Anginal pectoris refractory to standard medical therapy i

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  • Introduction of late I Na inhibitors has extended antianginal options for clinicians. Clinical experience to date with ranolazine, the first of this class to be approved, indicates that it has potential applications in a broad range of patients. Summary
  • Stable CAD: Multiple treatment options
  • Stable CAD: Multiple treatment options
  • While PCI relieves angina and improves exercise capacity in the short term, its long-term benefits are less certain. Its impact on disease progression and thromboembolic events is not known. In addition, PCI does not abolish the need for a second coronary revascularization procedure. What is the definitive role of PCI in chronic angina and stable CAD?
  • Stable CAD: Multiple treatment options
  • Michalsen et al randomized 101 patients with established CAD to a 1-year lifestyle intervention program (n = 48) or to a group that received printed lifestyle advice only (n = 53). The lifestyle intervention program began with a 3-day nonresidential retreat, followed by weekly 3-hour meetings for 10 weeks, and finally 2-hour meetings every other week for 9 months. Participants in the lifestyle intervention program received advice on the Mediterranean diet in one-on-one sessions, group discussions, and cooking classes. Regular exercise and increased daily physical activity were strongly recommended. Subjects in this group also practiced various relaxation techniques according to personal choice, including mediation, guided imagery, and yoga. They also practiced techniques to reduce cognitive and affective components of stress. SAFE-LIFE: Evaluation of intensive lifestyle intervention
  • The severity of chest pain (as assessed by the 6-point Likert scale) decreased by 31% in the lifestyle intervention group and by 13% in the advice-only group (P = 0.015). Frequency of angina attacks decreased by 54% in the lifestyle intervention group and increased by 11% in the advice-only group (P = 0.01). This study provides further evidence for inclusion of comprehensive lifestyle modification in a CV prevention program. SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention
  • Stable CAD: Multiple treatment options
  • Nitrates, beta-blockers, and calcium channel blockers (CCBs), the 3 major classes of antianginal/anti-ischemic agents, are the mainstay of angina treatment. However, many patients, particularly the elderly, cannot tolerate full doses of beta-blockers, calcium antagonists, or nitrates. Additionally, beta-blockers and many CCBs have similar (and, hence, additive) depressive effects on BP, heart rate, and atrioventricular conduction, limiting their use in combination to less-than-optimal doses. Chronic ischemic heart disease: Treatment gaps
  • Stable CAD: Multiple treatment options
  • The three main nonpharmacologic antianginal techniques currently under evaluation are enhanced external counterpulsation, transmyocardial revascularization, and spinal cord stimulation. They are generally reserved for refractory angina. EECP uses three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated then deflated. TMR involves the creation of channels in the myocardium with a laser. SCS uses an implanted device with an electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level. 1 Their mechanisms of action are not completely understood and a number of hypotheses have been proposed. Current nonpharmacologic antianginal strategies Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/ stable.pdf.
  • The three main nonpharmacologic antianginal techniques currently under evaluation are enhanced external counterpulsation, transmyocardial revascularization, and spinal cord stimulation. They are generally reserved for refractory angina. EECP uses three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated then deflated. TMR involves the creation of channels in the myocardium with a laser. SCS uses an implanted device with an electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level. 1 Their mechanisms of action are not completely understood and a number of hypotheses have been proposed. Current nonpharmacologic antianginal strategies Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/ stable.pdf.
  • Physical conditioning increases exercise duration and work capacity, prolonging time to angina. Exercise is associated with cardioprotective benefits beyond improvement in aerobic capacity alone. Molecular effects:  eNOS expression and activation  NAD(P)H expression and activity  AT 1 receptor expression  SOD expression Other effects  Intimal thickness  P selectin  VCAM-1  MCP-1  Ca 2+ in VSMC Potential cardioprotective benefits of exercise Functional effects: Vasculature  Endothelial function  Peripheral tone  Plasma volume  BP Myocardium  Vagal tone  HR  O 2 demand  Preconditioning Thrombosis  Fibrinolytic balance
  • The three main nonpharmacologic antianginal techniques currently under evaluation are enhanced external counterpulsation, transmyocardial revascularization, and spinal cord stimulation. They are generally reserved for refractory angina. EECP uses three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated then deflated. TMR involves the creation of channels in the myocardium with a laser. SCS uses an implanted device with an electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level. 1 Their mechanisms of action are not completely understood and a number of hypotheses have been proposed. Current nonpharmacologic antianginal strategies Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/ stable.pdf.
