Reactive Oxygen Species Following Aortic Valve Replacement (ROS)

September 5, 2018 updated by: University Hospital Southampton NHS Foundation Trust

Oxidative Stress Response in Patients With Severe Aortic Stenosis Undergoing Transcatheter or Surgical Aortic Valve Replacement (ROS Study)

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.

Study Overview

Status

Completed

Conditions

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.

Study Type

Observational

Enrollment (Actual)

3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Hampshire
      • Southampton, Hampshire, United Kingdom, SO16 6YD
        • University Hospital Southampton NHS Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with severe symptomatic aortic stenosis undergoing transcatheter or surgical aortic valve replacement.

Description

Inclusion Criteria:

1. Severe symptomatic aortic stenosis defined as aortic valve area <1 cm2, mean aortic gradient >40 mm Hg or Vmax > 4 m/s amenable for transcatheter or surgical aortic valve replacement.

Exclusion Criteria:

  1. Severe comorbidities , advance age, frailty or thoracic anatomy unfavorable for surgical aortic valve replacement.
  2. Anatomy precluding transcatheter aortic valve replacement.
  3. Requirement for concomitant coronary artery bypass grafting.
  4. Requirement for concomitant mitral, tricuspid, or pulmonary valve surgery.
  5. Allergy to aspirin or clopidogrel.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Transcatheter Aortic Valve Replacement
ROS Post TAVR
Surgical Aortic Valve Replacement
ROS Post SAVR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ascertain the concentrations of serum isoprostanes, nitrites and sulphides following transcatheter and surgical aortic valve replacement.
Time Frame: 24 hours
Serum measurements will be undertaken using standard immunoassay techniques.
24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with cardiovascular mortality.
Time Frame: 30 days clinical follow-up
Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.
30 days clinical follow-up
Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with myocardial infarction.
Time Frame: 30 days clinical follow-up.
Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.
30 days clinical follow-up.
Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with stroke.
Time Frame: 30 days clinical follow-up.
Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.
30 days clinical follow-up.
Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with major bleeding.
Time Frame: 30 days clinical follow-up.
Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.
30 days clinical follow-up.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Southampton NHS Foundation Trust

Investigators

  • Study Director: Gabriel Maluenda, MD, Centro Cardiovascular, Hospital San Borja, Chile

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 29, 2016

Primary Completion (Actual)

March 31, 2017

Study Completion (Actual)

March 31, 2017

Study Registration Dates

First Submitted

July 13, 2016

First Submitted That Met QC Criteria

July 21, 2016

First Posted (Estimate)

July 22, 2016

Study Record Updates

Last Update Posted (Actual)

September 6, 2018

Last Update Submitted That Met QC Criteria

September 5, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RHM CAR0508

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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