1. Proof of Concept #1: Occluded Arteries Cause Acute MI Proof of Concept #1: Occluded Arteries Cause Acute MI Proof of Concept #2: Drugs (in this case IC SK) Recanalize Occluded Arteries Proof of Concept #2: Drugs (in this case IC SK) Recanalize Occluded Arteries The “Code White” Team of Dr. William Ganz: 1979

2. Results of the NIH Sponsored TIMI 1 Trial % Arteries Opened Documented to be Closed % Arteries Opened Documented to be Closed % All Arteries Open at 90 Min. % All Arteries Open at 90 Min. % of Patients Cheesboro et al, Circulation 1987;76: 142-154 DSMB stopped trial early; felt that greater rate of patency would necessarily translate into improved outcomes

3. The Dark Days of the Open Artery Hypothesis: Results of Early Megatrials The Dark Days of the Open Artery Hypothesis: Results of Early Megatrials Despite the fact that TIMI 1 showed superior patency for tPA over SK, early megatrials showed no difference in mortality Early megatrials used 3 hour dosing of tPA (not front-loaded) and late SQ heparin (not early IV heparin) Despite the fact that TIMI 1 showed superior patency for tPA over SK, early megatrials showed no difference in mortality Early megatrials used 3 hour dosing of tPA (not front-loaded) and late SQ heparin (not early IV heparin)

5. Occlusion Penetration Slow Flow Normal Flow TIMI 0 TIMI 1 TIMI 2 TIMI 3 % Mortality 9.3% 6.1% 3.7% p<0.0001 vs TIMI 0/1 p<0.0001 vs TIMI 2 p<0.0001 vs TIMI 0/1 p<0.0001 vs TIMI 2 P=0.003 vs TIMI 0/1 Team 2 German GUSTO 1 TAM I 1-7 TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B CM Gibson 1998 in Acute Coronary Syndromes Sample Size of Pooled Analysis: 5,498 10163334442784131991518 2934 Restoration of “Normal” Epicardial Flow Yields Better Outcomes Unfortunately rate of agreement only 71%

7. LAD Frame 1: Dye Touches Both Borders & Moves Forward Frame 0: Dye Touches One or No Borders Last Frame Definition Frame 21: Dye first enters landmark First Frame Definition RCA LCX Distal Landmark Normal Flow in the Absence of MI : 21.0 + + 3.1 frames 1st branch off posterolateral Last branch off most distal OM “Whale’s tail” or “pitchfork” or most distal branch LAD at apex Gibson, Circulation 1996; 93: 879-888

8. Even Faster Epicardial Coronary Blood Flow is Better CTFC < 14 CTFC > 40 0.0% (n=41) (n = 18/640) (n =35/563) 2.8% p= 0.003 “TIMI 4” Flow TIMI 3 Flow 14 < CTFC < 40 6.2% % Risk of In Hospital Mortality Gibson, Circulation 1999; 99: 1945-1950 Hyperemic Flow Reproducibility: r = 0.97 between readers Accuracy: r=0.88 vs Doppler velocity Reproducibility: r = 0.97 between readers Accuracy: r=0.88 vs Doppler velocity 21 0 0 10 15 5 5

9. Percent Stenosis 67.8% Percent Stenosis 67.8% Percent Stenosis 69.5% Percent Stenosis 69.5% Percent Stenosis 67.1% Percent Stenosis 67.1% Distal to Stenosis: 11.8 cm or 76.6% Distal to Stenosis: 9.2 cm or 70.1% Distal to Stenosis: 7.8 cm or 59.8% Diameter: 2.97 mm Diameter: 3.10 mm Diameter: 3.23 mm SBP 120.2 mmHg SBP 120.2 mmHg SBP 120.6 mmHg SBP 120.6 mmHg SBP 121.7 mmHg SBP 121.7 mmHg Wedge Pressure: 18.0 mm Hg Wedge Pressure: 16.4 mm Hg Wedge Pressure: 19.7 mm Hg N = 1,044 N = 264 N = 778 RCA: 90 Min. TIMI 3 Flow: 64.2% Composes 2/3 rds of TIMI 3 flow 90 Min. CTFC: 33.4 Post PTCA CTFC 25.5 Thin walled RV Low filling pressures RCA: 90 Min. TIMI 3 Flow: 64.2% Composes 2/3 rds of TIMI 3 flow 90 Min. CTFC: 33.4 Post PTCA CTFC 25.5 Thin walled RV Low filling pressures LCX: 90 Min. TIMI 3 Flow: 56.4% 90 Min. CTFC: 40.4 Post PTCA CTFC 36.5 Thick walled LV High filling pressures LCX: 90 Min. TIMI 3 Flow: 56.4% 90 Min. CTFC: 40.4 Post PTCA CTFC 36.5 Thick walled LV High filling pressures LAD: 90 Min. TIMI 3 Flow: 46.0% Composes 2/3rds of TIMI 2 flow 90 Min. CTFC: 39.1 Post PTCA CTFC 30.0 Thick walled LV High filling pressures LAD: 90 Min. TIMI 3 Flow: 46.0% Composes 2/3rds of TIMI 2 flow 90 Min. CTFC: 39.1 Post PTCA CTFC 30.0 Thick walled LV High filling pressures Differences Among the Three Epicardial Arteries Following Thrombolytic Administration in 2,068 TIMI Patients Differences Among the Three Epicardial Arteries Following Thrombolytic Administration in 2,068 TIMI Patients CM Gibson J Am Coll Cardiol 1999; 34: 1403-12