Reactive Oxygen Species Following Aortic Valve Replacement

Aortic Stenosis Clinical Trial

— ROS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02841917
• Other study ID #: RHM CAR0508
• Status: Completed
• Start date: November 29, 2016
• Est. completion date: March 31, 2017

Study information

• Verified date: September 2018
• Source: University Hospital Southampton NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: March 31, 2017
• Est. primary completion date: March 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Valve Stenosis
• Constriction, Pathologic

Locations

Country	Name	City	State
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton	Hampshire

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Southampton NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (12)

Bach DS, Siao D, Girard SE, Duvernoy C, McCallister BD Jr, Gualano SK. Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk. Circ Cardio — View Citation

Cavalca V, Tremoli E, Porro B, Veglia F, Myasoedova V, Squellerio I, Manzone D, Zanobini M, Trezzi M, Di Minno MN, Werba JP, Tedesco C, Alamanni F, Parolari A. Oxidative stress and nitric oxide pathway in adult patients who are candidates for cardiac surg — View Citation

Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol. 1988 Dec;255(6 Pt 2):H1269-75. Review. — View Citation

Hausenloy DJ, Yellon DM. The evolving story of "conditioning" to protect against acute myocardial ischaemia-reperfusion injury. Heart. 2007 Jun;93(6):649-51. — View Citation

Larmann J, Theilmeier G. Inflammatory response to cardiac surgery: cardiopulmonary bypass versus non-cardiopulmonary bypass surgery. Best Pract Res Clin Anaesthesiol. 2004 Sep;18(3):425-38. Review. — View Citation

Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S; PARTNER Trial Inves — View Citation

Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. Br J Anaesth. 2003 Feb;90(2):221-32. Review. — View Citation

Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O'Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Creager MA, Curtis LH, DeMets D, Guyton RA, Hochman JS, — View Citation

Rodrigo R, Korantzopoulos P, Cereceda M, Asenjo R, Zamorano J, Villalabeitia E, Baeza C, Aguayo R, Castillo R, Carrasco R, Gormaz JG. A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardi — View Citation

Scolletta S, Carlucci F, Biagioli B, Marchetti L, Maccherini M, Carlucci G, Rosi F, Salvi M, Tabucchi A. NT-proBNP changes, oxidative stress, and energy status of hypertrophic myocardium following ischemia/reperfusion injury. Biomed Pharmacother. 2007 Feb — View Citation

Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ; PARTN — View Citation

Zimmerman JJ. Defining the role of oxyradicals in the pathogenesis of sepsis. Crit Care Med. 1995 Apr;23(4):616-7. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ascertain the concentrations of serum isoprostanes, nitrites and sulphides following transcatheter and surgical aortic valve replacement.	Serum measurements will be undertaken using standard immunoassay techniques.	24 hours
Secondary	Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with cardiovascular mortality.	Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.	30 days clinical follow-up
Secondary	Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with myocardial infarction.	Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.	30 days clinical follow-up.
Secondary	Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with stroke.	Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.	30 days clinical follow-up.
Secondary	Ascertain potential differences in the generation of reactive oxygen species that have been outlined in the primary outcomes with major bleeding.	Clinical follow-up will be undertaken either by a clinic visit or by telephone contact.	30 days clinical follow-up.