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Clinical Implications
of Ischemic Pre and
Postconditioning
‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
Dr. Mohamed Ahmed Hamouda
MD car...
• A pivotal feature of ischemia is that oxygen
supply to the mitochondria is inadequate to
support oxidative phosphorylati...
Myocardial protective mechanisms include:
• Ischemic preconditioning
• Ischemic post conditioning
• Hibernating and stunni...
The Preconditioning Phenomenon
Definition:
The protection conferred to ischemic
myocardium by preceding brief periods of
s...
The Preconditioning Phenomenon
Preconditioning protocol
The Preconditioning Phenomenon
Components:
• Classical precoditioning( (First window)
Starts immediately wanes after 1-2 h...
Pathogenesis of preconditioning
• IPC protects the heart by preserving
mitochondrial function and reducing the
oxidative s...
Pathogenesis of preconditioning
• Glycogen depletion
• Adenosine, acting on A1 or A3 receptor
• Bradykinin
• Opioids
• The...
Pathogenesis of precoditioning
Other types of conditioning
• Remote ischemic precoditioning — localized
ischemia of one vascular bed can protect distant
...
Manifestations of preconditioning in
the human heart
• There are obvious ethical constraints to
studying IPC in humans.
• ...
Manifestations of preconditioning in
the human heart
• In vitro preparations
Isolated human cells and isolated human
atria...
Manifestations of preconditioning in
the human heart
• Warm up phenomenon:
A second episode of ischemia induced
by exercis...
Manifestations of preconditioning in
the human heart
• Variant angina — on Holter monitoring;
Episodes of ST segment eleva...
Manifestations of preconditioning in
the human heart
• Preinfarct angina reduces infarct size and is
associated with bette...
Manifestations of preconditioning in
the human heart
• During PCI, Repeat balloon inflations result in
less chest pain, ST...
Manifestations of preconditioning in
the human heart
• Aortic cross clamping preserves myocardial
ATP during CABG but this...
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-H...
History of Any Angina - TIMI 4
No Angina Angina
TotalCKunits
0
100
120
140
160 154
119
Therapeutic applications of
preconditioning
• Early and complete reperfusion remains the
most effective means of limiting ...
Therapeutic applications of
preconditioning
Acute coronary syndromes
• Despite pharmacologic and interventional
approaches...
Therapeutic applications of
preconditioning
• Stable angina
Patients should warm-up prior to exercise.
• Cardiac surgery.
...
Manifestations of preconditioning in
the human heart
Certain preconditioning mimetic agents
can reduce ischemia during bal...
Therapeutic applications of
preconditioning
Certain preconditioning mimetic agents
can reduce ischemia during balloon infl...
Therapeutic applications of
preconditioning
Role of nitroglycerin.
Four-hour infusion of nitroglycerin 24 to 48 hours
befo...
Therapeutic applications of
preconditioning
Impairment of Preconditioning
The protective effect of IPC is suppressed by
co...
Therapeutic applications of
preconditioning
Diabetes mellitus and preconditioning
• IPC is mediated at least in part by ac...
Postconditioning
Refers to the ability of a series of brief coronary artery
occlusions after a severe ischemic insult to p...
For many years it has been shown that the size of a
myocardial infarction is not only determined by
ischemic damage, but a...
Postconditioning protocols
Mechanism of postconditioning
Potential Mechanisms of
Postconditioning
A. Triggers including:
1. Adenosine
2. Opioids
3. Erythropoietin
4. Endogenous ni...
Postconditioning
Primary PCI for STEMI
Repeat 30-60 sec balloon inflation at low
pressure results in:
• Greater attenuatio...
Postconditioning
Forearm studies
After 20 minutes of sustained forearm
ischemia, three 10 or 30 second cycles of
alternate...
Postconditioning
• Some of the drugs demonstrating myocardial
salvage when administered at reperfusion
include:
Adenosine,...
Percutaneous Intermittent
Coronary Sinus Occlusion device
Another mechanical solution that may work by
• improving collate...
Endovascular cooling
Endovascular coils and external cooling
blankets are used to bring the core temperature
of a patient ...
CONCLUSIONS
Ischemic Conditioning
• Reducing myocardial infarct size
• Reducing cardiac damage during PCI
• Protecting the...
CONCLUSIONS
• Unstable angina
• Before activities that cause angina in patients
with stable angina
• Protecting donor hear...
Thank you
Clinical Implications  of Ischemic Pre and Postconditioning
Clinical Implications  of Ischemic Pre and Postconditioning
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Clinical Implications of Ischemic Pre and Postconditioning

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Clinical Implications of Ischemic Pre and Postconditioning

  1. 1. Clinical Implications of Ischemic Pre and Postconditioning ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬ Dr. Mohamed Ahmed Hamouda MD cardiology, Benha faculty of medicine
  2. 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. 3. Myocardial protective mechanisms include: • Ischemic preconditioning • Ischemic post conditioning • Hibernating and stunning myocardium • The long term development of coronary collaterals
  4. 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. 5. The Preconditioning Phenomenon
  6. 6. Preconditioning protocol
  7. 7. 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
  8. 8. Pathogenesis of preconditioning • IPC protects the heart by preserving mitochondrial function and reducing the oxidative stress that occurs during ischemia/reperfusion.
  9. 9. 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
  10. 10. Pathogenesis of precoditioning
  11. 11. 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.
  12. 12. 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
  13. 13. Manifestations of preconditioning in the human heart • In vitro preparations Isolated human cells and isolated human atrial trabeculae recapitulate preconditioning behaviors
  14. 14. 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
  15. 15. 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
  16. 16. Manifestations of preconditioning in the human heart • Preinfarct angina reduces infarct size and is associated with better clinical outcome
  17. 17. 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
  18. 18. 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.
  19. 19. 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
  20. 20. History of Any Angina - TIMI 4 No Angina Angina TotalCKunits 0 100 120 140 160 154 119
  21. 21. Therapeutic applications of preconditioning • Early and complete reperfusion remains the most effective means of limiting ischemic injury. The human myocardium is amenable to preconditioning
  22. 22. 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.
  23. 23. Therapeutic applications of preconditioning • Stable angina Patients should warm-up prior to exercise. • Cardiac surgery. • Cardiac transplantation.
  24. 24. 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.
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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.
  31. 31. Postconditioning protocols
  32. 32. Mechanism of postconditioning
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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.
  37. 37. 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
  38. 38. 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.
  39. 39. 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
  40. 40. 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
  41. 41. Thank you

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