The document discusses a presentation given by Anwar Abd-Elfattah at the 18th Egyptian Society of Cardiothoracic Surgery conference on targeting post-ischemic reperfusion injury. It focuses on using selective adenosine deaminase inhibitors and nucleoside transport blockers to entrap intracellular adenosine and protect against reperfusion injury during cardiac surgery involving aortic cross-clamping. The presentation examines the role of the adenosine A1 receptor in this protective effect.
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18th ESCTS Conference Plenary Lecture on Myocardial Ischemia and Protection
1. 18th ESCTS Conference Plenary Lecture
Myocardial Ischemia and Protection:
Current and Future Considerations
Anwar S. Abd-Elfattah, Ph.D., FAHA, AFSTS
Director of Cardiothoracic Surgery Research,
Division of Cardiothoracic Surgery
Department of Surgery
Medical College of Virginia Health System ,Virginia Commonwealth University
Richmond, Virginia, USA
The 18th Egyptian Society of Cardiothoracic Surgery,
Cairo Marriot Hotel , Zamalek, Cairo, EGYPT
March 6-9 2012
2. Off-Pump and On-Pump Targeting of
Post-Ischemic Reperfusion Injury
Anwar S. Abd-Elfattah, Ph.D., FAHA, AFSTS
Director of Cardiothoracic Surgery Research,
Division of Cardiothoracic Surgery
Department of Surgery
Medical College of Virginia Health System ,Virginia Commonwealth University
Richmond, Virginia, USA
The 18th Egyptian Society of Cardiothoracic Surgery,
Cairo Marriot Hotel , Zamalek, Cairo, EGYPT
March 6-9 2012
9. Abd-Elfattah, AS, 2005
Stress
Physical Environmental Chemical Diseases
Chemical
Oxidative Mediation Oxidative
Stress Stress
Dose-dependent
Low Doses Homeostasis Abnormalities High Doses
Signaling Signaling
Mechanisms Mechanisms
Metabolic Molecular Apoptosis
Priming Priming Necrosis
Early Late Death
Adaptive Response Adaptive Response
10. Myocardial Ischemia
⢠Partial (10-99%) vs. total (100%)
⢠Acute vs. Chronic
⢠Regional vs. global
⢠Symptomatic vs. silent
⢠Collateral blood flow vs. lack of collaterization
⢠Arrhythmias and fibrillation
11. Cardiac Surgeons should consider
Cardiac Surgeons should consider
the evolution of clinical stages in their practice
the evolution of clinical stages in their practice
NORMAL
No symptoms
No symptoms
Normal exercise
Normal exercise
Asymptomatic
Normal LV fxn
Normal LV fxn LV Dysfunction
No symptoms
No symptomsCompensated
Normal exercise
Normal exercise
Abnormal LV fxn
Abnormal LV fxnCHF
Decompensated
No symptoms
No symptoms
Exercise
Exercise
CHF
Abnormal LV fxn
Abnormal LV fxn
Refractory
Symptoms
Symptoms
Exercise
Exercise
CHF
Abnormal LV fxn
Abnormal LV fxn
Symptoms not controlled
Symptoms not controlled
with treatment
with treatment
From AHA modified by Abd-Elfattah AS 2012
12. Angina
Sequence of Events Following Occlusion of a Coronary Artery Following coronary artery occlusion
diastolic, systolic, and electrocardiographic (ECG) changes precede the development of angina. From
Conti, Bavry, Petersen Silent Ischemia, JACC 2012 ;59.
13. Possible Cause of Chest Pain âAnginaâ
Ammonia
Ammonia-induced pain
Ammonia
Adenosine deaminase Ammonia
Adenosine Inosine + NH4
Na+, Ca2+, lactate
Demand>Supply
ATP, Glutamate
Lack of O2
Sympathetic Tachycardia
Stimulation
Catecholamine,
ATP release
Modified by Abd-Elfattah AS 2012
14. Abd-Elfattah AS
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
Nucleotides
during Ischemia
ATP
ATP
ADP
Ecto--5â-NTDase
ADP AMP
AMP Adenosine
A1R Inosine
Adenosine
Inosine Es-ENT1 Inosine
Oxygen delivery
IPLase during Reperfusion
During Ischemia . Hypoxanthine
4X O-2- O2 XO
. XO
xanthine
4 X O-2-
O2 During Reperfusion
21. Ischemic Myocardial Reperfusion
Injury
Amelioration of Reperfusion-
Mediated
Ventricular Dysfunction
Improved
Recovery and
Survival
Abd-Elfattah, Anwar
22.
