Prof. Dr. Rainer Schulz Physiologisches Institut Ischemia and Reperfusion: Pharmacological treatment options
Prof. Dr. Rainer Schulz
Physiologisches Institut
Ischemia and Reperfusion:Pharmacological treatment
options
Ischemic myocardium(ACS, NSTEMI, STEMI)
Plaque rupture and myocardial ischemia
Acute plaque rupture(Stary VI)
Stable plaque
Unstable plaque, plaque ruptur
Plaque ruptur and thrombosis
0
15
30
45
60
75
< 50 50-70 > 70Diameter stenosis (%)
% MI-Patients
68
18 14
Falk et al., Circulation 92: 657-671, 1995
Virmani et al., ESC Stockholm September 2010
Aging and plaque ruptur
Ischemia
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemic injury
TIME IS MUSLCE
Guinea pig
Infarct size(% area at risk)
Schaper et al., Prog Cardiovasc Dis 31: 57-77,1988
0 20 45 90 180 360 (min)
100
80
60
40
20
0
Dog
Extent of collaterals
Rabbit
Rat
Cat
HumansPig
Ischemia-reperfusion injury
Ischemia
Duration of ischemia and mortality
Terkelsen et al., JAMA 304: 763-771, 2010
Cumulative mortality (Kaplan-Meier) in patients with STEMI and PCI (n=6.209)
Duration of ischemiain minutes
0-6061-120121-180181-360
Mor
talit
y (%
)
Follow up (years)
Log-Rank p<0,001
0
10
20
30
0 1 2 3 4 5 6 7
0-60 347 311 278 230 192 138 8761-120 2643 2339 1906 1420 1006 667 375121-180 2092 1836 1503 1183 843 533 278181-360 1127 923 765 647 491 332 172
Patient
CHD
Re-opening ofthe vessel
Reperfused myocardium
Reperfusion Patient
CHD
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Treatment options:Before, during, following ischemia
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Treatment options before ischemia:plaque stabilization, collateralization, preconditioning
Development of an unstable plaque
Libby und Aikawa, Nature Med 8: 1257-1262, 2002
A. Endo, Journal of Antibiotics 29:1346-1348, 1976
Avoiding plaque rupture: statins (1976)
4S 1994WOSCOP 1995CARE 1996AFCAPS 1998LIPID 1998HPS 2002LIPS 2002PROSPER 2002ASCOT 2003Kombiniert
Statine Plazebo
0.5 1 2
Studie Jahr
Akira Endo
Meta-Analysis: 69000 PatientsDeath or myocardial infarction
Cheung et al., Br J Clin Pharmacol 57:640-651, 2004
Catheter
X
Coronary occlusion
CatheterX
Coronary occlusion
Collateral vessel growthPatient
CHD
Ischemia
Inflammation
Collateral vesselgrowth
MCP-1
TNFα
Stenosis orPartial occlusion
Collateral vessel growth
Normalblood flow
Patient
CHD
Coronary occlusion
Control
Pre-con(Ischemia/Drugs) hrs
hrs
Infarct size(% Area at risk)
Control Pre-con
30
25
10
20
15
5
0
p<0.05
Endogenous cardioprotection: Ischemic Preconditioning
First window (<2 hrs)Second window (>24hrs)Third window (>6hrs)
STOMACH
LUNGS
LIVER
SKIN FLAP UPPER LIMB
LOWER LIMB
KIDNEY
SMALL INTESTINE
SKELETALMUSCLE
BRAIN
Endogenous cardioprotection: Remote Preconditioning
Endogenous cardioprotection: Ischemic Preconditioning
Kloner et al., Circulation 91: 37-47, 1995
Death
Heart failure/shock
Pre-infarction angina
Yes No
Death/shock
CK-release (24 h)
Collaterals
4/155 (3%) 18/254 (6%)
1/155 (1%) 15/254 (6%)
4/155 (3%) 25/254 (10%)
115 U 151 U
8/85 (9%) 33/146 (23%)
Endogenous cardioprotection: Ischemic Pre- and Postconditioning
„ … both phenomena work perfectly in healthy hearts, however, protection might be lost with co-morbidities…! “
Heusch, Boengler, Schulz, Circulation 118: 1915-1919, 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
GPCR
PI3K
ROS
PKG
mitochondrium
p38
adenosinebradykininopioids, UCN
NO
IL-6 typecytokines
gp130 TNF-R
JAK
TNFα
KATP
PKC
mitochondrium
Akt ERK
P70S6K
adenosine bradykininopioids, UCN
GPCR PI3K
sGC
Akt
eNOS
NO
eNOS
NO
NPR
ANPBNP
IGF-1FGF-2
GSK3β
aldose reductase
