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Dr Julian Johny Thottian INTRODUCTION Chronic angina is a condition that impairs quality of life and is associated with decreased life expectancy Cardiac metabolism- LCFAs are the major source of energy (80%) and Glucose (20%) in aerobic conditions. In fetus , the main source of energy is glucose and shift to FFA is in the early post natal period. Cardiac metabolism Current therapies that reduce angina frequency and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include : Drugs :Nitrates, β-blockers, Calcium antagonist Exercise conditioning Enhanced External Counterpulsation Coronary revascularization Current antianginal strategies TMR EECP Exercise training Non pharmacologic Chelation therapy SCS Current anti-anginal strategies Fasudil Pharmacologic Trimetazidine Nicorandil Ivabradine Ranolazine Consequences associated with dysfunction of late sodium current • Diseases (eg, ischemia, heart failure) Na+ channel • Pathological milieu (Gating (reactive O2 species, mechanism ischemic metabolites) malfunction) • Toxins and drugs (eg, ATX-II, etc.) Mechanical dysfunction • Abnormal contraction and relaxation • ↑ diastolic tension (↑LV wall stiffness) Oxygen supply and demand • Increase ATP consumption • Decrease ATP formation Electrical instability • Early after potentials • Beat-to-beat ΔAPD • Arrhythmias (VT) Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply Increased myocardial tension during diastole: Increases myocardial O2 consumption Compresses intramural small vessels Reduces myocardial blood flow Worsens ischemia and angina Advances 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 Ranolazine (N-(2,6-dimethyphenyl)-4-[2-hydroxy-3(2-methoxyphenoxy)-propyl]-1-piperazineacetamide) is a substituted piperazine compound. pFOX inhibitor -that ranolazine only inhibits fattyacid oxidation during the periods of elevated plasma FFA levels associated with myocardial ischaemia Late sodium current blocker Understanding Angina at the Cellular Level Ischemia ↑ Late INa Ranolazine Na+ Overload Ca++ Overload Diastolic relaxation failure Extravascular compression Chaitman BR. Circulation. 2006;113:2462-2472 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 Na+/Ca2+ overload and ischemia Myocardial ischemia Intramural small vessel compression ( O2 supply) Late Na+ current O2 demand Na+ overload Diastolic wall tension (stiffness) Ca2+ overload Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13. Myocardial ischemia causes enhanced late INa 0 Sodium Current Ischemia Late 0 Sodium Current Late Na+ Peak 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. 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. 1. 2. pFOX Late Na inward entry blockade 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 pFOX = partial fatty acid oxidation 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. Pharmacologic Classes for Treatment of Angina Medication Class Beta Blockers Calc Channel Blockers Nitrates Ranolazine Impact Impact Physiologic on HR on BP Mechanism Decrease pump function Decrease Pump function + Vasodilitation Vaso-dilitation O O Reduced Cardiac Stiffness Myocardial ischemia: Sites of action of anti-ischemic medication Development of ischemia ↑ O2 Demand Heart rate Blood pressure Preload Contractility ↓ O2 Supply Traditional anti-ischemic medications: β-blockers Nitrates Ca2+ blockers Consequences of ischemia Ischemia Ca2+ overload Electrical instability Myocardial dysfunction (↓systolic function/ ↑diastolic stiffness) Ranolazine Courtesy of PH Stone, MD and BR Chaitman, MD. 2006. 