23. Post-Ischemic Resuscitation with
Selective Adenosine Deaminase Inhibitor,
EHNA, and Nucleoside Transport
Blocker, NBMPR
Anwar S. Abd-Elfattah, Ph.D., FAHA
Cardiothoracic Surgery Division
Department of Surgery
Medical College of Virginia Hospitals of
Virginia Commonwealth University
Richmond, Virginia
24. Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
Nucleotides
during Ischemia
ATP
ATP
ADP
Ecto--5â-NTDase
ADP AMP
AMP Adenosine
A1R Inosine
Adenosine
Inosine Es-ENT1 Inosine
Oxygen delivery
IPLase during Reperfusion
During Ischemia . Hypoxanthine
4X O-2- O2 XO
. XO
xanthine
4 X O-2-
O2 During Reperfusion
26. Myocardial tissue and plasma level
of inosine is a sensitive marker of
acute and progressive ischemia
27. NBMPR is a selective blocker of the es-ENT1 nucleoside transporter protein
EHNA is a potent inhibitor of adenosine deaminase
Abd-Elfattah, Anwar
28. Abd-Elfattah, Anwar
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
During Ischemia Nucleotides
ATP
ATP ADP
ADP Ecto--5â-NTDase AMP
Adenosine
AMP
EHNA/NBMPR
Adenosine A1R
Inosine
EHNA Es-ENT1 NBMPR
ADA
Inosine IPLase Oxygen delivery
during Reperfusion
Hypoxanthine
During Ischemia .
4 X O-2- O2 XO
. XO
4 X O-2- xanthine
O2
During Reperfusion
40. On-pump inhibition of es-ENT1 nucleoside transporter
and adenosine deaminase during aortic cross clamping
entraps intracellular adenosine and protects against
reperfusion injury:
Role of adenosine A1 receptor
Abd-Elfattah AS, Ding M, Jessen ME, Wechsler AS.
J Thorac Cardiovasc Surg. 2012 Feb 9.
[Epub ahead of print] PubMed PMID: 22325325.
41. The Role of Adenosine A1 Receptor in EHNA/NBMPR-Mediated Protection
against On-Pump Warm Aortic Cross Clamping and Reperfusion Injury
Myocardial ATP
Control 8-SPT DPCPX E/N E/N+8-SPT E/N+DPCPX
45
40
35
*
(nmoles/mg protein)
Myocardial ATP
30
* *
* *
25 * * *
* * *
20 * * *
* * *
15
10
5
0
Baseline Vehicle/E/N 30'-Ischemia 30'-Reperfusion 60'-reperfusion
Abd-Elfattah et al JTCVS 2012
42. The Role of Adenosine A1 Receptor in EHNA/NBMPR-Mediated Protection
against On-Pump Warm Aortic Cross Clamping and Reperfusion Injury
Myocardial Adenosine
Control
20 8-SPT
*
Myocardial Adenosine
DPCPX
* E/N
(nmoles/mg protein)
15 E/N+8-SPT
*
* E/N+DPCPX
10
*
5
*
*
*
0
30'-Ischemia 30'-Reperfusion 60'-Reperfusion
Abd-Elfattah et al JTCVS 2012
43. The Role of Adenosine A1 Receptor in EHNA/NBMPR-Mediated Protection
against On-Pump Warm Aortic Cross Clamping and Reperfusion Injury
Myocardial Inosine
20
15
Control
8-SPT
(nmoles/mg protein)
Myocardial Inosine
DPCPX
E/N
10 E/N+8-SPT
E/N+DPCPX
5
* * * *
* * *
* *
0
30'-Ischemia 30'-Reperfusion 60'-Reperfusion
Abd-Elfattah et al JTCVS 2012
44. The Role of Adenosine A1 Receptor in EHNA/NBMPR-Mediated Protection
against On-Pump Warm Aortic Cross Clamping and Reperfusion Injury
Control 8-SPT DPCPX E/N E/N+8-SPT E/N+DPCPX
Recovery of Left Ventricular Performance
120
*#
110
100
90
80
(% Baseline)
70
60 *
50
40 *
30
20
10
0
Control 8-SPT DPCPX E/N E/N+8-SPT E/N+DPCPX
p<0.05 between groups, ANOVA,
* p<0.05 vs. the Control group, # p<0.05 vs. all other groups (n=8).
Abd-Elfattah et al JTCVS 2012
45. The Role of Adenosine A1 Receptor in EHNA/NBMPR-Mediated Protection
against On-Pump Warm Aortic Cross Clamping and Reperfusion Injury
60
Differences in LV Function between groups
50
40
(% of Baseline)
* *
30
20
10
0
Control-8-SPT EN-8-SPT Control-DPCPX EN-DPCPX
Abd-Elfattah et al JTCVS 2012
46. On-Pump Risk Factors
⢠Low vs. high risk patients
⢠Hypertrophied cardiomyopathy on/off pump
(Case Report).
⢠Low EF on/off Pump
⢠Extracorporeal circulation (platelets, neutrophils,
cytokines, complements, vascular injury
stunning).
