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Physiologisches Institut

Ischemia/reperfusion injury:
Pharmacological treatment
options

PD Dr. Kerstin Boengler


Plaque rupture and
myocardial ischemia

Acute plaque rupture


(Stary VI)

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 (%)

Falk et al., Circulation 92: 657-671, 1995


Myocardial damage Ischemic injury

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

0 20 45 90 180 360 (min)

Schaper et al., Prog Cardiovasc Dis 31: 57-77,1988


Patient

Myocardial infarction and prognosis

6 Month
mortality
(%)

Infarct size (% area at risk)


Burns et al., J Am Coll Cardiol 39:3036, 2002
Patient
Duration of ischemia
and mortality
CHD

Cumulative mortality (Kaplan-Meier) in patients with STEMI and PCI (n=6.209)


30
Duration of ischemia
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)

0-60 347 311 278 230 192 138 87


61-120 2643 2339 1906 1420 1006 667 375
121-180 2092 1836 1503 1183 843 533 278
181-360 1127 923 765 647 491 332 172

Terkelsen et al., JAMA 304: 763-771, 2010


Patient
Reperfusion

CHD

Re-opening of
the vessel

Reperfused myocardium
Myocardial damage Ischemia-reperfusion injury

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time


Ischemia-reperfusion injury

Treatment options:
Before, during, following ischemia
Myocardial damage

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time


Ischemia-reperfusion injury

Treatment options before ischemia:


plaque stabilization, collateralization, preconditioning
Myocardial damage

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time


Development of an unstable plaque

Libby und Aikawa, Nature Med 8: 1257-1262, 2002


Avoiding plaque rupture: statins (1976)

A. Endo, Journal of Antibiotics 29:1346-1348, 1976

Meta-Analysis: 69000 Patients


Death or myocardial infarction

Study Year Statin Plazebo

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

Cheung et al., Br J Clin Pharmacol 57:640-651, 2004


Collateral vessel growth

Postmortem angiograms of rabbit hindlimbs

control 7d occlusion of the femoral artery


Patient
Collateral vessel growth

CHD

Catheter Catheter

Coronary occlusion

X
Coronary occlusion
X
Patient
Collateral vessel growth

CHD

Ischemia Stenosis or Normal


Partial occlusion blood flow

Inflammation
TNF
Collateral vessel
growth

MCP-1
Endogenous cardioprotection:
Ischemic Preconditioning

Coronary occlusion Infarct size


(% Area at risk)
30
First window (<2 hrs) 25
Control Second window (>24hrs)
20 p<0.05
hrs
Pre-con 15
(Ischemia/
Drugs) 10
hrs
5

0
Control Pre-con
Endogenous cardioprotection:
Remote Preconditioning
BRAIN

SKIN FLAP UPPER LIMB

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%)

Heart failure/shock 1/155 (1%) 15/254 (6%)

Death/shock 4/155 (3%) 25/254 (10%)

CK-release (24 h) 115 U 151 U

Collaterals 8/85 (9%) 33/146 (23%)

Kloner et al., Circulation 91: 37-47, 1995


Endogenous cardioprotection:
Ischemic Pre- and Postconditioning

both phenomena work perfectly in healthy hearts,


however, protection might be lost with co-morbidities!
Preconditioning: Signal transduction

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

Boengler et al., Basic Res Cardiol 104: 141-147, 2009


sGC eNOS P70S6K
iNOS
SIRT1
MnSOD
p38 PKG Grbe
NO et al., Am J Physiol Heart Circ Physiol. 2011aldose
Marreductase
11

ROS PKC GSK3


MPTP mitochondrium nucleus
MPTP

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

Treatment options during ischemia:


hemodynamics, per-conditioning
Myocardial damage

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time


Patient
Ischemia-reperfusion injury:
-blockade

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

Heart rate reduction [1/min]


Patient
Endogenous cardioprotection:
Perconditioning
CHD
Patient
Endogenous cardioprotection:
Perconditioning
CHD

Perconditioning

RIPC RIPC + morphine


Ischemia-reperfusion injury

Treatment options following ischemia:


Postconditioning
Myocardial damage

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time


Endogenous cardioprotection:
Pre- and Post-conditioning

Coronary occlusion Infarct size


(% Area at risk)
30

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

(min) Duration of Ischemia Occluded


coronary artery
Reperfusion (%) Area at Risk
500 50
ns
ns
400 Control 40

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

(perfusion defect index %)


4000
40 25
(AUC x 104)

3000 -36% (p<0.05) p<0.05 p<0.05


30 20
2000 15
20
1000 10
10
5
0
4h 8h 24h 48h 72h
0 0
Reperfusion Control PostC Control PostC
PCI

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

sGC eNOS P70S6K


SIRT1 iNOS
MnSOD
p38 PKG NO aldose reductase

ROS PKC GSK3


MPTP mitochondrium nucleus
MPTP

: 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

Area at risk (%LV) Infarct size (%AAR)

Gomez et al., Am J Physiol 293: H1654-H1661, 2007


Patient
Pharmacological Postconditioning

CHD Cyclosporine A (or saline)


(2.5 mg/kg, IV bolus)
Day 1-3
CK / TnI release
Coronary artery occlusion Direct stenting
Infarct size

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

Piot et al., New Engl J Med 359, 473-481, 2008


Ischemia-reperfusion injury

Treatment options:
Before, during, following ischemia
Myocardial damage

Reperfusion-
Injury

Ischemic-
Injury

Ischemia Reperfusion Time