  • The role of Ca 2+ in activating myosin light chain kinase (MLCK) and phosphorylating myosin to cause contraction is well known. Dephosphorylation by myosin phosphatase causes subsequent dilation. More recently, the involvement of Rho kinase has been identified. In the absence of increases in intracellular Ca 2+ , Rho (a member of the Ras superfamily of small G proteins) activates Rho kinase, which in turn deactivates myosin phosphatase. This causes accumulation of phosphorylated myosin. Other abbreviations used in the figure: IP 3 = inositol triphosphate PIP 2 = phosphatidylinositol biphosphate PLC = phospholipase C ROC = receptor-operated channel SR = sarcoplasmic reticulum VOC = voltage-operated channel Rho kinase inhibition: Fasudil
  • The free fatty acid oxidation hypothesis arose out of advances in understanding of myocardial metabolic pathways. Myocardial cells derive their energy via fatty acid and glucose metabolism. During ischemia the fatty acid pathway predominates. However, this pathway requires more oxygen than the glucose pathway. 1 Theoretically, inhibition of fatty acid oxidation should promote a shift towards the more oxygen-efficient glucose pathway. Lopaschuk et al and Stanley have reported experimental data showing that the antianginal trimetazidine is an inhibitor of partial fatty acid oxidation (pFOX). However, MacInnes et al did not observe any inhibition with trimetazidine in other experimental models. Thus, inhibition of fatty acid oxidation as a major antianginal mechanism for trimetazidine remains to be definitively established. Metabolic modulation (pFOX): Trimetazidine Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al, for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol . 2004;43:1375-1382.
  • Nicorandil possesses a nitrate moiety and, therefore, produces hemodynamic effects similar to those of long-acting nitrates. It activates cyclic GMP (cGMP), dilates capacitance vessels, and decreases preload. Nicorandil is also capable of opening ATP-sensitive K + (K ATP ) channels. These channels are involved in dilation of coronary resistance arterioles, which decreases afterload, and are also thought to mimic ischemic preconditioning, a potential cardioprotective effect. Preconditioning: Nicorandil
  • Ivabradine selectively targets the Na + /K + current (I f current) in pacemaker cells of the sinoatrial node. Channels that carry the I f current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking I f blockers. 1 Sinus node inhibition: Ivabradine Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J . 2005;26:2529-2536.
  • Ivabradine selectively targets the Na + /K + current (I f current) in pacemaker cells of the sinoatrial node. Channels that carry the I f current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking I f blockers. 1 Sinus node inhibition: Ivabradine Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J . 2005;26:2529-2536.
  • Ivabradine selectively targets the Na + /K + current (I f current) in pacemaker cells of the sinoatrial node. Channels that carry the I f current are unique to the sinoatrial node, although ion channels in the retina have a similar structure and are probably the source of mild, transient visual disturbances in some patients taking I f blockers. 1 Sinus node inhibition: Ivabradine Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J . 2005;26:2529-2536.
