Role of Adenosine in Acute Role of Adenosine in Acute Myocardial InfarctionMyocardial Infarction

Role of Adenosine in Acute Role of Adenosine in Acute Myocardial InfarctionMyocardial Infarction

Presented by:

Mervyn B. Forman, MD, PhD, FACC

Potential Sequelae of Reperfusion on Ischemic Myocardium

Potential Sequelae of Reperfusion on Ischemic Myocardium

Reperfusion Injury• Conversion of reversibly injured endothelial and

myocardial cells to irreversibly injured cells

Myocardial Stunning• Prolonged left ventricular dysfunction of

reversibly injured myocytes

Reperfusion Arrhythmias

Myocardial Reperfusion InjuryMyocardial Reperfusion InjuryMyocardial Reperfusion InjuryMyocardial Reperfusion Injury

Definition: Conversion of reversibly injured endothelial and myocardial cells to irreversibly injured cells during the peri-reperfusion period.

Not synonymous with entity of acceleration of necrosis of cells that are already irreversibly injured.

Vascular Changes Vascular Changes with Reperfusionwith Reperfusion

Vascular Changes Vascular Changes with Reperfusionwith Reperfusion

A3

A2AA2B

A1(Very high affinity)

(High affinity)(Low affinity)

(Low affinity)

Gi

Gs

ACKATPPLC Ca2+PLA2

Isoforms have distinct, but overlapping, cellular distribution

and are widely expressed inmost cells/tissues/organs

of the body.

Adenosine Receptors: SignalAdenosine Receptors: SignalTransduction MechanismsTransduction Mechanisms

Adenosine Receptors: SignalAdenosine Receptors: SignalTransduction MechanismsTransduction Mechanisms

Effects of Adenosine A1Effects of Adenosine A1

SA NODE AV NODE VENTRICLE MYOCYTE BLOOD VESSELS

Θ Θ Θ Θ

CHRONOTROPIC EFFECT

DROMOTROPIC EFFECT

INOTROPIC EFFECT

PRE- & POST- CONDITIONING

NEURO-TRANSMITTER

RELEASE

A1

Effects of Adenosine A2A/A2B

Effects of Adenosine A2A/A2B

VESSELS PLATELETS NEUTROPHILS VSMC’S & CARDIAC

FIBROBLASTS

ENDOTHELIAL CELL

Θ Θ Θ DILATATION AGGREGATION

TxB2 RELEASEADHERANCE TO

EC’s & FREE RADICAL RELEASE

PROLIFERATION & MIGRATION

AND ECM PRODUCTION

ANGIO- & VASCULO- GENESIS

A2A/A2B

Effects of Adenosine AEffects of Adenosine A33Effects of Adenosine AEffects of Adenosine A33

MYOCYTE ENDOTHELIAL

VSM CELLS

PRE-CONDITIONING,

↑ANTI-OXIDANT

ENZYMES

↑ANTI-OXIDANT

ENZYMES

A3

Reperfusion

Mechanisms of Myocardial Reperfusion Mechanisms of Myocardial Reperfusion Injury and Effects of AdenosineInjury and Effects of Adenosine

LeukocytesTxA2, PAF,Ang II, NE, ET-1

Calcium OxygenPlatelets

A2A/2B AngiogenesisVasculogenesis

MPOProteases

Cellular CalciumOverload

PlateletAggregation

VasoconstrictionOxygen

FreeRadicals

No Reflow

Vascular Plugging

Cell Death

A2A A2AA2A A1

A3

ADENOSINE

Infarct Size with Infarct Size with Intracoronary AdenosineIntracoronary Adenosine

Infarct Size with Infarct Size with Intracoronary AdenosineIntracoronary Adenosine

Olafsson et al. Circulation 1987; 76:1135-45

42% 44%40.9%

*9.9%

18%

** 4.6%

0%

10%

20%

30%

40%

50%

AR/LV AN/AR AN/LV

Control

Adenosine

* p<0.001

**p=0.002

Effect of IV AdenosineEffect of IV AdenosineEffect of IV AdenosineEffect of IV Adenosine

Pitarys et al. Circulation 1991; 83: 237-47

30.2

*39.1

35.3

**17.1

11

7

0

10

20

30

40

50

(%)

AR/LV AN/AR AN/LV

Control

Adenosine

* p<.05

**p<.01

Transverse Myocardial Slice in Transverse Myocardial Slice in Adenosine and Control AnimalAdenosine and Control AnimalTransverse Myocardial Slice in Transverse Myocardial Slice in Adenosine and Control AnimalAdenosine and Control Animal

Regional Ventricular Regional Ventricular Function in Ischemic ZoneFunction in Ischemic Zone

Regional Ventricular Regional Ventricular Function in Ischemic ZoneFunction in Ischemic Zone

Significant improvement noted at 3 and 72 hours after reperfusion.

