranolazine: Key concepts • Ischemia is associated with ↑ Na+ entry into cardiac cells – Na+ efflux in recovery by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload – Ca2+ overload may cause electrical and mechanical dysfunction • ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload • 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.

15. Myocardial ischemia: Sites of action of anti-ischemic medication Development of ischemia Consequences of ischemia Ischemia Ranolazine ↑ O2 Demand Heart rate Blood pressure Preload Contractility ↓ O2 Supply Ca2+ overload Electrical instability Myocardial dysfunction(↓systolic function/ ↑diastolic stiffness) Traditional anti-ischemic medications: β-blockers Nitrates Ca2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

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 If and late INa currents • Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects • Mechanisms of action are complementary to traditional agents