⢠Hypothermia; Slow vs. Rapid Cooling
⢠Cardioplegia depolarized vs. hyperpolarized and
electrophysiologic abnormalities.
Abd-Elfattah et al JTCVS 2012
48. The Recipient
⢠59 yo x-marine
⢠Ischemic CM, EF 10-25%
⢠Listed for HTx, status 1B
⢠Sensitized, requires prospective cross-
match
⢠2 donors rejected due to â+â cross-match
Katlaps G
49. The Donor
⢠55 yo male
⢠Collapsed at work, unresponsive taken
to ED
⢠CT- huge Intracranial hemorrhage
⢠Brain death dx. next day
⢠Referred for organ donation 3 hrs later
⢠EF=67%
Abd-Elfattah, Anwar
50. Explanted heart had hypertrophied cardiomyopathy.
Endocardium infarction due to low perfusion pressure
while on-pump and LVAD
Katlaps G
52. Off-Pump Targeting of Post-Ischemic Reperfusion
Injury
I
Abd-Elfattah AS, Aly H, Hanan S, Wechsler AS
Myocardial protection in beating heart cardiac surgery:
I: Pre- or postconditioning with inhibition of es-ENT1
nucleoside transporter and adenosine deaminase
attenuates post-MI reperfusion-mediated ventricular
fibrillation and regional contractile dysfunction.
J Thorac Cardiovasc Surg. 2012 Feb 11. [Epub ahead
of print] PubMed PMID: 22329983.
53. Abd-Elfattah et al JTCVS 2012
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
Nucleotides
during Ischemia
ATP
ATP
ADP
Ecto--5â-NTDase
ADP AMP
AMP Adenosine
A1R Inosine
Adenosine
Inosine Es-ENT1 Inosine
Oxygen delivery
IPLase during Reperfusion
During Ischemia . Hypoxanthine
4X O-2- O2 XO
. XO
xanthine
4 X O-2-
O2 During Reperfusion
54. Abd-Elfattah et al JTCVS 2012
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
During Ischemia Nucleotides
ATP
ATP ADP
ADP Ecto--5â-NTDase AMP
Adenosine
AMP
EHNA/NBMPR
Adenosine A1R
Inosine
EHNA Es-ENT1 NBMPR
ADA
Inosine IPLase Oxygen delivery
during Reperfusion
Hypoxanthine
During Ischemia .
4 X O-2- O2 XO
. XO
4 X O-2- xanthine
O2
During Reperfusion
55. Abd-Elfattah et al JTCVS 2012
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
During Ischemia Nucleotides
ATP ATP
ADP ADP
Ecto--5â-NTDase
AMP AMP
Adenosine
Adenosine A1R
Inosine
ADA Es-ENT1 NBMPR
NBMPR
Oxygen delivery
Inosine IPLase during Reperfusion
Hypoxanthine
During Ischemia .
4 X O-2- O2 XO
. XO
4 X O-2- xanthine
O2
During Reperfusion
56. Groups and Experimental Protocols
Group 1, untreated animals:
Baseline 90â LAD Occlusion 120â Reperfusion
Vehicle, iv.
Group 2 , EHNA/NBMPR-preconditioned animals:
Baseline 90â LAD Occlusion 120â Reperfusion
EHNA/NMBPR, iv., before ischemia
Group 3: , EHNA/NBMPR-post-conditioned animals:
Baseline 90â LAD Occlusion 120â Reperfusion
EHNA/NBMPR, iv., at 90â ischemia
before reperfusion
Abd-Elfattah et al JTCVS 2012
57. Myocardial ATP
40 Control E/N-PreC E/N-PostC Non-Ischemic LV
30
(nmoles/mg Protein)
Myocardial ATP
20
*#
*
* *
* *
10 *
* *
0
Baseline 90' LAD Occlusion 30' Reperfusion 120' Reperfusion
p<0.05 between groups, ANOVA
*p<0.05 vs. Baseline and Non-Ischemic LV, # p<0.05 vs all other groups, (n=8/group)
Abd-Elfattah et al JTCVS 2012
58. Myocardial Adenosine
*# *#
9
*#
Control
8
E/N Pre-Ischemic
7
Myocardial Adenosine
E/N Post-Ischemic
(nmoles/mg Protein)
6 *#
Non-Ischemic LV
5
*#
4
3
2 *
*#
*#
1 * *
* *
0
Baseline 30 60 90 30 60 90 120
LAD Occlusion Time (min) Reperfusion Time (min)
<0.05 between groups, ANOVA,
*p<0.05 vs. Baseline and Non-Ischemic LV, # p<0.001 vs. other groups (N=8)
Abd-Elfattah et al JTCVS 2012
59. Myocardial Inosine
Control E/N Pre-Ischemia E/N Post-Ischemia Non-Ischemic LV
10 *#
9 *#
*#
8
*#
(nmoles/mg Protein)
*#
Myocardial Inosine
7
*#
6
5
* * *
4 *
3 * *
* *
2 *
* *
1
0
Baseline 30 60 90 30 60 90 120
