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Current anti- anginal therapy

Current anti- anginal therapy. TMR. EECP. Chelation therapy. Exercise training. SCS. Fasudil. Nicorandil. Trimetazidine. Ivabradine. Ranolazine. Current antianginal strategies. Non pharmacologic. Current anti-anginal strategies. Pharmacologic. Exercise Training

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Current anti- anginal therapy

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  1. Current anti-anginal therapy

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

  3. Exercise Training Enhanced external counterpulsation (EECP)  Endothelial function Promotes coronary collateral formation  Peripheral vascular resistance  Ventricular function Placebo effect Chelation therapy 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 Current nonpharmacologic antianginal strategies 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 NO production ROS generation ROS scavenging Other mechanisms Vasculature Myocardium Thrombosis 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.

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

  6. EECP - Enhanced External CounterPulsation

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

  8. EECP - Enhanced External CounterPulsation • 35 total treatments • 5 days per week x 7 weeks • 1 hour per day • Appears to reduce severity of Angina • Not shown to improve survival or reduce myocardial infarctions • Indicated for CAD not amenable to revascularization • Anatomy not amenable to procedures • High risk co-morbidities with excessive risk • 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 • Bleeding diathesis • Active thrombophlebitis & severe lower extremity vaso-occlusive disease • Presence of significant AAA • Pregnancy

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

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

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

  13. power source conducting wires electrodes at stimulation site Spinal Cord Stimulation 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 * p<0.0001 * * * * * * * Episodes/wk (DiPede, et al. AJC 2003;91:951)

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

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

  17. Rho Fasudil Rho kinase Rho kinase inhibition: Fasudil • 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.

  18. Trimetazidine Metabolic modulation (pFOX): Trimetazidine • O2 requirement of glucose pathway is lower than FFA pathway • During ischemia, oxidized FFA levels rise, blunting the glucose pathway Myocytes Glucose FFA Acyl-CoA Pyruvate β-oxidation Acetyl-CoA Energy for contraction pFOX = partial fatty acid oxidation FFA = free fatty acid 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.

  19. 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.

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

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

  22. Sinus node inhibition: Ivabradine • 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 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.

  23. 0 0 SodiumCurrent Late SodiumCurrent Late Peak Peak Myocardial ischemia causes enhanced late INa Ischemia Na+ 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.

  24. Ranolazine Late Na+ current inhibition: 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.

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

  26. 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.

  27. Ranolazine Ischaemia ( oxygen supply/ Demand)  Vascular compression •  late Na+ current • Na+/Ca++ exchange pump activation  Diastolic wall tension (stiffness)  [Na+]i [Ca2+] overload

  28. Ranolazine – hemodynamic affects • 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. • Ranolazine has twin pronged action. • pFOX • 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 • Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition • Ranolazine does not inhibit pFOX substantially at clinically relevant doses • 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 • Na+ efflux 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.

  31. Ischemia Reperfusion 90 60 30 0 12 8 4 0 0 10 20 30 40 50 60 Na+ and Ca2+ during ischemia and reperfusion 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.

  32. Pharmacologic Classes for Treatment of Angina

  33. 10 20 30 40 50 Late Na+ accumulation causes LV dysfunction 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.

  34. 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 *P < 0.05 Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7. Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.

  35. Development of ischemia Consequences of ischemia Ischemia Ranolazine Myocardial ischemia: Sites of action of anti-ischemic medication ↑ 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.

  36. 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

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

  38. Stable CAD: Multiple treatment options Lifestyle intervention Medicaltherapy Reduce symptomsTreat underlying disease Alternative TX PCI & CABG

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

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