1. Examining the Science Underlying Myocardial Ischemia

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

3. Major cardiac events occur in non-target areas following successful PCI Hazard rate (%) Cutlip DE et al. Circulation. 2004;110:1226-30. Substantial number of cardiac events could be prevented if non-obstructive, high-risk lesions were identified Target lesion event Non-target lesion event 0 5 10 15 20 123 Year 45

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

5. Proposed classification scheme for atherosclerotic plaque Plaque trajectoryHistopathology Progression rate Vascular remodeling Proclivity to rupture Clinical manifestation Quiescent plaque Small lipid core Thick fibrous cap MinimalCompensatory expansive remodeling LowAsymptomatic Stenotic plaque Small lipid core Very thick fibrous cap GradualConstrictive remodeling LowStable angina High-risk plaque Large lipid core Thin and inflamed fibrous cap IncreasedExcessive expansive remodeling HighACS Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

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

7. Substrate Vulnerable ischemic zone Intracoronary thrombus Autonomic influence Hemodynamic compromise Ventricular arrhythmogenesis in ischemic myocardium Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90. VPC = ventricular premature contraction VT = ventricular tachycardia 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 + Ventricular fibrillation

8. Causes and consequences of myocardial ischemia: New understanding Consequences of ischemia Electrical instability Myocardial dysfunction Ischemia Heart rate Blood pressure Preload Contractility Development of ischemia  O 2 demand  O 2 supply Na + and Ca 2+ overload Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

9. Overview of the sodium channel out in out in Na + /Ca 2+ Exchanger Ca 2+ Na + Resting closed Na + Activated Inactivated Na + Ca 2+ [ Na + ] = 140 mM ~10mM Courtesy of L Belardinelli, MD. Ca 2+ [ Na + ]

10. Origin of late I Na 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 Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14. Sodium current 0 Late Peak

11. Sodium current 0 Late Peak 0 Late Peak Sodium current Ischemia Myocardial ischemia causes enhanced late I Na Enhanced late I Na 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 [Na + ] i = intracellular [Na + ] NCX = Na + /Ca 2+ exchanger APD = action potential duration Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14. Disease(s) and pathological states linked to imbalance of O 2 supply/demand  Cytosolic Ca 2+ NCX  Late I Na  Na + entry ([Na + ] i ) Mechanical dysfunction Abnormal contraction and relaxation  Diastolic tension Electrical instability Afterpotentials Beat-to-beat  APD Arrhythmias (VT)

13. Diastolic relaxation failure adversely affects myocardial O 2 supply and demand Sustained contraction of ischemic tissue during diastole: –Increases MVO 2 –Compresses intramural small vessels Reduces myocardial blood flow Courtesy of PH Stone, MD. Exacerbates ischemia MVO 2 = myocardial oxygen consumption

14. Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8. Late I Na inhibition blunts Ca 2+ accumulation 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 alone ATX-II = sea anemone toxin (selectively  late I Na ) Indo fluorescence (F405/F485 ratio) 0.30 0.25 0.20 0.15 0.10 01020304050 LV work (L/min per mm Hg) 12 8 4 0 ATX-II RAN 01020304050 RAN ATX-II * * * *

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