PD Dr. Kerstin Boengler

Physiologisches Institut

Ischemia/reperfusion injury: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, thrombosis andmyocardial death

0

15

30

45

60

75

< 50 50-70 > 70Diameter stenosis (%)

% MI-Patients

68

18 14

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

Ischemia

Ischemic-InjuryM

yoca

rdia

l dam

age

Time

Ischemic injury

TIME IS MUSCLE

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

Burns et al., J Am Coll Cardiol 39:30–36, 2002

6 Monthmortality(%)

Infarct size (% area at risk)

Myocardial infarction and prognosisPatient

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 2003combined

Statin Plazebo

0.5 1 2

Study Year

Akira Endo

Meta-Analysis: 69000 PatientsDeath or myocardial infarction

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

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)

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

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

RIPC RIPC + morphine

Ischemia Reperfusion

Reperfusion-Injury

Ischemic-InjuryM

yoca

rdia

l dam

age

Time

Ischemia-reperfusion injury

Treatment options following ischemia:Postconditioning

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