  • Na + influx is controlled by a number of channels. The current flowing through voltage-gated Na + channels is responsible for the upstroke of the action potential. Activation of these channels permits Na + entry, with inactivation occurring a few milliseconds after. The channels remain closed and nonconducting throughout the plateau phase of the action potential. However, a small proportion of channels either do not close or close and then reopen. These channels allow a sustained current of Na + to enter. This current is referred to as the late Na + current to distinguish it from the peak current. Emerging data indicate that a number of pathologic diseases or conditions may be associated with a prolongation of the late Na + current. Among these pathologic diseases is myocardial ischemia. Accumulation of Na + secondary to enhanced late I Na leads to activation of the reverse mode of the Na + /Ca 2+ exchanger, with subsequent efflux of excess Na + and influx of Ca 2+ . Eventually, Ca 2+ overload of the cell results. Myocardial ischemia causes enhanced late I Na
  • Late Na + current inhibition: Ranolazine Myocardial ischemia is associated with ↑ Na + entry into cardiac cells. ↑ Na + activates the Na + /Ca 2+ exchanger, causing efflux of Na + and influx of Ca 2+ . ↑ Ca 2+ (Ca 2+ overload) may cause electrical and mechanical dysfunction. ↑ Late I Na is an important contributor to the Na + -dependent Ca 2+ overload. If the late Na + current is an important contributor to myocardial ischemia through Ca 2+ overload, then inhibition of this current with ranolazine will blunt the adverse effects of ischemia.
  • Ischemia is associated with disruptions in cellular sodium and calcium homeostasis. An enhanced late sodium current is likely to contribute to the sodium overload observed in ischemia. Late phase sodium channels have been shown to remain open longer in ischemic conditions. Sodium overload may result from decreased efflux and increased influx during ischemia, with greater intracellular accumulation of sodium as the duration of ischemia increases. This is followed by an increase in intracellular Calcium through the Na/Ca exchanger on the myocyte wall. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258. Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464.
  • It is proposed that Na + -related Ca 2+ overload mediates a vicious cycle of ischemia begetting more ischemia. Ca 2+ overload may result in increased left ventricular diastolic tension. As a result, myocardial O 2 consumption increases and intramural small vessels are compressed, causing increased O 2 demand and decreased O 2 supply, respectively. Positive feedback during ischemia increases the imbalance between myocardial oxygen supply and demand. Na + /Ca 2+ overload and ischemia
  • MacInnnes et al reported experimental data demonstrating that ranolazine partially inhibits fatty acid oxidation in a dose-dependent manner. At a concentration of 100 µmol/L, they observed 12% inhibition of oxidation. This concentration is substantially greater than the concentration achieved in humans at currently recommended doses (~2–6 μ mol/L). Thus, inhibition of fatty acid oxidation is not a major antianginal mechanism for ranolazine. An alternative mechanism has been proposed and will be discussed in later slides. Metabolic modulation (pFOX) and ranolazine
  • Ranolazine: Key concepts In summary, experimental data suggest that inhibition of the late Na + current blunts the adverse effects of ischemia.
  • Tani and Neely measured ion fluxes in isolated rat hearts. Global ischemia was induced for 30 minutes and was followed by 30 minutes of aerobic perfusion. Na + levels rose during ischemia and the first 2 minutes of reperfusion. Reperfusion also resulted in a 16-fold increase in Ca 2+ . The rate of Ca 2+ intake during reperfusion was linearly correlated with elevated diastolic pressure, reduced developed pressure, and decreased recovery of ventricular function. Data suggest that Ca 2+ influx and Na + efflux are mediated by the Na + /Ca 2+ exchanger. 1 Na + and Ca 2+ during ischemia and reperfusion Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: A potential drug target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J Suppl . 2004;6(suppl I):I3-I7.
