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

Overview

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.

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).

Primary outcome measures

• Pre-operative leukocyte DNA methylation rate [Time frame: Within one week after the procedure]

Secondary outcome measures (10)

• Variation of the leukocyte DNA methylation rate during the TAVI procedure [Time frame: At time between the pre (day-1) and postprocedural (day 1) samples]
• Pre-operative leukocyte DNA methylation rate (stroke/TIA) [Time frame: One day before the procedure and within one week after the procedure]
• Mortality [Time frame: At 1 year after procedure]
• MMSE score variation [Time frame: At day-1 before TAVI procedure, at 6 months and at 1 year after procedure]
• Change of EQ-5D questionnaire [Time frame: At day-1 before TAVI procedure, at 6 months and at 1 year after procedure]
• Change of modified Rankin Scale (mRS) [Time frame: At day-1 before TAVI procedure, at 6 months and at 1 year after procedure]
• Change of National Institutes of Health Stroke Scale (NIHSS) [Time frame: At day-1 before TAVI procedure, at 6 months and at 1 year after procedure]
• Clinical and Biological predictors of new cerebral events [Time frame: At day-1 before TAVI procedure, at 6 months and at 1 year after procedure]
• Hemostasis predictors of new cerebral events [Time frame: 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 [Time frame: Within one week after the procedure]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 1 center

• Hôpital cardiologie, CHRU — Lille

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. PMID 24129642
• 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. PMID 20177005
• 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. PMID 18577732
• 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. PMID 20805753
• 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 PMID 24566199
• 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, Gr PMID 22551129
• 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 PMID 35722876

Identifiers

NCT: NCT02972008 · 2015_92 · 2016-A01035-46 · PHRCI_2015

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