3 ranolazine trials Baseline characterstics NO MUCH BENEFIT IN ACS Contraindications Ranolazine is known to increase the QT interval on the electrocardiogram. Mean increase in the corrected QT interval (QTc) is approximately 6 msec, about 5% of individuals may have QTc prolongations of 15 msec or longer. (MARISA) It blocks Ikr and hence prolongs the QT interval. Clinical experience in coronary syndrome population did not show an increased risk of proarrhythmia or sudden death Strong CYP3A4 inhibitors and drug that interact with P glycoprotein Contd… Used with caution with other CYP3A4 inhibitors and also drugs that prolong QT. INTERACTS with Digoxin , simvastatin ,cyclosporine, diltiazem, verapamil, ketoconazole, macrolides , grape fruit juice Other beneficial effects US FDA has granted permission for- HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits according to the results of MERLIN TIMI 36 trial. Uses in heart failure and neuropathic pain are being studied extensively. Side effects The most common adverse events that led to discontinuation placebo were Dizziness (1.3% versus 0.1%) Nausea (1% versus 0%) Asthenia, Constipation Headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. Conclusions from CARISA MARISA & ERICA Sinus node inhibition: Ivabradine SA node AV node Common bundle Bundle branches Purkinje fibers IVABRADINE DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. Sinus node inhibition: Ivabradine Control Ivabradine 0.3 µM 40 20 0 –20 –40 –60 Potential (mV) 0.5 If current is an inward Na+/K+ current that activates pacemaker Time cells of the SA node (seconds) Ivabradine Selectively blocks If in a current-dependent fashion Reduces slope of depolarization, slowing HR DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. Trials associated It produces similar effects to those of atenolol, as measured in the randomized double-blind INITIATIVE trial, which compared ivabradine (5, 7.5 and 10 mg bid) with atenolol at doses of 50 and 100 mg per day and found to be non inferior. It is safe agent and no changes in QT interval. ASSOCIATE Trial is double blind RCT done on 889 patients which found that ivabradine was better than placebo in anti anginal and anti ischaemic efficacy. Combination of this drug and betablockers was definitely effective without untoward effects. BEAUTifUL TRIAL-post hoc analysis The BEAUTIFUL investigators sought to analyze, post hoc, the effect of ivabradine on patients with limiting angina at baseline within the BEAUTIFUL trial. Patients with limiting angina -13.8% of the trial population. 24% reduction in the primary endpoint [cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction (MI) or heart failure HR, 0.76; 95% CI, 0.58–1.00] and a 42% reduction in hospitalization for MI (HR, 0.58; 95% CI, 0.37– 0.92). In patients with heart rate ≥70 bpm, there was a 73% reduction in hospitalization for MI (HR, 0.27; 95% CI, 0.11–0.66) and a 59% reduction in coronary revascularization (HR, 0.41; 95% CI, 0.17– 0.99). These results indicate that ivabradine is most helpful to reduce adverse cardiac events in patients with limiting angina and that in this population, its benefit may extend well beyond symptom control. Side effect /effects Blurring of vision No QT prolongation No negative inotropic properties Improvements in exercise tolerance and prevention of exercise-induced ischaemia Metabolic modulation (pFOX): Trimetazidine Myocytes Glucose FFA Acyl-CoA Pyruvate β-oxidation Trimetazidine Acetyl-CoA O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway 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. It is piperazine derivative (1-[2,3,4-trimethoxibenzyl)]- piperazine). Launched as a cytoprotective agent. No significant negative inotropic or vasodilator properties either at rest or during dynamic exercise TRIMPOL II –RCT of 426 patients with CSA who were randomised to either trimetazidine 20 mg three times a day or placebo in addition to metoprolol 50mg. This study demonstrated an improvement in time to STsegment depression on exercise tolerance testing (ETT), total exercise workload, mean nitrate consumption, and angina frequency in patients randomised to receive trimetazidine Large multicentric trial of 19000 patients post MI by EMIP-FR group showed no benefit of iv infusion of trimetazidine immediately post MI over 48hrs MOA – CPT -1 inhibitor and also acts in inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase (LC 3- KAT)[Kantor et al] VASCO ,largest RCT , showed no benefit as an add on in angina Safety issues and adverse effects ????? Side effects Extrapyramidal and parkinsonian symptoms recently published by EMA 2012 Restless leg syndrome. Use is limited in severe renal impairment. Perhexilene