Myocardial ischemia reperfusion injury: from basic science to clinical bedside

Abstract

Myocardial ischemia reperfusion injury contributes to adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. Primarily, no blood flow to the heart causes an imbalance between oxygen demand and supply, named ischemia (from the Greek isch, restriction; and haema, blood), resulting in damage or dysfunction of the cardiac tissue. Instinctively, early and fast restoration of blood flow has been established to be the treatment of choice to prevent further tissue injury. Indeed, the use of thrombolytic therapy or primary percutaneous coronary intervention is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. Unfortunately, restoring blood flow to the ischemic myocardium, named reperfusion, can also induce injury. This phenomenon was therefore termed myocardial ischemia reperfusion injury. Subsequent studies in animal models of acute myocardial infarction suggest that myocardial ischemia reperfusion injury accounts for up to 50% of the final size of a myocardial infarct. Consequently, many researchers aim to understand the underlying molecular mechanism of myocardial ischemia reperfusion injury to find therapeutic strategies ultimately reducing the final infarct size. Despite the identification of numerous therapeutic strategies at the bench, many of them are just in the process of being translated to bedside. The current review discusses the most striking basic science findings made during the past decades that are currently under clinical evaluation, with the ultimate goal to treat patients who are suffering from myocardial ischemia reperfusion-associated tissue injury.

Figure 1. Mediators in Myocardial Reperfusion Injury

During myocardial reperfusion the rapid restoration of physiological pH (1), Ca²⁺ overload (2) and further ATP-depletion through opening of the mitochondrial permeability transition pore, mPTP (3) leads to the generation of reactive oxygen species (ROS, 4). ROS is responsible for the release of pro inflammatory factors (TNF-α, NF-κb, TLRs and DAMPs, 5). The release of these chemoattractants leads to the invasion of neutrophils (6).

Figure 2. Relationship between ischemia, metabolism and inflammation

Ischemia and Reperfusion leads to significant metabolic changes followed by inflammatory processes. Therapeutic interventions have demonstrated that metabolic modulators have a positive influence on metabolism and heart function with concomitant inhibition of inflammation.

Figure 3. From Bench to Bedside: Ischemic Preconditioning, Pharmacological Preconditioning and Ischemic Postconditioning in the Clinical Setting

Remote preconditioning (RIPC) can be achieved by intermittent cuff inflation before heart surgery mimicking ischemic preconditioning, one of the most powerful cardioprotective mechanism found at the bench. Pharmacolgical preconditioning can be achieved by the administration of nitrates prior to surgery, where they are metabolized to NO under ischemic conditions. Ischemic postconditioning during percutaneous transluminal coronary angioplasty is induced by repetitive inflating and deflating of the catheter balloon with the onset of successful reperfusion.

Figure 4. Anti-Inflammatory effects of Adenosine

Adenosin receptor (ARs) or Toll-like receptor (TLR) activation protects the heart from ischemia-reperfusion injury by inactivating the ischemia-reperfusion-induced inflammatory response.

Figure 5. Metabolism as therapeutic target in I/R

Light as a central regulator of circadian rhythmicities may be a novel therapeutic option in the treatment of patients suffering from myocardial ischemia by improving cardiomyocyte cell metabolism after myocardial ischemia and reperfusion. Modulators of metabolism like Dichloracetate, Glucose-Potassium-Insulin (GKI), Etoxomir and Trimetazidine are already used in a clinical setting and can improve cardiac function through shifting cell metabolism from fatty acid β-oxidation to preferred glucose oxidation.