  • The sea anemone toxin ATX-II enhances late I Na . Exposure of isolated rat hearts to this toxin results in adverse changes in peak LV +dP/dt and LV –dP/dt. When ranolazine was coadministered, this effect was virtually abolished. This finding implicates enhancement of late I Na in the adverse consequences of ischemia/reperfusion. Late Na + accumulation causes LV dysfunction
  • Experimental data suggest that late I Na blockade blunts post-ischemic contractile abnormalities. Isolated rabbit hearts were exposed to 30 minutes of ischemia followed by 60 minutes of reperfusion. Pretreatment with ranolazine 10 minutes prior to ischemia and reperfusion blunted the increase in left ventricular end diastolic pressure and the increase in rate of pressure development (dP/dt) in isolated rabbit hearts. Late I Na blockade blunts experimental ischemic LV damage
  • Ranolazine, in contrast to older antianginal medications, appears to work downstream of the ischemic insult, complementing traditional medications’ mechanism of action. Myocardial ischemia: Sites of action of anti-ischemic medication
  • Ischemic heart disease and associated symptoms continue to present a major public health challenge. A number of new therapeutic approaches are under investigation, including Rho kinase inhibition Metabolic modulation Preconditioning via K + channel activation Inhibition of I f and late I Na currents Two of these approaches (late I Na inhibition and inhibition of fatty acid oxidation) reduce angina with minimal or no pathophysiologic effects. Thus, they are potentially complementary to traditional medications ( beta-blockers, calcium channel blockers, and nitrates). Summary
  • Ischemic heart disease and associated symptoms continue to present a major public health challenge. A number of new therapeutic approaches are under investigation, including Rho kinase inhibition Metabolic modulation Preconditioning via K + channel activation Inhibition of I f and late I Na currents Two of these approaches (late I Na inhibition and inhibition of fatty acid oxidation) reduce angina with minimal or no pathophysiologic effects. Thus, they are potentially complementary to traditional medications ( beta-blockers, calcium channel blockers, and nitrates). Summary
  • Stable CAD: Multiple treatment options
  • Anginal pectoris refractory to standard medical therapy i

    1. 1. Refractory angina: The scope for ranolazine. Dr. B. K. Iyer
    2. 2. Chronic / Refractory angina <ul><li>What is this condition? </li></ul><ul><li>It is the disabling chest pain that persists </li></ul><ul><ul><li>Despite lifestyle adjustment and </li></ul></ul><ul><ul><li>Despite optimal medical therapy and </li></ul></ul><ul><ul><li>Despite invasive coronary interventions. </li></ul></ul>
    3. 3. Correlation - symptom severity and ischaemic burden <ul><li>1. Pain out of proportion to ischaemia </li></ul><ul><ul><li>20% of patients undergoing angiography because of angina have normal coronary arteries </li></ul></ul><ul><li>2. Ischaemia with no pain </li></ul><ul><ul><li>70% ischaemic episodes in the community are silent </li></ul></ul><ul><ul><li>25% of infarcts are silent </li></ul></ul><ul><li>3. No significant differences in objective measures of ischaemia between patients with angina and silent ischaemics </li></ul><ul><ul><li>Klein et al. Circulation 1994;89:1958-66 </li></ul></ul><ul><ul><li>See also Warren J. NEJMS 1812;1:1-11 </li></ul></ul>
    4. 4. Correlation - anxiety and ischaemic burden ‘ Angina is damaging my heart ’ Restricted lifestyle Increasing anxiety, depression Reduced activity Deconditioning Worsening symptoms at lower thresholds
    5. 5. Correlation – doctor’s demands and patient expectations I have this new operative approach that will help you Why don’t we ask him what he wants? How about EECP & angiogenesis? Thanks Doc; but once is enough. Any new medicines? The patient-centered approach
    6. 6. Angina Pectoris - Understanding the options when Standard Therapy Fails Dr. B. K. Iyer
    7. 7. Basis <ul><li>Patients experience angina despite medical therapy & / or revascularization </li></ul><ul><li>Clinical variations in broad range of patients unresponsive to current treatment options </li></ul><ul><ul><li>Elderly </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>LV dysfunction or heart failure </li></ul></ul><ul><li>Late Na + blockade is a potentially effective new antianginal option with a mechanism of action complementary to traditional agents </li></ul>
