Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly (METHYSTROKE)

Over the past ten years, the number of endovascular procedures has increased by 5% per year in Europe with the development of interventional cardiology, such as percutaneous coronary angioplasty, aortic valve replacements (TAVR), and vascular endoprosthesis.

The neurological lesions detected on cerebral MRI caused by these endovascular procedures are frequent with an incidence of about 30-70%. These events, although subclinical, have an impact on morbidity and mortality and especially on long-term cognitive decline.

TAVR is the reference treatment for symptomatic elderly patients with stenosis of the aortic valve, considered by a multidisciplinary "Heart Team" as at high surgical risk due to comorbidities, age and high perioperative risk scores ( Euroscore 2 and STS scores). Despite the net clinical benefit, an increase of silent neurological events was detected on post-procedural cerebral MRI with an incidence of approximately 70%.

The epigenetic involvement in the occurrence of ischemic cerebral lesions is still largely unknown. Epigenetic mechanisms, such as DNA methylation, can be associated with aging processes and modulate the risk of developing cerebrovascular pathologies. They are likely to provide new biomarkers that predict the risk of brain damage.

Hypomethylation of leukocyte DNA is directly related to atherosclerosis in humans. This hypomethylation of DNA would represent an easily measurable marker reflecting the presence and progression of atherosclerosis. Because atherosclerotic lesions often precede the clinical manifestation of ischemic cardiovascular disease, such as ischemic heart disease and stroke, DNA hypomethylation could be used to identify individuals at risk for cerebrovascular events.

The investigator hypothesize that hypomethylation of leukocyte DNA can predict the risk of developing new ischemic brain lesions especially after a TAVI procedure.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Cognitive Decline

Detailed Description

This is a french multicenter prospective cohort study. Patients with severe symptomatic aortic stenosis referred for a TAVI procedure to the cardiology departments of the university hospitals of Lille, Caen, Amiens and the Pitié-Salpêtrière hospital (APHP) are analyzed for inclusion in this prospective study. The cases are selected after a discussion between the members of the local TAVI "Heart Team" (cardiologists, cardiac surgeons, anesthetists), as recommended by the guidelines of the European Society of Cardiology. Written consent is obtained in accordance with international recommendations for clinical research (Helsinki Declaration). Participation in the study is proposed to patients during preoperative consultation.

The collection of clinical data, including postoperative cerebral MRI, is collected prospectively during hospitalization and during the clinical visit to each institution at one year. An evaluation of cognitive function is performed by a mini-mental state (MMS) the day before the TAVI intervention and then at 1 year. The study ends after the last evaluation. A cerebral MRI is performed within 1-3 days after the TAVI procedure to detect new cerebral ischemic lesions (emboli).

Blood samples will be taken during the patient's stay: the day before TAVI, during the procedure and after the TAVI procedure at day 1 and day 4.

The follow-up visit to 1 year will be conducted by cardiologists or cardiac surgeons with an evaluation of the cognitive function by the mini-mental state (MMS).

• Study Type: Observational
• Enrollment (Anticipated): 542

Contacts and Locations

• Study Contact: Name: Nicolas Debry, MD; Phone Number: +33 +33 3 20 44 59 62; Email: nicolas.debry@chru-lille.fr

Study Locations

• France
  • Lille, France
    • Recruiting
    • Hôpital cardiologie, CHRU
    • Principal Investigator: Nicolas Debry, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients over 70 years with severe aortic stenosis requiring percutaneous aortic valve replacement (TAVI)

Description

Inclusion Criteria:

• Patients over 70 years with severe aortic stenosis requiring percutaneous aortic valve replacement (TAVI)

Exclusion Criteria:

• Patient contraindicated for the TAVI procedure
• Patient with a pace-maker
• Patient with contra-indication for cerebral MRI
• Ongoing cancer
• Patient already involved in therapeutic research
• Major persons under protection of justice.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Cerebral Lesion; Patient over 70 years with severe aortic stenosis requiring percutaneous aortic valvular replacement (TAVI) having at least one new cerebral ischemic lesion on postoperative cerebral MRI
No Cerebral Lesion; Patient over 70 years with severe aortic stenosis requiring percutaneous aortic valvular replacement (TAVI) with no cerebral ischemic lesion on postoperative cerebral MRI
patients with constitutional von Willebrand factor (vWF) deficiency

