Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities

Abstract

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.

Keywords: Acute myocardial infarction; Ascorbate; Deferoxamine; N-acetylcysteine; Oxidative stress; Repefusion injury.

Figure 1

Generation of reactive oxygen species and mobilization of iron after myocardial reperfusion. There is a massive production of reactive oxygen species and iron mobilization by the different cellular types of the myocardial tissue. The iron reacts with superoxide anion to produce hydroxyl radical by the Fenton reaction. Inside cardiomyocyte, there is intracellular production of reactive oxygen species through NADPH oxidase, eNOS uncoupled, xanthine oxidase and mitochondrion. NOX: NADPH oxidase; ROS: Reactive oxygen species; Fe: Iron; eNOS: Endothelial nieric oxide synthases.

Figure 2

Role of reactive oxygen species and iron mobilization in myocardial reperfusion injury and its clinical implications. MVO: Microvascular obstruction; ONOO*: Peroxynitrite; NO: Nitric oxide; OH *: Radical hydroxyl; Fe: Iron; RyR: Ryanodine receptor channel; SERCA: Sarco/endoplasmic reticulum Ca²⁺-ATPase.

Figure 3

Central role of calcium in the electro-mechanical dissociation of cardiomyocyte after myocardial reperfusion. RyR: Ryanodine receptor channel; SERCA: Sarco / endoplasmic reticulum Ca²⁺-ATPase; mPTP: Mitochondrial permeability transition pore; Ca: Calcium; ROS: Reactive oxygen species.

Figure 4

Experimental, pharmacological and clinical approaches to prevent myocardial reperfusion injury at cellular level. RISK: Reperfusion injury salvage kinase pathway; SAFE: Survivor activating factor enhancement pathway; GSH: Reduced glutathione; GSSG: Oxidized glutathione; NAC: N-acetylcysteine; DFO: deferoxamine; ONOO*: Peroxynitrite; NO: Nitric oxide; OH *: Radical hydroxyl; mPTP: Mitochondrial permeability transition pore.