    8. 8. CAD: Multiple treatment options Reduce symptoms Treat underlying disease Lifestyle intervention Alternative TX Medical therapy PCI & CABG
    9. 9. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
    10. 10. Invasive Treatment of CAD <ul><li>Acute Coronary Syndrome and Acute MI </li></ul><ul><ul><li>Aggressive treatment unquestionably shown to save lives and reduce future MIs. </li></ul></ul><ul><li>Stable Angina Pectoris </li></ul><ul><ul><li>What is the role of Coronary Revascularization ? </li></ul></ul><ul><li>CABG is better than Medical Therapy for </li></ul><ul><ul><li>3 vessel disease </li></ul></ul><ul><ul><li>CAD that involves Prox LAD (European Coronary Surgery Study) </li></ul></ul><ul><ul><li>3 vessel CAD with low EF (CASS) </li></ul></ul>
    11. 11. PCI in chronic angina and stable CAD <ul><li>PCI improves angina and exercise capacity </li></ul><ul><li>However, compared to optimal medical therapy, does PCI </li></ul><ul><ul><li>Prolong survival? </li></ul></ul><ul><ul><li>Reduce risk of subsequent MI? </li></ul></ul><ul><ul><li>Reduce hospitalization for unstable angina? </li></ul></ul><ul><ul><li>Decrease need for subsequent CABG? </li></ul></ul><ul><ul><li>Improve quality of life? </li></ul></ul>
    12. 12. 55 yr old female with stable angina
    13. 13. Revascularization for Stable CAD <ul><li>Acute Coronary Syndrome and Acute MI </li></ul><ul><ul><li>Clearly shown to improve survival </li></ul></ul><ul><li>Chronic Stable Angina </li></ul><ul><ul><li>Goal may be to just reduce symptoms and improve quality of life </li></ul></ul><ul><li>1 year after PCI or CABG </li></ul><ul><ul><li>25 to 60% of patients still have ongoing angina </li></ul></ul><ul><li>Many patients are deemed “inoperable” </li></ul><ul><ul><li>Condition not suitable for PCI or CABG </li></ul></ul><ul><ul><li>Co-morbidities make procedure too high risk </li></ul></ul>Benefit Risk
    14. 14. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
    15. 15. SAFE-LIFE: Evaluation of intensive lifestyle intervention Michalsen A et al. Am Heart J. 2006;151:870-7. Advice on Mediterranean diet Stress management ≥30 min daily Encouraged to  physical activity 3-day nonresidential retreat Weekly 3-hr meetings x 10 weeks Biweekly 2-hr meetings x 9 months Control group received printed lifestyle advice only N = 101 with CAD
    16. 16. SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention Michalsen A et al. Am Heart J. 2006;151:870-7. P = 0.015 P = 0.01
    17. 17. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
    18. 18. Chronic CAD – Conventional Medical therapy <ul><li>Decrease Myocardial Oxygen demand </li></ul><ul><ul><li>Decrease in HR (Beta blockers and some Calcium Channel Blockers) </li></ul></ul><ul><ul><li>Decrease in Myocardial Contractility (BB and some CCBs) </li></ul></ul><ul><li>Increase Oxygen supply </li></ul><ul><ul><li>Long Acting Nitrates </li></ul></ul><ul><ul><li>Calcium Channel Blockers </li></ul></ul>
    19. 19. Chronic ischemic heart disease: Treatment gaps <ul><li>Many patients have relative intolerances to maximum doses of traditional antianginal agents (  -blockers, CCBs, and nitrates) </li></ul><ul><li>Antianginal drugs without these limitations are needed </li></ul><ul><li>Patients continue to experience myocardial ischemia </li></ul><ul><li> -blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects </li></ul>
    20. 20. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
    21. 21. Current antianginal strategies Current anti-anginal strategies Non pharmacologic Pharmacologic Trimetazidine Fasudil Nicorandil Ivabradine Ranolazine Exercise training EECP Chelation therapy SCS TMR
    22. 22. <ul><li>Exercise Training </li></ul><ul><li>Enhanced external counterpulsation (EECP) </li></ul><ul><ul><li> Endothelial function </li></ul></ul><ul><ul><li>Promotes coronary collateral formation </li></ul></ul><ul><ul><li> Peripheral vascular resistance </li></ul></ul><ul><ul><li> Ventricular function </li></ul></ul><ul><ul><li>Placebo effect </li></ul></ul><ul><li>Chelation therapy </li></ul>Current nonpharmacologic antianginal strategies <ul><li>Transmyocardial revascularization (TMR) </li></ul><ul><ul><li>Sympathetic denervation </li></ul></ul><ul><ul><li>Angiogenesis </li></ul></ul><ul><li>Spinal cord stimulation (SCS) </li></ul><ul><ul><li> Neurotransmission of painful stimuli </li></ul></ul><ul><ul><li> Release of endogenous opiates </li></ul></ul><ul><ul><li>Redistributes myocardial blood flow to ischemic areas </li></ul></ul>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.
