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Ischemia/reperfusion injury:
Pharmacological treatment
options
Ischemic myocardium
(ACS, NSTEMI, STEMI)
Plaque ruptur, thrombosis and
myocardial death
Stable plaque
% MI-Patients
75
60
45 68
30
Unstable plaque, plaque ruptur
15
18 14
0
< 50 50-70 > 70
Diameter stenosis (%)
TIME IS
MUSCLE
Ischemic-
Injury
Ischemia Time
Ischemia-reperfusion injury
Ischemia
Infarct size
(% area at risk)
Extent of
100 collaterals
Humans
80 Pig
Rabbit
60
Rat
40
Dog Cat
20
0 Guinea pig
6 Month
mortality
(%)
in minutes
20 0-60
61-120
121-180
10 181-360
Log-Rank p<0,001
0
0 1 2 3 4 5 6 7 Follow up (years)
CHD
Re-opening of
the vessel
Reperfused myocardium
Myocardial damage Ischemia-reperfusion injury
Reperfusion-
Injury
Ischemic-
Injury
Treatment options:
Before, during, following ischemia
Myocardial damage
Reperfusion-
Injury
Ischemic-
Injury
Reperfusion-
Injury
Ischemic-
Injury
4S 1994
WOSCOP 1995
CARE 1996
AFCAPS 1998
LIPID 1998
Akira Endo
HPS 2002
LIPS 2002
PROSPER 2002
ASCOT 2003
combined
0.5 1 2
CHD
Catheter Catheter
Coronary occlusion
X
Coronary occlusion
X
Patient
Collateral vessel growth
CHD
Inflammation
TNF
Collateral vessel
growth
MCP-1
Endogenous cardioprotection:
Ischemic Preconditioning
0
Control Pre-con
Endogenous cardioprotection:
Remote Preconditioning
BRAIN
LOWER LIMB
LIVER
SKELETAL
MUSCLE
LUNGS KIDNEY
STOMACH
SMALL INTESTINE
Endogenous cardioprotection:
Ischemic Preconditioning
Pre-infarction angina
Yes No
Death 4/155 (3%) 18/254 (6%)
adenosine
adenosine NO
bradykinin IGF-1
bradykinin ANP opioids, UCN FGF-2 IL-6 type
opioids, UCN BNP cytokines TNF
adipo-
PI3K GPCR NPR
GPCR NPR Heinzel et al., Circ Res 97:583-586, 2005 nectin
gp130 TNF-R
Akt pGC
JAK CB-R
Boengler et al., Cardiovasc Res 67: 234-244, 2005
only PI3K
eNOS
adenosine H11K
Rodriguez-Sinovas et al., Circ Res 99:93-101, 2006
AMPK
NO Akt ERK STAT3 NO
Cx43
: age-dependent
KATP
: species-dependent
mitochondrium mitochondrium
Heusch, Boengler, Schulz, Circulation 118: 1915-1919, 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
Ischemia-reperfusion injury
Reperfusion-
Injury
Ischemic-
Injury
CHD
Patient
Creatine kinase release
Kjekshus, Am J Cardiol 57: 43F-49F (1986)
-50
Infarct size
reduction [%]
-40
Atenolol
-30 Propranolol
Timolol
-20
Metoprolol
Metoprolol
-10
Propranolol
0
-4 -8 -12 -16 -20 -24
Perconditioning
Reperfusion-
Injury
Ischemic-
Injury
25
Control
20 p<0.05
hrs
Precon 15
(Ischemia/
Drugs) 10
hrs
5
Postcon
(Ischemia/ 0
hrs Control Precon Postcon
Drugs)
Endogenous cardioprotection:
Ischemic Postconditioning
Direct stenting
300 1 1 1 1 30
Postcond 1 1 1 1
200 20
Control PostC Balloon inflations - deflations Control PostC
CK release (AUC)
5000 Control
PostC Day 13 CK release SPECT at 6 months
30
Staat et al., Circulation 112: 2143-2148, 2005 Thibault et al., Circulation 117:1037-44, 2008
Pre- and Post-conditioning:
Signal transduction
adenosine
adenosine NO
bradykinin IGF-1
bradykinin ANP opioids, UCN FGF-2 IL-6 type
opioids, UCN BNP cytokines TNF
GPCR adipo-
PI3K NPR
GPCR NPR nectin
gp130 TNF-R
Akt pGC
JAK CB-R
only PI3K
eNOS
adenosine H11K AMPK
NO Akt ERK STAT3 NO
: age-dependent
KATP
: species-dependent
mitochondrium mitochondrium
Heusch, Boengler, Schulz, Circulation 118: 1915-1919, 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
Ischemic Postconditioning:
Signal transduction
Mice
(Cyclosporine A analogue)
P<0.05
6000 250
CK release Control TnI release
CsA
5000 200
4000
(UI/L)
150
3000
100
2000
50
1000
P<0.05 P<0.05
0 0
Treatment options:
Before, during, following ischemia
Myocardial damage
Reperfusion-
Injury
Ischemic-
Injury