Earlier designed as a CCB but doesnot act like a CCB It doesnot affect the heart rate or SVR Multiple randomised trials show that it has anti anginal effect as monotherapy or as combination. Inhibition of CPT-1 and, to a lesser extent, CPT-2, resulting in increased glucose and lactate utilisation S/E hepatotoxicity and peripheral neuropathy due to phospholipid accumulation as a result of CPT ½ inhibition. Cole et al confirmed the safety of perhexiline in a randomised, double-blind, crossover study following initiation of 100 mg of perhexiline BD with subsequent plasma-guided dose titration; none of the developed the dreaded side effects. Other s/e nausea ,dizziness and hypoglycaemia Other uses – symptomatic aortic stenosis Circulation 1990;81(4):1260–70 Etomoxir/ Oxfenicine Potential anti anginal agent Launched as an anti diabetic agent due to hypoglycaemic effects CPT 1 INHIBITOR Improvement in LV function in rats- Turcani & Rupp Single study available on humans (15 patients) with NYHA II – III Etomoxir 80mg was administered.\ Only animal studies on oxfenicine. Preconditioning: Nicorandil Activation of ATP-sensitive K+ channels • Ischemic preconditioning • Dilation of coronary resistance arterioles N O HN O NO2 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. DOSAGE- 20mg bid Tolerance is seen with chronic dosage No cross tolerance with nitrates The Impact Of Nicorandil in Angina (IONA) trial showed a significant reduction of major coronary events in stable angina patients treated with nicorandil compared with placebo as add-on to conventional therapy Also used in unstable angina. It also reduces the number of further attacks Additive effects with nitrates Rho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Ca2+ Ca2+ Agonist PLC VOC ROC Receptor PIP2 Fasudil IP3 Rho Rho kinase SR Ca2+ Myosin Myosin phosphatase MLCK Ca2+ Calmodulin Myosin-P Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8. Fasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration. Double-Blind, Placebo-Controlled, Phase 2 Trial on 84 patients J Am Coll Cardiol. 2005;46(10):1803-1811 Molsodomine & linsodomine Anti anginal and anti ischaemic Acts like nitrates Metabolises in liver to form linsodomine Orally active Metabolised in liver TMLR Surgical surgeons use the laser to make holes between 20 and 40 tiny (one-millimeter-wide) Surgical incision made Done along with CABG sometimes Percutaneous TMR Rationale Improved perfusion by stimulation of angiogenesis Potential placebo effect Anesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibers Peri-procedural infarction. 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 remodelling TMLR – Direct Trial Only major blinded study High Surgical Risk 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 (Mortality 5%) Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed. EECP EECP Increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). Cuffs are wrapped around the patients legs and sequential pressure (300mmHg) is applied in early diastole. 3 pairs of cuffs Patient selection Angina class III/IV Refractory to medical therapy Reversible ischemia of the free wall not amenable for revascularization Excluded if LVEF<20% or had current major illness EECP - Enhanced External CounterPulsation External, pneumatic compression of lower extremities in diastole. EECP - Enhanced External CounterPulsation EECP - Enhanced External CounterPulsation Sequential inflation of cuffs Simultaneous deflation of cuffs in late Diastole Retrograde aortic pressure wave Increased Coronary perfusion pressure Increased Venous Return Increased Preload Increased Cardiac Output Lowers Systemic Vascular Resistance Reduced afterload Decreased Cardiac workload Decreased Oxygen Consumption 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. EECP – Contraindications & Precautions Arrhythmias that interfere with machine triggering Bleeding diathesis Active thrombophlebitis & severe lower extremity vaso- occlusive disease Presence of significant AAA Pregnancy MUST EECP Blinded RCT on 139 patients to check the safety and efficacy of EECP Patients with CSA were given 35hrs of EECP/WK Exercise duration increased . Time to ≥1-mm STsegment depression increased significantly . Patients saw a decrease in angina episodes (p < 0.05). Nitroglycerin usage decreased. 