    23. 23. 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 Vasculature Thrombosis Myocardium
    24. 24. EECP - Enhanced External CounterPulsation <ul><li>External, pneumatic compression of lower extremities in diastole. </li></ul>
    25. 25. EECP - Enhanced External CounterPulsation
    26. 26. EECP - Enhanced External CounterPulsation <ul><li>Sequential inflation of cuffs </li></ul><ul><li>Retrograde aortic pressure wave </li></ul><ul><li>Increased Coronary perfusion pressure </li></ul><ul><li>Increased Venous Return </li></ul><ul><li>Increased Preload </li></ul><ul><li>Increased Cardiac Output </li></ul><ul><li>Simultaneous deflation of cuffs in late Diastole </li></ul><ul><li>Lowers Systemic Vascular Resistance </li></ul><ul><li>Reduced Preload </li></ul><ul><li>Decreased Cardiac workload </li></ul><ul><li>Decreased Oxygen Consumption </li></ul>
    27. 27. EECP - Enhanced External CounterPulsation <ul><li>35 total treatments </li></ul><ul><ul><li>5 days per week x 7 weeks </li></ul></ul><ul><ul><li>1 hour per day </li></ul></ul><ul><li>Appears to reduce severity of Angina </li></ul><ul><li>Not shown to improve survival or reduce myocardial infarctions </li></ul><ul><li>Indicated for CAD not amenable to revascularization </li></ul><ul><ul><li>Anatomy not amenable to procedures </li></ul></ul><ul><ul><li>High risk co-morbidities with excessive risk </li></ul></ul><ul><li>May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication. </li></ul>
    28. 28. EECP – Contraindications & Precautions <ul><li>Arrhythmias that interfere with machine triggering </li></ul><ul><li>Bleeding diathesis </li></ul><ul><li>Active thrombophlebitis & severe lower extremity vaso-occlusive disease </li></ul><ul><li>Presence of significant AAA </li></ul><ul><li>Pregnancy </li></ul>
    29. 29. TMLR - Transmyocardial Laser Revascularization <ul><li>High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow </li></ul><ul><li>Possible explanations for effect </li></ul><ul><ul><li>Myocardial angiogenesis </li></ul></ul><ul><ul><li>Myocardial denervation </li></ul></ul><ul><ul><li>Myocardial fibrosis with secondary favorable remodeling </li></ul></ul>
    30. 30. TMLR – Direct Trial <ul><li>Only major blinded study </li></ul><ul><ul><li>298 pts with low dose, high dose, or no laser channels </li></ul></ul><ul><li>No benefit to TMLR vs Med therapy to </li></ul><ul><ul><li>Patient survival </li></ul></ul><ul><ul><li>Angina class </li></ul></ul><ul><ul><li>Quality of life assessment </li></ul></ul><ul><ul><li>Exercise duration </li></ul></ul><ul><ul><li>Nuclear perfusion imaging </li></ul></ul><ul><ul><li>Leon MB, et al. JACC 2005; 46:1812 </li></ul></ul><ul><li>High Surgical Risk (Mortality 5%) </li></ul><ul><li>Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed. </li></ul>
    31. 31. Chelation Therapy <ul><li>IV EDTA infusions </li></ul><ul><ul><li>30 treatments over about 3 months </li></ul></ul><ul><ul><li>Cost – about $3,000 </li></ul></ul><ul><ul><li>Aggressive marketing by 500 to 1000 physicians offering this treatment </li></ul></ul><ul><ul><li>PLACEBO effect only </li></ul></ul><ul><li>Claimed pathophysiologic effects </li></ul><ul><ul><li>Liberation of Calcium in plaque </li></ul></ul><ul><ul><li>Lower LDL, VLDL, and Iron stores </li></ul></ul><ul><ul><li>Inhibit platelet aggregation </li></ul></ul><ul><ul><li>Relax vasomotor tone </li></ul></ul><ul><ul><li>Scavenge “free radicals” </li></ul></ul>
    32. 32. Spinal Cord Stimulation Stimulation typically administered for 1-2 hrs tid Therapeutic mechanism appears to be alteration of anginal pain perception power source conducting wires electrodes at stimulation site