nucleusmitochondrium
STAT3 NO
pGC
MPTP
onlyadenosine H11K
iNOS
MPTP
MnSODSIRT1
CB-R
adipo-nectin
AMPK
: age-dependent: species-dependent
NPR
Preconditioning: Signal transduction
Cx43
Boengler et al., Cardiovasc Res 67: 234-244, 2005
Boengler et al., Basic Res Cardiol 104: 141-147, 2009
Rodriguez-Sinovas et al., Circ Res 99:93-101, 2006
Heinzel et al., Circ Res 97:583-586, 2005
Rottlaender et al., J Clin Invest 120:1441–1453, 2010
Görbe et al., Am J Physiol Heart Circ Physiol. 2011 Mar 11
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Treatment options during ischemia:hemodynamics, per-conditioning
Heart rate reduction [1/min]
Infarct size reduction [%]
-50
-40
-30
-20
-10
0
PropranololAtenolol
Timolol
Metoprolol
Metoprolol
Propranolol
Ischemia-reperfusion injury: ß-blockade
-4 -8 -12 -16 -20 -24
PatientCreatine kinase releaseKjekshus, Am J Cardiol 57: 43F-49F (1986)
Patient
CHD
Patient
CHD
Endogenous cardioprotection: Perconditioning
Patient
CHD
Endogenous cardioprotection: Perconditioning
Perconditioning
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Treatment options following ischemia:Postconditioning, spreading of injury
Ca overloadand hyper-contracture
2+
Physicalinteraction
(interc. discs)Adjacentcells
Spreadingof injury
Chemicalinteraction
(GJ)
Reperfusion injury
BDM: Uncoupler of gap junctions(phosphatase inhibitor)
Reperfusion injury
40
30
20
10
0 Control BDM-Treated
p<0.05
Infarct size(% Area atrisk)
Anesthetized pig
Garcia-Dorado et al., Circulation 85:1160-74, 1992
Coronary occlusion
Control
Precon(Ischemia/Drugs)
Postcon(Ischemia/Drugs)
hrs
hrs
hrs
Infarct size(% Area at risk)
Control Precon Postcon
30
25
10
20
15
5
0
p<0.05
Endogenous cardioprotection: Pre- and Post-conditioning
1’ 1’ 1’ 1’
1’1’1’1’
ReperfusionOccludedcoronary artery
Direct stenting
Balloon inflations - deflations
Postcond
Control
200
300
400
500
ns
Control PostC
(min)
20
30
40
50
Control PostC
ns
(%) Area at RiskDuration of Ischemia
0
1000
2000
3000
4000
5000
4h 8h 24h 48h 72h
ControlPostC
CK release (AUC)
PCI
-36% (p<0.05)
Control PostC0
5
10
15
20
25
30
0
10
20
30
40
(AU
C x
104
)
(per
fusi
on d
efec
t ind
ex %
)
PostCControl
p<0.05
Day 1–3 CK release SPECT at 6 months
Staat et al., Circulation 112: 2143-2148, 2005 Thibault et al., Circulation 117:1037-44, 2008
p<0.05
Reperfusion
Endogenous cardioprotection: Ischemic Postconditioning
Heusch, Boengler, Schulz, Circulation 118: 1915-1919, 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
GPCR
PI3K
ROS
PKG
mitochondrium
p38
adenosinebradykininopioids, UCN
NO
IL-6 typecytokines
gp130 TNF-R
JAK
TNFα
KATP
PKC
mitochondrium
Akt ERK
P70S6K
adenosine bradykininopioids, UCN
GPCR PI3K
sGC
Akt
eNOS
NO
eNOS
NO
NPR
ANPBNP
IGF-1FGF-2
GSK3β
aldose reductase
nucleusmitochondrium
STAT3 NO
pGC
MPTP
onlyadenosine H11K
iNOS
MPTP
MnSODSIRT1
CB-R
adipo-nectin
AMPK
: age-dependent: species-dependent
NPR
Pre- and Post-conditioning: Signal transduction
Gomez et al., Am J Physiol 293: H1654-H1661, 2007
Area at risk (%LV) Infarct size (%AAR)
Mice
Ischemic Postconditioning: Signal transduction
(Cyclosporine A analogue)
P<0.05
0
1000
2000
3000
4000
5000
6000 CK release ControlCsA
(UI/L
)
0
50
100
150
200
250 TnI release
P<0.05P<0.05
Piot et al., New Engl J Med 359, 473-481, 2008
Pharmacological Postconditioning
Direct stentingCoronary artery occlusion
Cyclosporine A (or saline)(2.5 mg/kg, IV bolus)
Day 1-3CK / TnI release
Infarct size
Patient
CHD
Ischemia Reperfusion
Reperfusion-Injury
Ischemic-InjuryM
yoca
rdia
l dam
age
Time
Ischemia-reperfusion injury
Treatment options:Before, during, following ischemia