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” Spinal Cord Stimulation power source conducting wires electrodes at stimulation site Stimulation typically administered for 1-2 hrs tid Therapeutic mechanism appears to be alteration of anginal pain perception Long-term Outcomes Following SCS Prospective Italian Registry: 104 Patients, Follow-up 13.2 Months 20 Baseline SCS 15 * p<0.0001 10 5 * * * * * CCS Class # Hosp Adms * * 0 Total Angina Angina at Rest Exert Angina NTG Use/wk Days in Hosp Episodes/wk (DiPede, et al. AJC 2003;91:951) 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) 18 16 14 Mean 12 number 10 8 per 6 week 4 2 0 16.2 15.2 14.6 * 4.4 13.7 * * 5.2 4.1 * Baseline 6 months 3.1 *P < 0.0001 Anginal attacks NTG consumption Anginal attacks Spinal cord stimulation (n=53) NTG consumption CABG (n=51) No difference in symptom relief between SCS and CABG (Mannheimer, et al. Circulation 1998;97:1157) Potential cardioprotective benefits of exercise NO production ROS generation Vasculature ROS scavenging Myocardium Other mechanisms 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. THANK YOU BOOK REFERENCES Braunwald`s heart diseases -9th edition-Unit 7 Chapt-57 Cardiovascular medicine 3rd edition –Brian GriffinSection-1 Chapt-5 Hurst-The Heart -13th edition. Part 8 Chapt-54 Harrisons Principles of internal medicine –18th edition Part 10 Section 5 Chapt-243 US FDA APPROVAL OF RANOLAZINE 2008 REFERENCES Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13 PH Stone, MD and BR Chaitman, MD. 2006 DiPede, et al. AJC 2003;91:951 Domenech R. Circulation. 2006;113:e1-3. Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:96372 Mannheimer, et al. Circulation 1998;97:1157 Leon MB, et al. JACC 2005; 46:1812 Circulation 1990;81(4):1260–70 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 Chaitman et al JAMA 2004; 43: 1375 PH Stone Circulation 2005;11 Question 1 All are partial fatty acid oxidase inhibitors except? a) Fasudil b) Trimetazidine c) Etomoxir d) Oxfenicine Question 2 a) IONA trial proves efficacy of nicorandil in ACS b) Activation of ATP-sensitive K+ channels c) Helps in Ischemic preconditioning d) Dilation of coronary resistance arterioles e) Vasodilation of coronary epicardial arteries Question 3 False statement regarding ischaemia at cellular level a) Calcium overload b) Sodium overload c) Decreased late sodium current d) Increased early after potentials Question 4 False regarding ranolazine trials a) CARISA- ranolazine as an adjunct with other anti anginals b) MARISA- effect of various doses of ranolazine as monotherapy compared with placebo c) ERICA- effect of ranolazine with amlodipine d) ASSOCIATE – ranolazine in ACS patients Question 5 True about ranolazine are all except a) Does not affect double product b) Decrease diastolic stiffness c) Blockade of Late sodium current d) Prolongs QT interval e) Decrease Hb A1C levels Question 6 False regarding TMR a) Improved perfusion by stimulation of angiogenesis b) Potential placebo effect c) Anesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibers d) Free radical scavenging Question 7 False regarding EECP a) Sequential inflation and simultaneous deflation b) MUST EECP shows definite benefit in decreasing angina c) Contraindicated in pregnancy d) Can be done in those with EF < 20% Question 8 False about ivabradine a) INITIATIVE trial compared ivabradine with betablockers b) ASSOCIATE trial compares ivabradine with placebo and found it definitely better AND also found beneficial when combined with beta blockers c) Prolongs QT interval d) Beautiful Trial proved the anti anginal efficacy of ivabradine. Question 9 False about SCS a) Stimulates spinal cord at level C7-T4 b) No added benefits when compared to CABG c) Mechanism of action is pain modification by gate control mechanism. d) Eddicks et al proved it to be more beneficial than TLR Question 10 Which is a false match a) IONA – NICORANDIL b) TRIMPOL – MOLSODOMINE c) MERLIN TIMI 36- RANOLAZINE d) ASSOCIATE – IVABRADINE