Reactive Oxygen Species Following Aortic Valve Replacement
Condition: Aortic Stenosis
MeSH terms: Aortic Valve Stenosis; Constriction, Pathologic
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with severe symptomatic aortic stenosis undergoing transcatheter or surgical
        aortic valve replacement.
      
Biospecimen description: 
      Blood samples will be taken for measurement of reactive oxygen species