Reactive Oxygen Species Following Aortic Valve Replacement

Overview

Surgical aortic valve replacement (SVAR) is currently the 'Gold Standard' therapy for patients with severe symptomatic aortic stenosis (AS). Approximately 30-50% of patients with severe AS are deemed inoperable due to comorbidities such as severe respiratory disease, chronic renal disease and peripheral vascular disease. Transcatheter aortic valve replacement (TAVR) has emerged as a novel therapeutic modality for inoperable patients and an effective alternative to SAVR in selected high and intermediate-risk patients. Myocardial ischemia and reperfusion injury (MRI), mediated by reactive oxygen species (ROS), related to cardiopulmonary bypass has been linked to adverse clinical outcomes following cardiac surgery. In contrast to SAVR, transcatheter deployment of aortic prostheses requires shorter time of ischemia and hypotension and may be associated with less ROS mediated MRI. Inflammatory responses and reperfusion injury following TAVR have not been previously described nor compared to SAVR. The aim of this study is therefore to compare the oxidative stress response in patients with isolated severe symptomatic AS undergoing SAVR or TAVR and determine whether it correlates with clinical outcomes.

Myocardial ischemia and reperfusion injury (MRI) related to cardio-pulmonary bypass has been linked to adverse clinical outcomes following cardiac surgery. Changes in ROS following SAVR have been well documented in the literature. Furthermore, pre-operative ROS markers such as malondialdehyde have been shown to be predictors of adverse outcomes after 30-day and 1-year follow-up. In contrast to SAVR, TAVR is associated with shorter duration of myocardial ischemia and hypotension ad may thus be associated with a lower degree of MRI. Inflammatory responses and reperfusion injury following TAVR have not been described nor have they been compared with SAVR. Cellular respiration leads to the generation of partially reduced oxygen derivatives called ROS. Under normal physiological conditions, ROS serve as integral components of cellular signaling pathways. A balanced redox state is established between the major ROS producing systems (NADPH oxidase, xanthine oxidase, nitric oxide synthase, myeloperoxidase and lipoxygenases) and the major antioxidant systems (catalase, α-tocopherol, ascorbic acid, superoxide dismutase, glutathione peroxidase and glutathione S transferases that conjugate reduced GSH to hydrophobic organic compounds and glutathione). Excess production or reduced degradation of ROS by the antioxidant defense systems imposes an oxidative burden upon the cellular environment leading to modification of numerous biomolecules and functional defects. In MRI the enzyme xanthine oxidase catalyzes the formation of uric acid with the coproduction of superoxide. Superoxide release results in the recruitment and activation of neutrophils and their adherence to endothelial cells, which stimulates the formation of xanthine oxidase in the endothelium, with further superoxide production. Oxidation of DNA and proteins may then follow leading to membrane damage because of lipid peroxidation leading to alterations in membrane permeability, modification of protein structure and functional changes. Oxidative damage to the mitochondrial membrane can also occur resulting in membrane depolarization and the uncoupling of oxidative phosphorylation with altered cellular respiration. This can ultimately lead to mitochondrial damage, release of cytochrome c, activation of caspases and apoptosis. Although TAVR may not expose the myocardium to the same level of MRI than SAVR, patients undergoing TAVR have greater numbers of co-morbidities and may thus have a greater baseline ROS burden than patients undergoing SAVR. As the generation of ROS in patients undergoing TAVR and whether differences in ROS levels in such patients correlates with clinical outcomes has not been described. The prospective study will attempt to address both of these questions.