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Examining the Science Underlying Myocardial Ischemia

This article explores the underlying science of myocardial ischemia, comparing the characteristics of severe obstruction (angina, no rupture) and mild obstruction (no angina, likely to rupture). Topics covered include vulnerable plaque, plaque rupture, acute MI, unstable angina, and more.

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Examining the Science Underlying Myocardial Ischemia

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  1. Examining the Science Underlying Myocardial Ischemia

  2. Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture) • Vulnerable plaque • Minor obstruction • Eccentric plaque • Lipid pool • Thin cap • Severe fibrotic plaque • Severe obstruction • No lipid • Fibrosis, Ca2+ • Plaque rupture • Acute MI • Unstable angina • Sudden death • Exertional angina • (+) ETT Revascularization Anti-anginal Rx Pharmacologic stabilization Early identification of high-risk? Courtesy of PH Stone, MD.

  3. Major cardiac events occur in non-target areas following successful PCI 20 15 Hazardrate (%) 10 Non-target lesion event 5 Target lesion event 0 1 2 3 Year 4 5 Substantial number of cardiac events could be prevented if non-obstructive, high-risk lesions were identified Cutlip DE et al. Circulation. 2004;110:1226-30.

  4. Local determinants of the natural history of individual coronary lesions Opportunities for identification and intervention Local factors Shear stress Quiescent, stable plaque No symptoms • Proliferation • Inflammation • Remodeling Quiescence Inflammation Thin cap Fibroatheroma MI, sudden death Proliferation Calcification Fibrotic/ scarred plaque Angina Courtesy of PH Stone, MD and R Gerrity, PhD.

  5. Proposed classification scheme for atherosclerotic plaque Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

  6. The spectrum of CAD ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

  7. Ventricular arrhythmogenesis in ischemic myocardium • Risk factors • Age • Heredity • Gender • Smoking • Lipids • Hypertension • Diabetes • Obesity • Clinical or subclinical susceptibility • Structural substrate present High risk of transient acute ischemia reperfusion • Triggers • VPC • VT • Reentry • Substrate • Vulnerable ischemic zone • Intracoronary thrombus • Autonomic influence • Hemodynamic compromise Ventricular fibrillation + VPC = ventricular premature contraction VT = ventricular tachycardia Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90.

  8. Causes and consequences of myocardial ischemia: New understanding Development of ischemia Consequences of ischemia Ischemia O2 demand Na+ and Ca2+ overload Heart rate Blood pressure Preload Contractility Electrical instability Myocardial dysfunction O2 supply Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  9. Overview of the sodium channel Na+ Na+ Na+ Resting closed Inactivated Activated out Na+ Na+ in [Na+] Na+ Na+ [Na+] = 140 mM Na+ Na+ ~10mM Ca2+ Ca2+ in Ca2+ Ca2+ Na+ Ca2+ Ca2+ out Na+/Ca2+ Exchanger Na+ Ca2+ Courtesy of L Belardinelli, MD.

  10. During the plateau phase of the action potential, a small proportion of sodium channels either do not close, or close and then reopen These late channel openings permit a sustained Na+ current to enter myocytes during systole Origin of late INa 0 Sodiumcurrent Late Peak Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  11. Myocardial ischemia causes enhanced late INa 0 Sodiumcurrent Late Peak 0 Ischemia Sodiumcurrent Late Peak Enhanced late INa appears to be a major contributor to increased intracellular Na+ during ischemia Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  12. Role of altered ion currents in adverse consequences of myocardial ischemia Disease(s) and pathological states linked to imbalance of O2 supply/demand Late INa Na+ entry ([Na+]i) NCX Cytosolic Ca2+ • Electrical instability • Afterpotentials • Beat-to-beat APD • Arrhythmias (VT) • Mechanical dysfunction • Abnormal contraction and relaxation • Diastolic tension [Na+]i = intracellular [Na+]NCX = Na+/Ca2+ exchanger APD = action potential duration Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

  13. Sustained contraction of ischemic tissue during diastole: Increases MVO2 Compresses intramural small vessels Reduces myocardial blood flow Diastolic relaxation failure adversely affects myocardial O2 supply and demand Exacerbates ischemia MVO2 = myocardial oxygen consumption Courtesy of PH Stone, MD.

  14. Late INa inhibition blunts Ca2+ accumulation 0.30 12 ATX-II RAN 0.25 Indo fluorescence(F405/F485 ratio) 8 * LV work(L/min per mm Hg) * 0.20 * 4 * 0.15 ATX-II RAN 0.10 0 0 10 20 30 40 50 0 10 20 30 40 50 Time of perfusion (min) ATX-II alone (n = 11) ATX-II + ranolazine 4 μM (n = 9) or 9 μM (n = 9) *P < 0.05 vs ATX-II aloneATX-II = sea anemone toxin (selectively late INa) Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8.

  15. Ranolazine blunts sotalol-induced action potential prolongation in dogs d-Sotalol + Ranolazine 5 uM + Ranolazine 10 uM Transmembrane action potentials (superimposed) Control 50 mV 1 sec Antzelevich C et al. Circulation 2004;110:904-10.

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