    33. 33. 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)
    34. 34. 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
    35. 35. Current pharmacologic antianginal strategies <ul><li>New mechanistic approaches to angina </li></ul><ul><ul><li>Rho kinase inhibition ( fasudil ) </li></ul></ul><ul><ul><li>Metabolic modulation ( trimetazidine ) </li></ul></ul><ul><ul><li>Preconditioning ( nicorandil ) </li></ul></ul><ul><ul><li>Sinus node inhibition ( ivabradine ) </li></ul></ul><ul><ul><li>Late Na+ current inhibition ( ranolazine ) </li></ul></ul>
    36. 36. Rho kinase inhibition: Fasudil <ul><li>Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin </li></ul>Adapted from Seasholtz TM. Am J Physiol Cell Physiol . 2003;284:C596-8. Ca 2+ Ca 2+ PLC SR Ca 2+ Receptor Agonist Myosin Myosin-P Myosin phosphatase PIP 2 IP 3 MLCK VOC ROC Ca 2+ Calmodulin Rho Rho kinase Fasudil
    37. 37. Metabolic modulation (pFOX): Trimetazidine <ul><li>O2 requirement of glucose pathway is lower than FFA pathway </li></ul><ul><li>During ischemia, oxidized FFA levels rise, blunting the glucose pathway </li></ul>FFA Glucose Acyl-CoA Acetyl-CoA Pyruvate Energy for contraction Myocytes β -oxidation 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 Trimetazidine
    38. 38. Preconditioning: Nicorandil <ul><li>Nitrate-associated effects </li></ul><ul><li>Vasodilation of coronary epicardial arteries </li></ul><ul><li>Activation of ATP-sensitive K + channels </li></ul><ul><li>Ischemic preconditioning </li></ul><ul><li>Dilation of coronary resistance arterioles </li></ul>IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J . 2004;6:e34. N O O NO 2 HN
    39. 39. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial
    40. 40. 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
    41. 41. Sinus node inhibition: Ivabradine <ul><li>I f current is an inward Na+/K+ current that activates pacemaker cells of the SA node </li></ul><ul><li>Ivabradine </li></ul><ul><ul><li>Selectively blocks I f in a current-dependent fashion </li></ul></ul><ul><ul><li>Reduces slope of diastolic depolarization, slowing HR </li></ul></ul>DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. 40 20 0 – 20 – 40 – 60 0.5 Potential (mV) Control Ivabradine 0.3 µM Time (seconds) SA = sinoatrial
    42. 42. Myocardial ischemia causes enhanced late INa Na + Impaired Inactivation Na + Ischemia 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. Sodium Current 0 Late Peak 0 Late Peak Sodium Current
    43. 43. 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
    44. 44. Understanding Angina at the Cellular Level <ul><li>Ischemia impairs cardiomyocyte sodium channel function </li></ul><ul><li>Impaired sodium channel function leads to: </li></ul><ul><ul><li>Pathologic increased late sodium current </li></ul></ul><ul><ul><li>Sodium overload </li></ul></ul><ul><ul><li>Sodium-induced calcium overload </li></ul></ul><ul><li>Calcium overload causes diastolic relaxation failure, which: </li></ul><ul><ul><li>Increases myocardial oxygen consumption </li></ul></ul><ul><ul><li>Reduces myocardial blood flow and oxygen supply </li></ul></ul><ul><ul><li>Worsens ischemia and angina </li></ul></ul>Ischemia ↑ Late I Na Na + Overload Diastolic relaxation failure Extravascular compression Ca ++ Overload Chaitman BR. Circulation. 2006;113:2462-2472 Ranolazine
    45. 45. 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
