Myocardial Ischemia and Preconditioning

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Oxidative stress. In the first few minutes of myocardial reperfusion, a burst of oxidative stress 22 , 23 is produced by a variety of sources Figure 1.


This detrimental oxidative stress mediates myocardial injury and cardiomyocyte death through a number of different mechanisms Figure 1. Based on these observations, antioxidant therapy was naturally considered to be an appropriate option to prevent such injury. However, both experimental and clinical studies have reported mixed results with the administration of antioxidant therapy at the onset of myocardial reperfusion. The reason for this may in part be due the inability of the antioxidant to enter the cell In this regard, the discovery of mitochondrial-specific antioxidants may be more effective However, not all experimental studies using this therapeutic strategy have been positive.

Clinical studies of calcium channel blockers administered at the onset of myocardial reperfusion have not shown beneficial results The rapid restoration of physiological pH at the time of reperfusion. During acute myocardial ischemia the intracellular pH decreases to less than 7.

This pH shift contributes to the cardiomyocyte death of lethal myocardial reperfusion injury 30 by permitting MPTP opening and cardiomyocyte rigor hypercontracture in the first few minutes of reperfusion. Reperfusion of ischemic animal hearts with an acidic buffer can reduce MI size The MPTP: an important target for cardioprotection. Many of the above proponents of myocardial reperfusion injury appear to converge on the MPTP. The MPTP is a nonselective channel of the inner mitochondrial membrane, the opening of which results in mitochondrial membrane depolarization and uncoupling of oxidative phosphorylation, leading to ATP depletion and cell death 34 , As such, the MPTP provides an important therapeutic target for preventing lethal myocardial reperfusion injury see section below.

Inflammation: guilty mediator or innocent bystander. It is unclear whether the inflammatory response that accompanies an acute MI contributes to the pathogenesis of lethal myocardial reperfusion injury or whether it is a reaction to the acute myocardial injury Although experimental studies have reported significant reduction of MI with therapeutic strategies designed to inhibit the inflammatory process at the time of myocardial reperfusion using antibodies against cell-adhesion molecules 43 — 45 and the inhibition of complement activation 46 , corresponding clinical studies using this therapeutic approach have been largely negative 47 — Late myocardial reperfusion injury: extending the window of cardioprotection.

The previously described stimulators of myocardial reperfusion injury all appear to operate in the first few minutes of myocardial reperfusion, providing a narrow window for reducing MI size in PPCI patients. However, several other important processes such as apoptosis and inflammation, which are also initiated during ischemia and continue over several hours into reperfusion, may contribute to the development of lethal myocardial reperfusion injury.

These contributing pathways provide a potential second therapeutic window for reducing MI size, even well after myocardial reperfusion has taken place. Consistent with this proposal are experimental data demonstrating an increase in MI size as reperfusion time progresses, suggesting a wave front of reperfusion injury that progress with time 3 , 50 , However, this is a controversial area of research, and some experimental studies have failed to demonstrate an increase in MI size with reperfusion time Whether this therapeutic window exists in patients with STEMI who are undergoing PPCI is of great investigational interest, as such a window would allow a cardioprotective intervention to be administered some hours after the PPCI procedure.

This area of research is still in its infancy but may suggest or provide an additional therapeutic window to target late into the reperfusion phase. For patients presenting with a STEMI, the most effective and well-established therapeutic strategy for reducing acute myocardial ischemic injury and limiting MI size is timely myocardial reperfusion using either thrombolytic therapy or PPCI.

The duration of acute myocardial ischemia is a critical determinant of MI size, and as such, minimizing the time from chest pain onset to PPCI is the treatment priority. In the pre-hospital phase this includes increasing patient awareness of the symptoms of a MI in order to minimize the delay before the emergency services are contacted , and the rapid diagnosis and transfer of STEMI patients to the PPCI center At the hospital, reducing acute myocardial ischemic injury requires a treatment protocol that minimizes the door-to-PPCI time.

In situations in which the transfer time to the PPCI center is prolonged, there is an opportunity for paramedics to administer a therapeutic strategy in the ambulance that can delay acute myocardial ischemic injury until PPCI has taken place. In this respect, the recently published IMMEDIATE clinical trial investigated the effects of metabolic modulation using an intravenous glucose insulin potassium GIK therapy administered in the ambulance to patients experiencing acute myocardial ischemia with suspected acute coronary syndrome.

Ischemic preconditioning

However, the study failed to find any difference in the primary endpoint of progression to acute MI, although patients with STEMI administered GIK therapy experienced less cardiac arrest and in-hospital mortality compared with those administered placebo For patients presenting with a STEMI in whom acute myocardial ischemia has already taken place, the opportunity to intervene is limited to after the onset of myocardial ischemia or at the time of myocardial reperfusion PPCI.

The process of myocardial reperfusion by PPCI continues to be improved with earlier reperfusion, advances in PCI technology, and the introduction of more efficacious antiplatelet and antithrombotic agents for maintaining the patency of the infarct-related coronary artery. Unfortunately, therapeutic targeting of the individual components of lethal myocardial reperfusion injury, including oxidative stress, calcium overload, pH correction, and, more recently, inflammation have produced disappointing results, the reasons for which are discussed below 59 , However, a number of emerging therapeutic strategies for preventing lethal myocardial reperfusion injury have shown promise in small proof-of-concept clinical studies, and multicenter randomized clinical trials are currently underway to investigate the effects of these strategies on clinical outcomes in PPCI patients Tables 1 And 2.

Mechanical therapeutic interventions for preventing myocardial reperfusion injury in patients undergoing PPCI. It must be appreciated that IPost represents a form of modified reperfusion that was demonstrated in the s to be beneficial in the form of gradual reperfusion 62 — Staat et al.

The results of this study confirmed the existence of lethal myocardial reperfusion injury in humans A number of clinical studies have subsequently confirmed the beneficial effects of IPost, although not all studies have had positive results Table 1. Remote ischemic conditioning. IPost requires an invasive therapeutic intervention applied directly to the heart. However, the heart can be protected against acute IRI from a distance, by applying one or more cycles of brief, nonlethal ischemia and reperfusion to another organ or tissue, a phenomenon that has been termed remote ischemic conditioning RIC 68 , Javascript is currently disabled in your browser.

Preconditioning in experimental studies

Several features of this site will not function whilst javascript is disabled. Received 20 June Published 8 May Volume Pages — Review by Single-blind. Peer reviewers approved by Dr Colin Mak. Editor who approved publication: Dr Scott Fraser. The role of RIPC in protecting myocardial ischemia during hemodialysis is not yet established.

Remote Ischemic Preconditioning for Heart Surgery

The aim of the study was to evaluate RIPC myocardial protection as evaluated by ultrasensitive I troponin in hemodialysis outpatients. Intervention group received RIPC in three consecutive hemodialysis sessions. Blood samples were taken before and after each session.

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Ischemic preconditioning: Protection against myocardial necrosis and apoptosis

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