This document discusses ischemic preconditioning and postconditioning. It defines preconditioning as brief periods of sublethal ischemia that protect the heart from subsequent ischemia. Postconditioning involves brief coronary occlusions after reperfusion to reduce injury. Mechanisms involve preserving mitochondria and reducing oxidative stress. Human studies show preconditioning reduces infarct size with angina or repeated balloon inflations. Drugs like adenosine may induce preconditioning. Postconditioning involves similar pathways and reduces infarct size in heart attacks. Both techniques aim to reduce cardiac damage from ischemia and reperfusion injury.

1. Clinical Implications
of Ischemic Pre and
Postconditioning
‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
Dr. Mohamed Ahmed Hamouda
MD cardiology, Benha faculty of medicine

2. • A pivotal feature of ischemia is that oxygen
supply to the mitochondria is inadequate to
support oxidative phosphorylation
• After AMI, early reperfusion by thrombolysis
or PCI remains the most-effective strategy for
limiting the size of an evolving infarct.
• Ischemia/reperfusion injury as a composite
entity

3. Myocardial protective mechanisms include:
• Ischemic preconditioning
• Ischemic post conditioning
• Hibernating and stunning myocardium
• The long term development of coronary
collaterals

4. The Preconditioning Phenomenon
Definition:
The protection conferred to ischemic
myocardium by preceding brief periods of
sublethal ischemia.
If we can learn the mechanism of preconditioning,
it may lead to potentially important therapies.

5. The Preconditioning Phenomenon

7. Preconditioning protocol

8. The Preconditioning Phenomenon
Components:
• Classical precoditioning( (First window)
Starts immediately wanes after 1-2 hours
• Second window of protection
Starts after 12-24 hours, lasts up to 72
hours

10. Pathogenesis of preconditioning
• IPC protects the heart by preserving
mitochondrial function and reducing the
oxidative stress that occurs during
ischemia/reperfusion.

11. Pathogenesis of preconditioning
• Glycogen depletion
• Adenosine, acting on A1 or A3 receptor
• Bradykinin
• Opioids
• The role of protein kinases
• Opening of the mitochondrial permeability
transition pore (mPTP) during reperfusion, after
ischemia of sufficient duration

12. Pathogenesis of precoditioning

13. Other types of conditioning
• Remote ischemic precoditioning — localized
ischemia of one vascular bed can protect distant
sites during subsequent ischemia. This could
occur within the same organ or between different
organs
• Non ischemic preconditionig—may be induced
by an increase in oxygen demand as, for example,
during tachycardia.
• Ischemic postconditioning — a series of brief
coronary artery occlusions after a severe ischemic
insult protect against ischemic-reperfusion injury.

14. Manifestations of preconditioning in
the human heart
• There are obvious ethical constraints to
studying IPC in humans.
• Despite these limitations, there are now
several lines of evidence suggesting that the
human myocardium can be preconditioned

15. Manifestations of preconditioning in
the human heart
• In vitro preparations
Isolated human cells and isolated human
atrial trabeculae recapitulate preconditioning
behaviors

16. Manifestations of preconditioning in
the human heart
• Warm up phenomenon:
A second episode of ischemia induced
by exercise is associated with less chest
pain, ST segment change, and lactate
production than a first episode

17. Manifestations of preconditioning in
the human heart
• Variant angina — on Holter monitoring;
Episodes of ST segment elevation separated
from the previous one by less than 30 minutes
were less often associated with complex
ventricular arrhythmias than those separated
by a longer period despite a similar magnitude
and duration of ST segment elevation

18. Manifestations of preconditioning in
the human heart
• Preinfarct angina reduces infarct size and is
associated with better clinical outcome

19. Manifestations of preconditioning in
the human heart
• During PCI, Repeat balloon inflations result in
less chest pain, ST segment elevation, and
lactate production than upon an initial
inflation.
But because balloon inflation coupled with
stenting requires arterial occlusion for about
20–30 s, hardly producing significant ischemia
so not used except for high risk PCI

20. Manifestations of preconditioning in
the human heart
• Aortic cross clamping preserves myocardial
ATP during CABG but this can:
-prolong surgery by 15 to 30 minutes
represents an embolic risk
- and has not been examined in terms of
mortality and morbidity.

21. History of Any Angina - TIMI 4
(%)
0
2
4
6
8
10
12
14
No Angina
Angina
8%
3%
7%
1%
12%
4%p = 0.03
p = 0.006
p = 0.004
In-Hospital
Death
Severe CHF/
Shock
Death
Severe CHF
Shock

22. History of Any Angina - TIMI 4
No Angina Angina
TotalCKunits
0
100
120
140
160 154
119

23. Therapeutic applications of
preconditioning
• Early and complete reperfusion remains the
most effective means of limiting ischemic
injury.
The human myocardium is amenable to
preconditioning

24. Therapeutic applications of
preconditioning
Acute coronary syndromes
• Despite pharmacologic and interventional
approaches, there is still an appreciable incidence
of death or myocardial infarction within 30 days.
• These patients might benefit from pretreatment
with agents that trigger or augment myocardial
preconditioning over a period of several days or
weeks, maintaining the myocardium in
preconditioned state.

