adenosine information storage (purine base in dna) information retrieval (purine base in rna) energy...
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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