18th ESCTS Conference Plenary Lecture on Myocardial Ischemia and Protection

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

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

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

Ancient Egyptians’ Internal Medicine

Abd-Elfattah, Anwar

Ancient Egyptians’ Surgical Procedural Protocol

Abd-Elfattah, Anwar

DETERMINANTS OF VENTRICULAR FUNCTION

CONTRACTILITY

PRELOAD AFTERLOAD

STROKE
VOLUME

- Synergistic LV contraction
- Synergistic LV contraction HEART
- LV wall integrity
- LV wall integrity
- Valvular competence
RATE
- Valvular competence

CARDIAC OUTPUT

Abd-Elfattah, Anwar

Ischemia

Early Effects Late Effects

Epi release, tachycardia
ATP depletion
No-Reflow
ADP formation
Reperfusion
Inosine formation Platelets activation and
Granulocytes
plugging
Hypoxanthine
Xanthine
Xanthine oxidase

Superoxide radicals

Superoxide radicals .O2-

.O2-

Infarction Inflammation
Chemoattractants Apoptosis

Neutrophils infiltration Abd-Elfattah, Anwar

Hormesis
Biological explanation of the adaptive response to stress
“memory”

Adaptive Response Memory:

– Acute “short” (hours-3 days)
– Chronic with disease-mediated stress

Normal Physical & Stress &
Growth Environmental Stress Disease
Exercise Emotional Stress
Development
Differentiation Heat shock Elevated
Cell Cycle Cold shock Neurotransmitters
Toxic Pollutants
Metabolic Inhibitors Fever
Infection
Inflammation

Oxidative stress
(Ischemia, anoxia,
hypoxia, sickle
Receptor cell anemia,
Congenital
Anomalies-mediated
Receptor
cyanosis)
Receptor
Metabolic
Syndromes

Signal Gene Signal Hypertrophied and
Transduction Transduction dilated
Activation Cardiomyopathy
Tachycardia
Protein Synthesis Arrhythmias
Atrial Fibrillation

Abd-Elfattah, Anwar

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

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

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

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.

Possible Cause of Chest Pain “Angina”

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

Abd-Elfattah AS
Non-Cardiomyocyte
Cardiomyocyte Source of
ATP Pool Extracellular Adenine
Nucleotides
during Ischemia

ATP
ATP
ADP
Ecto--5’-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

Is it possible to separate and quantify ischemic and
reperfusion Injuries ?

Abd-Elfattah, Anwar

Targeting Post-Ischemic Reperfusion
injury

Scientific Dream and Clinical Reality

Abd-Elfattah, et al , J. New Surgery 2001; 1:40-51.

On-Pump Targeting of Post-Ischemic
Reperfusion Injury

Pre-operative

Ischemic Myocardial Reperfusion
Injury Injury Injury

Intraoperative:
CPB Post-Operative:
Warm Ischemia Vascular Stunning
Cold Shock Low cardiac output
Depolarization
Rewarming Shock

Ventricular Dysfunction
“Myocardial Stunning”,

Abd-Elfattah, Anwar

Ischemic Myocardial Reperfusion
Injury

Amelioration of Reperfusion-
Mediated
Ventricular Dysfunction

Improved
Recovery and
Survival
Abd-Elfattah, Anwar

Post-Ischemic Resuscitation with
Selective Adenosine Deaminase Inhibitor,
EHNA, and Nucleoside Transport
Blocker, NBMPR

Anwar S. Abd-Elfattah, Ph.D., FAHA

Cardiothoracic Surgery Division
Medical College of Virginia Hospitals of
Virginia Commonwealth University
Richmond, Virginia

Non-Cardiomyocyte
Nucleotides
during Ischemia

ATP
ATP
ADP
Ecto--5’-NTDase
ADP AMP

AMP Adenosine
A1R Inosine
Adenosine

Oxygen delivery

4X O-2- O2 XO
. XO
xanthine
4 X O-2-

Myocardial tissue and plasma level
of inosine is a sensitive marker of
acute and progressive ischemia