25. Therapeutic applications of
preconditioning
• Stable angina
Patients should warm-up prior to exercise.
• Cardiac surgery.
• Cardiac transplantation.

26. Manifestations of preconditioning in
the human heart
Certain preconditioning mimetic agents
can reduce ischemia during balloon
inflation or exercise testing and also in
preinfarct angina.

27. Therapeutic applications of
preconditioning
Certain preconditioning mimetic agents
can reduce ischemia during balloon inflation or
exercise testing and also in preinfarct angina.
• Adenosine, adenosine receptors agonists,
• The KATP channel/opener like nicorandil
• Delta opioids
• Volatile anesthetics generate small amounts of reactive
oxygen species that then trigger preconditioning
• Nitroglycerin

28. Therapeutic applications of
preconditioning
Role of nitroglycerin.
Four-hour infusion of nitroglycerin 24 to 48 hours
before exercise stress testing with stable angina showed
an increase in workload during the test and significant
improvements in the (ECG) manifestations of ischemia.
Nitroglycerin markedly enhanced the tolerance of
the heart to ischemia associated with repeated balloon
inflations.
Since NO has now been implicated in triggering
classical preconditioning nitroglycerin – an NO donor –
may act to reduce additional ischemic episodes acutely
via a preconditioning mechanism

29. Therapeutic applications of
preconditioning
Impairment of Preconditioning
The protective effect of IPC is suppressed by
conditions such as :
• Hypercholesterolemia
• hyperglycemia
• Hypertension
• LV hypertrophy
• Aging
• Obesity

30. Therapeutic applications of
preconditioning
Diabetes mellitus and preconditioning
• IPC is mediated at least in part by activation of
the KATP channel and this channel may be
altered in the diabetic heart;
• Certain oral hypoglycemic drugs (such as
glibenclamide) prevent IPC by blocking the
KATP channel and has been associated with an
increase in early mortality in diabetics
following primary PCI for AMI

31. Postconditioning
Refers to the ability of a series of brief coronary artery
occlusions after a severe ischemic insult to protect
against ischemic-reperfusion injury of the myocardium.
Postconditioning reduces the number of necrotic,
apoptotic, and autophagic cells
In animal models, ischemic postconditioning is almost as
effective as IPC and involves similar pathogenetic
mechanisms

32. For many years it has been shown that the size of a
myocardial infarction is not only determined by
ischemic damage, but also by reperfusion itself.
This reperfusion injury contributes to up to 50% of
the final infarct size.

33. Postconditioning protocols

34. Mechanism of postconditioning

35. Potential Mechanisms of
Postconditioning
A. Triggers including:
1. Adenosine
2. Opioids
3. Erythropoietin
4. Endogenous nitric oxide
5. Reactive oxygen species
6. Acetylcholine
7. Tissue factors
8. Pro-inflammatory cytokines and bradykinin
9. Hydrogen sulfide
B. Mediators –Reperfusion injury salvage kinase pathways
including:
1. Phosphoinositide-3-kinase
2. Extra-cellular signal regulated kinase (1/2) pathways
3. Protein kinases G and C
C. End-effectors such as:
1. Mitochondrial permeability transition pore mPTP
2. Mitochondrial potassium ATP channel

36. Postconditioning
Primary PCI for STEMI
Repeat 30-60 sec balloon inflation at low
pressure results in:
• Greater attenuation of ST-segment elevation
• Improved distal coronary artery flow
• A significant reduction of 36% in infarct size
• 7% improvement in EF at one year

37. Postconditioning
Forearm studies
After 20 minutes of sustained forearm
ischemia, three 10 or 30 second cycles of
alternate ischemia and reperfusion at the onset
of 20 minutes of reperfusion
Results: improved endothelial function

38. Postconditioning
• Some of the drugs demonstrating myocardial
salvage when administered at reperfusion
include:
Adenosine, nitric oxide, opioids,
bradykinin, and erythropoietin, as well as drugs
that activate PKC epsilon.

39. Percutaneous Intermittent
Coronary Sinus Occlusion device
Another mechanical solution that may work by
• improving collateral recruitment
• increased NO production and wash-out of
oxidative radicals

40. Endovascular cooling
Endovascular coils and external cooling
blankets are used to bring the core temperature
of a patient down to 33 degrees during PCI for
acute myocardial infarction showed reduction in
infarct size in the subgroup of patients with an
anterior MI.

41. CONCLUSIONS
Ischemic Conditioning
• Reducing myocardial infarct size
• Reducing cardiac damage during PCI
• Protecting the myocardium during CABG and other
procedures requiring cardiopulmonary bypass
• Protecting the vasculature during vascular surgery
procedures

42. CONCLUSIONS
• Unstable angina
• Before activities that cause angina in patients
with stable angina
• Protecting donor hearts before excision and
transport
• Protecting other organs (brain, kidney and
liver) during episodes of ischemia

43. Thank you