1. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Infarct transmurality and infarct size assessed by delayed enhancement magnetic resonance imaging: Association with time-to-treatment, ST- segment resolution, and TIMI-flow grades Holger Thiele, MD; Axel Linke, MD; Sandra Erbs, MD; Enno Boudriot, MD; Alexander Lebcke, MD; Dietmar Kivelitz, MD; and Gerhard Schuler, MD Department of Internal Medicine/Cardiology, University of Leipzig – Heart Center

2. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Background The TIMI flow, ST-segment resolution and time-to-reperfusion are associated with mortality in ST-elevation myocardial infarction (STEMI) after either fibrinolysis or percutaneous coronary intervention. Boersma et al. Lancet 1996;96:771-775 De Luca et al. J Am Coll Cardiol 2003; 42:991-997 GUSTO-I. N Engl J Med 1993; 329:1615-1623 Stone et al. Circulation 2001; 104:636-641 de Lemos et al. J Am Coll Cardiol 2001;38:1283-1294 As a result of excellent spatial resolution delayed enhancement magnetic resonance imaging allows assessment of infarct transmurality and infarct size. Simonetti et al. Radiology 2001;218:215-223 Whether these clinical, angiographic and ECG measures are also associated with infarct size and infarct transmurality, has not yet been investigated.

3. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Background As a consequence of excellent spatial resolution DE-MRI might also allow to assess the assumed “wavefront phenomenon” of myocardial necrosis in humans. Reimer et al. Circulation 1977;56:786-794

4. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Hypothesis We hypothesized that these measures (Time-to- Reperfusion / ST-Resolution / TIMI-Flow) would also be associated with infarct size and infarct transmurality as assessed by delayed enhancement MRI.

5. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Patients with Angina (< 6 h) n=164 Methods and Materials: Patients (Leipzig Prehospital Fibrinolysis Study) Prehospital Fibrinolysis (n=82) Facilitated PCI (n=82) Lost to 6 month follow-up (n=1) Primary Endpoint Analysis (Infarct Size) (n=66) Secondary Combined Endpoint Analysis (n=80) Primary Endpoint Analysis (Infarct Size) (n=69) Secondary Combined Endpoint Analysis (n=79) Lost to 6-month follow-up (n=0) Excluded, no infarction (n=2) Rescue Angioplasty (n=14) Excluded, no infarction (n=2) No Stent (n=4) not necessary (n=3) not possible (n=1) 12-lead-ECG STEMI Exclusion criteria?, Informed consent? Randomization and hospital assignment (3 PCI, 4 non-PCI-center) Prehospital combination fibrinolysis ASA 500 mg, Heparin (60IE/kg BW), Abciximab (0.25 mg/kg BW), Reteplase Double-Bolus 5 U Thiele H, et al. Eur Heart J 2005; 26:1956-1963

6. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Methods: MR Image Analysis Blinded observers: Manual drawing of endocardial, epicardial, papillary papillary, and infarct contours %Infarct Size = (Volume Infarct/Volume LV mass) 1 2 3 4 5 6 13 7 12 11 10 9 8 14 15 16 17 Transmurality for each segment of 17 segment model: > 50% transmurality

7. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Methods Patient Stratification 135 Patients 3 Groups: Defined by Tertile Symptom-Treatment-Interval Lower Tertile (<120 min) Middle Tertile (120-240 min) Upper Tertile (> 240 min) Median Symptom-Treatment-Time: 118 min. 135 Patients 3 Groups: Defined by ST-Segment Resolution No ST-Resolution (<30%) Intermediate ST-Resolution (30-70%) Complete ST-Resolution (>70%)

8. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Results: Infarct Size and Transmurality – Time to treatment 0 2 4 6 8 10 12 14 16 18 < 2h2-4 h> 4h Infarct Size (%LV) Prehospital lysis 8.2 (3.0;15.6) 14.3 (6.6;20.9) 14.5 (3.2;21.8) Facilitated PCI 3.9 (0.9;7.8) 10.3 (1.8;14.5) 12.8 (9.1;18.6) 7.5 (2.5;14.0) 14.0 (5.8;20.5) 13.5 (3.0;17.0) Infarct size 0 2 4 6 8 10 12 14 16 18 < 2h2-4 h> 4h Transmurality Score 5.0 (2.0;8.0) 11.0 (2.3;15.0) 12.0 (11.3;18.3) Transmurality Score P<0.001P=0.007P=0.02

9. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Results: Infarct Size and Transmurality - ST-Resolution 0 2 4 6 8 10 12 14 16 >70%70-30%<30% Infarct size (%LV) p<0.001 ST-segment resolution 4.2 (1.6; 10.5) 13.6 (8.0; 16.4) 12.4 (7.7; 17.9) 0 2 4 6 8 10 12 14 16 >70%70-30%<30% Transmurality Score p<0.001 5.0 (2.0; 10.8) 11.0 (8.8; 16.3) 13.0 (8.0; 19.5)

10. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M 0 2 4 6 8 10 12 TIMI 0-ITIMI II-III Results: Infarct Size and Transmurality -Pre-PCI TIMI-Flow IS (% LV) p = 0.002 10.8%LV (IQR 7.6; 17.3) 3.9%LV (IQR 0.9; 9.6) n=69, Facilitated PCI-Group 0 2 4 6 8 10 12 TIMI 0-ITIMI II-III Transmurality Score p = 0.003 11.5 (IQR 8.0; 16.5; ) 5.0 (IQR 2.0; 9.5)

11. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Wavefront Phenomenon - Human Data Time (min) 20 060 120 180 240 300 360 30 40 50 60 70 80 90 11 25 13 9 9 9 6 14 19 20 Prehospital Lysis Facilitated PCI Probability Transmurality >50% (%) Time (min) 0 60 120 180 240 300 360 80 70 60 50 40 30 20 10 20 19 6 14 9 9 9 13 11 25 Prehospital Lysis Facilitated PCI Probability Infarct Size >10% (%) Each 30 min delay in time-to-treatment  20-25% risk increase transmurality >50% Each 30 min delay in time-to-treatment  20-25% risk increase infarct size >10%

12. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M The time from symptom-onset-to-treatment, ST-resolution and pre-PCI TIMI- flow influence the final infarct size and infarct transmurality for either prehospital fibrinolysis or prehospital initiated facilitated PCI. This finding is in contrast to other studies with a primary PCI approach (STOPAMI 1+2 trial). These differences might be explained by the much shorter time to reperfusion in the current trial (mean 118 min vs. 180-215 min). A prehospital initiated facilitated PCI approach is superior to prehospital fibrinolysis alone in particular in the early time period after symptom onset. This underlines the assumed pathophysiological link between early flow restoration and perfusion in the infarct related artery, which is known as the “wavefront phenomenon”. Summary and Conclusions  Major goal in STEMI treatment is very early complete reperfusion