NBMPR is a selective blocker of the es-ENT1 nucleoside transporter protein

EHNA is a potent inhibitor of adenosine deaminase

Abd-Elfattah, Anwar

Abd-Elfattah, Anwar
Non-Cardiomyocyte
During Ischemia Nucleotides
ATP
ATP ADP
ADP Ecto--5’-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

Entrapment of intracellular
adenosine and/or inosine
abolishes post-ischemic
reperfusion injury in models of
warm global ischemia on pump

Effect of Normothermic Intermittent Aortic Cross Clamping
on Myocardial ATP in Dogs, in vivo

Abd-Elfattah et al JTCVS 1996

Effect of Normothermic Intermittent Aortic Cross Clamping
on Ventricular Functional Recovery in Dogs, in vivo


Intermittent Normothermic Aortic Cross Clamping Preconditions
against to the Left Ventricular Dysfunction

Sustained Aortic Cross Clamping

110 Intermittent Aortic Cross Clamping
Left Ventricular Performance

*p<0.05 vs. preischemia
ANOVA, n=8
90
dyn.cm2X103

70

50

*
30 *

10

Preischemia I Preischemia II 30'-Reperfusion 60'-Reperfusion

Abd-Elfattah , Anwar

Preconditioning of Stunned Heart

Stunned Heart

Abd-Elfattah et al , J Thoracic and Cardiovascular Surgery 1995

Abd-Elfattah et al J New Surgery, 2001, 1; 1:40-51

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.

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


Myocardial Adenosine

Control
20 8-SPT
*

DPCPX
* E/N
(nmoles/mg protein)

15 E/N+8-SPT
*
* E/N+DPCPX

10

*
5
*
*
*
0
30'-Ischemia 30'-Reperfusion 60'-Reperfusion

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



Recovery of Left Ventricular Performance

120
*#
110
100
90
80
(% Baseline)

70
60 *
50
40 *
30
20
10
0

p<0.05 between groups, ANOVA,
* p<0.05 vs. the Control group, # p<0.05 vs. all other groups (n=8).


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


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.

Case Presentation

A Difficult Heart Transplant

Katlaps G et al

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 ‘+’ cross-match

Katlaps G

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

Explanted heart had hypertrophied cardiomyopathy.
Endocardium infarction due to low perfusion pressure
while on-pump and LVAD

Katlaps G

Role es-ENT1 Nucleoside Transporter
in Post MI Ventricular Fibrillation

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.

Non-Cardiomyocyte
Nucleotides
during Ischemia

ATP
ATP
ADP
Ecto--5’-NTDase
ADP AMP

AMP Adenosine
A1R Inosine
Adenosine

Oxygen delivery

4X O-2- O2 XO
. XO
xanthine
4 X O-2-

Non-Cardiomyocyte
ATP
ATP ADP
ADP Ecto--5’-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

Non-Cardiomyocyte

ATP ATP

ADP ADP
Ecto--5’-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

Groups and Experimental Protocols

Group 1, untreated animals:

Baseline 90’ LAD Occlusion 120’ Reperfusion

Vehicle, iv.

Group 2 , EHNA/NBMPR-preconditioned animals:


EHNA/NMBPR, iv., before ischemia

Group 3: , EHNA/NBMPR-post-conditioned animals:


EHNA/NBMPR, iv., at 90’ ischemia
before reperfusion


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)



*# *#
9
*#
Control
8
E/N Pre-Ischemic
7

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)


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)


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 vs. control group,
# p<0.05 vs. post-ischemic treatment group (n=8/group)


Incidents of Ventricular Fibrillation

100
Incidents of Fibrillation

*
75
Percent

50 *#

25

0
Control E/N-PreC E/N-PostC
*p<0.05 vs Control Group
# p<0.05 vs other groups
(n=8/group) Abd-Elfattah et al JTCVS 2012

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 vs Control group
(n=8/group) Abd-Elfattah et al JTCVS 2012

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

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.

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.

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

P Ahmed Elwatidy
P Jeffry Danetz
P Anwar Abd-Elfattah

18th ESCTS Conference Plenary Lecture on Myocardial Ischemia and Protection

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18th ESCTS Conference Plenary Lecture on Myocardial Ischemia and Protection