LAD Occlusion Time (min) Reperfusion Time (min)
p<0.05, ANOVA
* p<0.05 vs. control group, # p<0.05 vs. PostC group (n=8/group)
Abd-Elfattah et al JTCVS 2012
60. Systolic Segmental Shortening (%SSS)
Systolic Segmental Shortening
100
*#
*#
50
Control
% of Baseline
E/N Pre-Ischemia
E/N Post-Ischemia
0
-50
-100 90' LADO 120' Rep
p<0.05 between groups, ANOVA
*p<0.05 vs. control group,
# p<0.05 vs. post-ischemic treatment group (n=8/group)
Abd-Elfattah et al JTCVS 2012
61. Incidents of Ventricular Fibrillation
100
Incidents of Fibrillation
*
75
Percent
50 *#
25
0
Control E/N-PreC E/N-PostC
p<0.05 between groups, ANOVA
*p<0.05 vs Control Group
# p<0.05 vs other groups
(n=8/group) Abd-Elfattah et al JTCVS 2012
62. Number of Fibrillation during Reperfusion
15.0
12.5
Number of ventricular Fibrillations
During Reperfusion
10.0
7.5
5.0
*
*
2.5
0.0
Control E/N-PreC E/N-PostC
p<0.05 between groups, ANOVA
* p<0.05 vs Control group
(n=8/group) Abd-Elfattah et al JTCVS 2012
63. Myocardial Protection in Beating Heart Cardiac Surgery:
II: Off-Pump activation of Cardiac Glutamate Receptors Pre
and Post conditions against MI
75
*p <0.05 vs. Control and 5-HD groups
(Infarct size/Area at Risk)
50
% INFARCT SIZE
25
*
*
0
Control Pre-ischemic Glutamate Post-ischemic Glutamate
-5-HD +5-HD -5-HD +5-HD
Abd-Elfattah, Anwar
64. Circ Cardiovasc Qual Outcomes. 2012 Jan 1;5(1):76-84. Epub 2012 Jan 10.
A Comparison of Long-Term Mortality for Off-Pump and
On-Pump Coronary Artery Bypass Graft Surgery
Wu C, Camacho FT, Culliford AT, Gold JP, Wechsler AS, Higgins RS, Lahey SJ,
Smith CR, Jordan D, Hannan EL.
Department of Public Health Sciences, Penn State Hershey College of Medicine,
Hershey PA; Department of Cardiothoracic Surgery, New York University Medical
Center, New York, NY; College of Medicine, University of Toledo, Toledo, OH;
Department of Cardiothoracic Surgery, Drexel University College of Medicine,
Philadelphia, PA; Division of Cardiac Surgery, Ohio State University, Columbus,
OH; Division of Cardiothoracic Surgery, University of Connecticut Health Center,
Farmington, CT; Department of Surgery, Columbia University, New York, NY;
Department of Anesthesiology, Columbia University, New York, NY; School of
Public Health, University at Albany, State University of New York, Rensselaer, NY.
65. Take Home Message
⢠In addition to injury mediated by ischemia, reperfusion
injury during PCI and on-pump and off pump CABG plays
a major role in post-operative outcome following cardiac
surgery.
⢠Purines and the es-ENT1 nucleoside transporter mediate
post-ischemic reperfusion injury.
⢠Selective pharmacologic interventions capable of
modifying the es-ENT1 nucleoside transporter provide
significant myocardial protection during on and off pump
cardiac surgery against ventricular dysfunction and
fibrillation.
⢠Clinical trials are warranted to determine the safety and
efficacy of NBMPR in PCI and CABG.
66. ACKNOWLGEMENT
Collaborators: CT Residents: Research Fellows
Andrew Wechsler, MD David Hamm, MD Mai Ding, MD
David Salter, MD Jim Morris, MD Mohanad Shehab, MD
Richard Embery, MD Charles Murphy, MD N. El-Singaby, Ph.D.
Roberto Bolli, MD Jacque Goldstein, MD Jian Hua Guo, MD.
Mohamed Jerudi, MD Louis Brusting, MD Shi Ping Gao, MD
James Downey, Ph.D. Gert Tuchy, MD Ralph Marktanner, MD
John Lekven, MD Scott Hannon, MD M. Mahgoub, MD
Richard Hopkins, MD C. Mac Dyke, MD M. Taher , MD.
Frances Lee. MD Yung Gu, MD
Gary Dowrking, MD R. Zimmerman, MD.
Rebecca Dignan, MD Ahmed El-Watidy, MD
Robert Messier, MD
Patric Domkowski