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre-operative leukocyte DNA methylation rate	This rate will be measured by the LUMA method in patients treated with TAVI according to the presence of at least one new cerebral ischemic lesion and/or microbleeds cerebral lesion appearing on post-procedural MRI	Within one week after the procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variation of the leukocyte DNA methylation rate during the TAVI procedure	This rate will be measured by the LINE-1 method in all patients	At time between the pre (day-1) and postprocedural (day 1) samples
Pre-operative leukocyte DNA methylation rate (stroke/TIA)	This rate will be measured by the LUMA method in patients treated with TAVI according to the presence of a neurological deficit (stroke, transient ischemic attack)	One day before the procedure and within one week after the procedure
Mortality	The mortality in patients treated with TAVI according to the presence of at least one new micro-ischemic cerebral lesion and/or one new microbleeds cerebral lesion detected on postoperative cerebral MRI and / or postprocedural ischemic stroke / TIA	At 1 year after procedure
MMSE score variation	The MMSE score variation is compared according to the presence or not of at least one new micro-ischemic cerebral lesion and/or one new microbleeds cerebral lesion	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Change of EQ-5D questionnaire	The evolution of quality of life is compared to the occurrence of new cerebral events one new micro-ischemic cerebral lesion and/or one new microbleeds cerebral lesion	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Change of modified Rankin Scale (mRS)	The MRS (measure degree of disability- troke) is compared to the occurrence of new cerebral events one new micro-ischemic cerebral lesion and/or one new microbleeds cerebral lesion	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Change of National Institutes of Health Stroke Scale (NIHSS)	TheNIHSS (quantify the impairment caused by a stroke) is compared to the occurrence of new cerebral events one new micro-ischemic cerebral lesion and/or one new microbleeds cerebral lesion	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Clinical and Biological predictors of new cerebral events	The clinical (measured before the procedure) and biological characteristics of the patients (measured before the procedure and after the procedure) and of the peri-procedural parameters associated with the occurrence of new events detected on post-procedural MRI (new ischemic and/or new microbleeds cerebral lesion appearing on post-procedural MRI)	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Hemostasis predictors of new cerebral events	Hemostasis parameters (measured before the procedure and after the procedure) including Willebrand factor parameters associated with the occurrence of new events detected on postoperative MRI (new ischemic and/or new microbleeds cerebral lesion)	At day-1 before TAVI procedure, at 6 months and at 1 year after procedure
Number of complications in peri-procedural according to VARC-2 criteria	Evaluation of multi criteria according to the Valve academic Research Consortium (VARC-2)	Within one week after the procedure

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Investigators: Principal Investigator: Nicolas Debry, MD, University Hospital, Lille

Publications and helpful links

General Publications

• Ghanem A, Kocurek J, Sinning JM, Wagner M, Becker BV, Vogel M, Schroder T, Wolfsgruber S, Vasa-Nicotera M, Hammerstingl C, Schwab JO, Thomas D, Werner N, Grube E, Nickenig G, Muller A. Cognitive trajectory after transcatheter aortic valve implantation. Circ Cardiovasc Interv. 2013 Dec;6(6):615-24. doi: 10.1161/CIRCINTERVENTIONS.112.000429. Epub 2013 Oct 15.
• Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F, Weber M, Johansson U, Wendt D, Jakob HG, Forsting M, Sack S, Erbel R, Eggebrecht H. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation. 2010 Feb 23;121(7):870-8. doi: 10.1161/CIRCULATIONAHA.109.855866.
• Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekstrom TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. Intra-individual change over time in DNA methylation with familial clustering. JAMA. 2008 Jun 25;299(24):2877-83. doi: 10.1001/jama.299.24.2877.
• Baccarelli A, Wright R, Bollati V, Litonjua A, Zanobetti A, Tarantini L, Sparrow D, Vokonas P, Schwartz J. Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology. 2010 Nov;21(6):819-28. doi: 10.1097/EDE.0b013e3181f20457.
• Van Belle E, Juthier F, Susen S, Vincentelli A, Iung B, Dallongeville J, Eltchaninoff H, Laskar M, Leprince P, Lievre M, Banfi C, Auffray JL, Delhaye C, Donzeau-Gouge P, Chevreul K, Fajadet J, Leguerrier A, Prat A, Gilard M, Teiger E; FRANCE 2 Investigators. Postprocedural aortic regurgitation in balloon-expandable and self-expandable transcatheter aortic valve replacement procedures: analysis of predictors and impact on long-term mortality: insights from the FRANCE2 Registry. Circulation. 2014 Apr 1;129(13):1415-27. doi: 10.1161/CIRCULATIONAHA.113.002677. Epub 2014 Feb 24.
• Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, Leprince P, Leguerrier A, Lievre M, Prat A, Teiger E, Lefevre T, Himbert D, Tchetche D, Carrie D, Albat B, Cribier A, Rioufol G, Sudre A, Blanchard D, Collet F, Dos Santos P, Meneveau N, Tirouvanziam A, Caussin C, Guyon P, Boschat J, Le Breton H, Collart F, Houel R, Delpine S, Souteyrand G, Favereau X, Ohlmann P, Doisy V, Grollier G, Gommeaux A, Claudel JP, Bourlon F, Bertrand B, Van Belle E, Laskar M; FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med. 2012 May 3;366(18):1705-15. doi: 10.1056/NEJMoa1114705.
• Van Belle E, Debry N, Vincent F, Kuchcinski G, Cordonnier C, Rauch A, Robin E, Lassalle F, Pontana F, Delhaye C, Schurtz G, JeanPierre E, Rousse N, Casari C, Spillemaeker H, Porouchani S, Pamart T, Denimal T, Neiger X, Verdier B, Puy L, Cosenza A, Juthier F, Richardson M, Bretzner M, Dallongeville J, Labreuche J, Mazighi M, Dupont-Prado A, Staels B, Lenting PJ, Susen S. Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort. Circulation. 2022 Aug 2;146(5):383-397. doi: 10.1161/CIRCULATIONAHA.121.057145. Epub 2022 Jun 20.

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2017
• Primary Completion (Anticipated): February 1, 2024
• Study Completion (Anticipated): February 1, 2024

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 22, 2016
• First Posted (Estimate): November 23, 2016

Study Record Updates

• Last Update Posted (Actual): February 15, 2022
• Last Update Submitted That Met QC Criteria: January 31, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: stroke; Aortic stenosis; Transaortic valve replacement; Epigenetic
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: 2015_92; 2016-A01035-46 (Other Identifier: ID-RCB number); PHRCI_2015 (Other Identifier: PHRC number, DGOS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No