clinical implications of ischemic pre and postconditioning

Clinical Implications of Ischemic Pre and

Postconditioning

الرحيم الرحمن الله بسم

Dr. Mohamed Ahmed HamoudaMD cardiology, Benha faculty of medicine

• 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

Myocardial protective mechanisms include:

• Ischemic preconditioning• Ischemic post conditioning• Hibernating and stunning myocardium• The long term development of coronary

collaterals

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.

Preconditioning protocol


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

Pathogenesis of preconditioning

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

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

Pathogenesis of precoditioning

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.

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


• In vitro preparations Isolated human cells and isolated human atrial trabeculae recapitulate preconditioning behaviors


• 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


• 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


• Preinfarct angina reduces infarct size and is associated with better clinical outcome


• 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


• 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.

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Therapeutic applications of preconditioning

• Early and complete reperfusion remains the most effective means of limiting ischemic injury.

The human myocardium is amenable to 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.


• Stable angina Patients should warm-up prior to exercise.• Cardiac surgery.• Cardiac transplantation.


Certain preconditioning mimetic agents can reduce ischemia during balloon inflation or exercise testing and also in preinfarct angina.


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


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


Impairment of Preconditioning

The protective effect of IPC is suppressed by conditions such as :• Hypercholesterolemia• hyperglycemia • Hypertension• LV hypertrophy • Aging• Obesity


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

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

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.

Postconditioning protocols

Mechanism of postconditioning

Potential Mechanisms of Postconditioning

A. Triggers including:1. Adenosine2. Opioids3. Erythropoietin4. Endogenous nitric oxide5. Reactive oxygen species6. Acetylcholine7. Tissue factors8. Pro-inflammatory cytokines and bradykinin9. Hydrogen sulfide

B. Mediators –Reperfusion injury salvage kinase pathways including:1. Phosphoinositide-3-kinase2. Extra-cellular signal regulated kinase (1/2) pathways3. Protein kinases G and C

C. End-effectors such as:1. Mitochondrial permeability transition pore mPTP2. Mitochondrial potassium ATP channel

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

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

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.

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

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.

CONCLUSIONSIschemic 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

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

Thank you

clinical implications of ischemic pre and postconditioning

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