1. Post-conditioning the human heart to reduce infarct size
Michel OVIZE
Inserm E 0226 and Cardiology Hospital
Lyon France

2. Acute Myocardial Infarction
common ( / year in USA)
affects outcome : mortality
disabling: heart failure

3. Infarct size is a determinant of mortality
Gibbons et al. JACC 2004;44:

4. Reperfusion improves outcome
van Domburg et al. JACC 2005:15–20

5. Reperfusion Injury « a double edged sword »
stunning : accepted
arrhythmias : accepted
no-reflow : accepted
necrosis : debated

6. Postconditioning * Zhao ZQ et al. Am J Physiol 2003 (% of tissue area)5 10 15 20 25 30 35
AR/LV AN/AR
(% of tissue area)
control
PostC
PreC *
Zhao ZQ et al. Am J Physiol 2003

7. Infarction: a two-component damage
coronary
occlusion
Ischemia
Reperfusion
reperfusion
injury
ischemic
Infarct size
time
Postconditioning
PreC

8. Current treatment of AMI
-blockers
ACE inhibitors
statins ….
improve post-MI outcome,
but not via a reduction in infarct size
Ischemic damage : YES
thrombolysis / PCI ischemia time
antiplatelet agents ischemia time
Reperfusion damage : NO
Action on
infarct size

9. A narrow time window
Loosing protection

10. Does Postconditioning protect the human heart ?
A « proof of concept » study

11. A « Human Model » of Postconditioning
Study population
A « Human Model » of Postconditioning
Inclusion criteria
Age ≥ 18
First acute (STE)MI / chest pain onset < 6 hrs
Need for emergency PTCA
Exclusion criteria
Cardiac arrest
Cardiogenic shock
Circumflex coronary artery as culprit for AMI

12. Experimental Design Eligible Patient TIMI 0 Coronary + LV Angio
Collat = 0
Coronary + LV Angio
Informed consent
Randomization
Angioplasty
reperf. TIMI > 2

13. Post-Conditioning algorythm1’
Reperfusion
Occluded
coronary artery
Direct stenting
Balloon inflations - deflations
Postcond
Control
Staat et al. Circulation. 2005;112:

14. Study Endpoints Total CK release over first 72 hrs of reperfusion
every 4 hr on Day 1
every 6 hr on Day 2
every 8 hr on Day 3

15. Results

16. Study population - baseline characteristics
Control
(n = 14)
Postconditioned
(n = 16)
p value
Age (y)
56±3
58±4 ns
Sex (M/F)
13/1
12/4
BMI
27±1
28±1
HBP (%) 36 38
Smokers (%) 56 57
Dyslipidemia (%) 50 80
Diabetes (%) 13 20
LV and coronary angiography
Culprit artery (LAD/RCA)
6/8
6/10
Ejection fraction (%)
49 ± 4
52 ± 2

17. Area at Risk estimation on LV angiogramB C D
Anterior infarct
B - C
A - D
ACS =
X 100 %
Length of the Abnormally Contracting Segments of the LVED endocardial perimeter
Length of the LVED endocardial perimeter
LV End Diastole
LV End Systole

18. Determinants of infarct size
Area at Risk size (ACS)
Duration of Ischemia 20 30 40 50
control
PostC ns
(%)
200
300
400
500 ns
control
PostC
min.

19. CK release during reperfusion
5000
Control
Post-Cond
4000
- 36 % (p < 0.05)
3000
CK release (AUC: arbitrary units)
2000
1000 4h 8h
24h
48h
72h
Adm.
Reperfusion
PTCA
Staat et al. Circulation. 2005;112:

20. (infarct size versus area at risk)
CK release versus ACS
(infarct size versus area at risk)
1.105
2.105
3.105
4.105
5.105
6.105
7.105
8. 105
9.105 20 40 60
ACS (%)
CK release (AUC)
Control
PostC

21. Estimation of « no reflow »
0,5 1
1,5 2
2,5 3 C
Blush grade
ST segment shift (mm)
PostC *
Staat et al. Circulation. 2005;112:

22. Toward New Clinical Strategies
Ischemic
PostC
PCI - thrombolysis
Pharmaco
PostC
adenosine, NO, K+ATP openers
survival kinases
mPTP inhibitors, …..
drug