1 / 16

New Mechanistic Approaches to Myocardial Ischemia

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

Télécharger la présentation

New Mechanistic Approaches to Myocardial Ischemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related