    46. 46. Ranolazine Ischaemia (  oxygen supply/  Demand) <ul><li> late Na + current </li></ul><ul><li> Na + /Ca ++ exchange pump activation </li></ul>[Ca 2+ ] overload  Diastolic wall tension (stiffness)  Vascular compression  [Na + ] i
    47. 47. Ranolazine – hemodynamic affects <ul><li>No affect of Blood Pressure or Heart Rate </li></ul><ul><li>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. </li></ul><ul><li>Ranolazine has twin pronged action. </li></ul><ul><ul><li>pFOX </li></ul></ul><ul><ul><li>Late Na inward entry blockade </li></ul></ul>
    48. 48. Metabolic modulation (pFOX) and ranolazine <ul><li>Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina </li></ul><ul><li>Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition </li></ul><ul><ul><li>Ranolazine does not inhibit pFOX substantially at clinically relevant doses </li></ul></ul><ul><li>Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine </li></ul>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
    49. 49. Ranolazine: Key concepts <ul><li>Ischemia is associated with ↑ Na+ entry into cardiac cells </li></ul><ul><ul><li>Na+ efflux by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload </li></ul></ul><ul><ul><li>Ca2+ overload may cause electrical and mechanical dysfunction </li></ul></ul><ul><li>↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload </li></ul><ul><li>Ranolazine reduces late INa </li></ul>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.
    50. 50. Na+ and Ca2+ during ischemia and reperfusion Tani M and Neely JR. Circ Res. 1989;65:1045-56. Na + ( μ mol/g dry) Ca 2+ ( μ mol/g dry) Time (minutes) Rat heart model Intracellular levels Ischemia Reperfusion 90 60 30 0 12 8 4 0 0 10 20 30 40 50 60
    51. 51. Pharmacologic Classes for Treatment of Angina Reduced Cardiac Stiffness O O Ranolazine Vaso-dilitation Nitrates Decrease Pump function + Vaso-dilitation Calc Channel Blockers Decrease pump function Beta Blockers Physiologic Mechanism Impact on BP Impact on HR Medication Class
    52. 52. 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 -4 -3 -2 -1 0 1 2 3 4 5 6 10 20 30 40 50
    53. 53. Late INa blockade - blunts experimental ischemic LV damage LV end diastolic pressure Baseline 15 30 45 60 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 Baseline 30 60 75 90 -1000 -800 -600 -400 -200 0 * * * * mm Hg/sec Reperfusion time (minutes) Vehicle (n = 12) Ranolazine 5.4 µM (n = 9) Isolated rabbit hearts
    54. 54. Myocardial ischemia: Sites of action of anti-ischemic medication Ca 2+ overload Electrical instability Myocardial dysfunction ( ↓ systolic function/ ↑ diastolic stiffness) ↑ O 2 Demand Heart rate Blood pressure Preload Contractility ↓ O 2 Supply Traditional anti-ischemic medications: β -blockers Nitrates Ca 2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006. Consequences of ischemia Ischemia Development of ischemia Ranolazine
    55. 55. Summary <ul><li>Ischemic heart disease is a prevalent clinical condition </li></ul><ul><li>Improved understanding of ischemia has prompted new therapeutic approaches </li></ul><ul><ul><li>Rho kinase inhibition </li></ul></ul><ul><ul><li>Metabolic modulation </li></ul></ul><ul><ul><li>Preconditioning </li></ul></ul><ul><ul><li>Inhibition of I f and late INa currents </li></ul></ul>
    56. 56. Summary <ul><li>Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects </li></ul><ul><ul><li>Mechanisms of action is complementary to traditional agents </li></ul></ul>
    57. 57. Stable CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
    58. 58. ECG R Q T U P S mV + - P Wave Space QRS ST T PQ

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