Pitarys et al. Circulation 1991; 83: 237-47

***

0

10

20

RS OCC vs 3H RS OCC vs 72H

(%)

Control Adenosine *p< .03 **p < .01

**

**

**

21

17.3

-2.6

5.5

11

20

-5

0

5

10

15

20

25

Base OCC Rep 3H Rep 72H

Isc

he

mic

Zo

ne

Ra

dia

l

Sh

ort

en

ing

(%

)

Control Adenosine * p<.03 **p<.01

IC Adenosine with IC Adenosine with PCI in AMIPCI in AMI

IC Adenosine with IC Adenosine with PCI in AMIPCI in AMI

Marzilli et al. Circulation 2000; 101:2154-2159

*2%

19%

*64%

36%

0%

20%

40%

60%

80%

100%

(%)

Remodeling Recovery

ADO

Saline

*p= 0.0001

27

*19

1

*7

0

5

10

15

20

25

30

Nu

mb

er o

f P

atie

nts

TIMI 3 No-Reflow

ADO

Saline

*p< 0.05

*0

5

*16

23

*5

13

0

5

10

15

20

25

Nu

mb

er o

f P

atie

nts

Death Q wave MI MACE

Saline*p < 0.05

ADO

Final Infarct Size Final Infarct Size (as a Percentage of the Left Ventricle)(as a Percentage of the Left Ventricle)

Final Infarct Size Final Infarct Size (as a Percentage of the Left Ventricle)(as a Percentage of the Left Ventricle)

AMISTAD TRIAL. J AM Coll Cardiol 1999; 34: 1711-20

Median values shown above horizontal lines

n=101n=96

n=39n=38

n=62n=58

p=0.96

p=0.014p=0.085

% o

f Le

ft

Ven

tric

le

0

20

40

60

80

Overall(33% reduction)

Anterior(67% reduction)

Nonanterior(0% reduction)

1319.5 15

45.5

11.5 11.5

Adenosine Placebo

AMISTAD IIAMISTAD IIAMISTAD IIAMISTAD II

Anterior Wall MI (STE, LBBB) 6h No contraindication for lysis No hypotension No bradycardia No obstructive airway disease

2118 PatientsASA

PlaceboAdenosine

50mcg/Kg/minX 3h

Adenosine70mcg/Kg/min

X 3h

Fibrinolysis or PTCA

Follow-up for 6 months

Infarct size (5 d)(243 patients)

AMISTAD II – Non MACE AMISTAD II – Non MACE Adverse EventsAdverse Events

AMISTAD II – Non MACE AMISTAD II – Non MACE Adverse EventsAdverse Events

PLACEBO ADENOSINE 50mcg/Kg/min

ADENOSINE 70mcg/Kg/min

Hypotension 14% 19% 18%

Bradycardia 2% 3% 3%

Tachycardia 4% 2% 4%

Nausea/Vomiting 7% 7% 8%

Premature Drug Discontinuation

4% 6% 5%

Second-degree AV Block 0% 0% 0%

Third-degree AV Block 0% 0% 0%

AMISTAD II Infarct SizeAMISTAD II Infarct SizeAMISTAD II Infarct SizeAMISTAD II Infarct Size

57% reduction in median infarct size with 70mcg/kg/min group relative to placebo

p=0.122

26%23%

11%

10%

20%

30%

40%

Placebo 50 mcg 70mcg

Median LV Infarct Size (%)

p=0.028

0%

26%

17%

0%

10%

20%

30%

40%

Median LV Infarct Size (%)

p=0.078

Placebo Pooled Adenosine

AMISTAD II- Post Hoc AnalysisAMISTAD II- Post Hoc Analysis AMISTAD II- Post Hoc AnalysisAMISTAD II- Post Hoc Analysis

Effect of early reperfusion treatment (3.1 hrs) on clinical outcomes

9.2%

5.2%

11.2%

7.3%

17.2%

12.0%

0%

5%

10%

15%

20%

Death at 1month

Death at 6months

Composite6 months

PlaceboPooled Adenosine* p=0.01**p=0.03+ p=0.02

+

***

Effect of Adenosine with Effect of Adenosine with Varying Duration of IschemiaVarying Duration of Ischemia

Effect of Adenosine with Effect of Adenosine with Varying Duration of IschemiaVarying Duration of Ischemia

CONTROLADENOSINE

*

P<0.03 (ADO vs. CONTROLP<0.01 (ADO vs. CONTROL)**

***

40 MIN 120 MIN 180 MIN

70

40

30

20

10

AN

/AR

(%

)

Overall Survival CurvesOverall Survival CurvesOverall Survival CurvesOverall Survival Curves

ATTACC Study. Eur J Clin Pharmacol 2003; 59:1-9

Placebo-anterior

Adenosine-anterior

1.00

0.90

0.85

0.80

0.75

0.70

0.95

R.R. 0.64, 95% C.I. 0.37 – 1.11, p = 0.13

600 800 1000 1200 14000 200 400

Time (days)

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing Complete Censored

Key PointsKey PointsKey PointsKey Points

Adenosine shown consistently to reduce infarct size

70mcg/kg/min infusion for 3 hours shows 57% relative reduction in infarct size

Strong trend toward less death and CHFSignificant reduction in death and composite endpoint at 6 months in Adenosine group treated early (~3.1 hrs) -post hoc analysis

MI patients who undergo reperfusion therapy: