Adenosine

Information Storage(Purine base in DNA)

Information Retrieval(Purine base in RNA)

Energy Metabolism(ATP/ADP)

N

NN

N

NH2

O

OHOH

HH

H

HO

H

Communications

(Adenosine importantly directs cell-to-cell signaling with significant consequences for

organ function.)

Intracellular Signaling

(cAMP)

A3 A2AA2BA1

(Very high affinity)(High affinity)

(Low affinity)

Gi/oGs

ACK+

Channels(KATP)

PLCCa2+

Channels

Subtypes have distinct, but overlapping, cellular distribution

and are widely expressed inmost cells/tissues/organs

of the body.

Adenosine Receptors: SignalAdenosine Receptors: SignalTransduction MechanismsTransduction Mechanisms

alphasalphaibeta/gamma

Gq/11

alphaq/11

Adenosine Production: During A Crisis Event

ATP

ADP

AMP

ADO

CELLATP

ADP

AMP

ADO

Intr

acell

ular

ATP Pat

hway

Ext

race

llula

r

AT

P Pa

thw

ay

Adenosine Production: Constitutive

ADO

SAH

CELL

ADO

SAM

Met

hyla

tion

Pathw

ay

Adenosine Production: Regulated

cAMP

CELL

cAMP

AMP

ADO

ATP

ACEcto-PDE

Ecto-5’NT

ParacrineAutocrine

Transp

orter

cAMP-Adenosine

Pathway

Heart: Protection from reperfusion injury

1,000,000 Americans suffer a heart attack (AMI) annually

200,000 (20%) die during or soon after AMI

TOO MUCH HEART DAMAGEIN AFTERMATH OF AMI!!

Mervyn B. Forman, MD, PhD, FACCAtlanta Cardiovascular Associates

Survivors: 22% of males and 46% of females are disable by heart failure

Survivors: up to 15-fold greater risk of death

Myocardial Reperfusion Injury

Angioplasty (with or without stenting)

ThrombolyticTherapy

Myocardial 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.

Myocardial Reperfusion InjuryMyocardial Reperfusion Injury

• Experimental Evidence of Reperfusion Injury• MRI evidence of time-related infarct

extension after reperfusion• Enhanced myocardial salvage with

therapeutic agents administered after reperfusion

• Differential histology between reperfused

and non-reperfused myocardium

Vascular Changes Vascular Changes with Reperfusionwith Reperfusion

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 A1/3

A1/3

ADENOSINE

Effect of IV Adenosine at Reperfusion Effect of IV Adenosine at Reperfusion on Infarct Size in a Dog Model of AMIon Infarct Size in a Dog Model of AMI

Implanted LAD snare in 22 dogs;5-7 days later, 90-min LAD occlusion in closed-chest dogs;

0.15 mg/kg/min adenosine IV for 150 min starting at reperfusion;AN/AR at 72 hrs post-AMI (Mallory’s trichrome stain/Monastral blue)

35 ± 4 %

17 ± 4 %

0

10

20

30

40

50

(%)

AN/AR

Control (n=13)

Adenosine (n=9)

p<0.01

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

Adenosine-Treated Control

Regional Ventricular Function in Ischemic ZoneRegional Ventricular Function in Ischemic Zone

Contrast ventriculography and calculation of radial shortening

**

**

**

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 S

ho

rten

ing

(%

)

Control Adenosine

**p<.01

Endocardial Blood Flow (ml/min/g) in Endocardial Blood Flow (ml/min/g) in Treated and Control AnimalsTreated and Control Animals

Base OCC REP 1 HR 2 HR 24 HR Base OCC REP 1 HR 2 HR 24 HR

EN

DO

CA

RD

IAL

FL

OW

1.0

2.0

ADENOSINE ADENOSINE

CONTROL ZONE CENTRAL ZONE

ADENOSINE CONTROL

*P<0.05 **P<0.01

Radioactive microspheres

Lab Bench

Bedside

Prospective clinical trials

• ATTACC STUDY (Phase 2)• AMISTAD TRIAL (Phase 2)• AMISTAD II TRIAL (Phase 3)

AMISTAD IIAMISTAD II

2118 Patients withAnterior STEMI & Reperfusion

Therapy within 6 Hrs of Symptoms

PlaceboAdenosine

50 μg/Kg/minX 3h

Adenosine70 μg/Kg/min

X 3h

Fibrinolysis or PTCA

Follow-up for 6 months

Infarct size (5 d)(243 patients)

13 Countries390 Study Sites

AMISTAD II – Adverse EventsAMISTAD II – Adverse Events

PLACEBO ADENOSINE 50 μg/Kg/min

ADENOSINE 70 μg/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 Size

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

p=0.122

26%23%

11%

10%

20%

30%

40%

Placebo 50 μg 70 μg

Median LV Infarct Size (%)

p=0.028

0%

Primary Clinical End Points AMISTAD II: INTENT-TO-TREAT

End Point PlaceboPooled

AdenosineP-value

 n 703 1,414

 Death 83 (11.8%) 146 (10.3%) 0.29

 In-hospital CHF 28 (4.0%) 60 (4.2%) 0.75

 Re-hospitalization for CHF

30 (4.3%) 56 (4.0%) 0.81

 Composite 126 (17.9%) 231 (16.3%) 0.43

JACC 2005, 45: 1775-80.

“…because animal studies demonstrate that adenosine’s beneficial effects are lost if myocardial

ischemia occurs for more than 3 h , adenosine would prevent reperfusion injury only in patients receiving

adenosine within the first 3 h after coronary occlusion. Therefore, a subset analysis of the adenosine groups

who were reperfused within 3 h may yield an even greater reduction in clinical end points.”

JACC 47, 1235, March , 2006(letter to editor of JACC by Forman and Jackson)

Aims The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II).

Methods and Results Patients presenting with ST-segment elevation anterior AMI were randomized toreceive placebo vs. adenosine (50 or 70 mg/kg/min) for 3 h starting within 15 min of reperfusiontherapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. or , the median 3.17 h, and by

reperfusion modality. In patients receiving reperfusion <3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P=0.014), 6-month mortality (7.3 vs. 11.2%, P =0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P =0.022). Patients reperfused beyond 3 h did not benefit from adenosine.

Conclusion In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

European Heart Journal 27: 2400-2405, Oct., 2006

DEATH AT 6 MONTHS IF DEATH AT 6 MONTHS IF THERAPY WITHIN 3 HOURSTHERAPY WITHIN 3 HOURS

Adenosine: 7.3% (n=716)

Placebo: 11.2% (n=350)

P=0.033

Adenosine: 800,000/y x 0.073 = 58,400/y

Placebo: 800,000/y x 0.112 = 89,600/y

Lives Saved: 89,600/y – 58,400/y = 31,200/y

Key PointsKey Points

– Adenosine reduces infarct size

– Adenosine reduces risk of death

AMI patients who undergo reperfusion therapy:

What is the “No-Reflow” Phenomenon?

The “no-reflow” phenomenon is defined as impaired tissue perfusion despite successful treatment

of the target macrovascular lesion.

How often does the “No-Reflow” Phenomenon Occur?

29-44% of reperfused patients

50-80% of reperfused patients with LAD lesion

Does the “No-Reflow” Phenomenon Affect Outcome?

YES!

Correlates with infarct size, ventricular function

and early and late mortality

What is the Mechanism of the “No-Reflow” Phenomenon?

Multifactorial:

Damage to the microvascular endothelium

Wash-in of potent vasoconstrictors

Neutrophil activation

Platelet activation

Reperfusion

Why Use Adenosine to Prevent the Why Use Adenosine to Prevent the No-Reflow Phenomenon?No-Reflow Phenomenon?

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 A1/3

A1/3

ADENOSINE