PROGENitors, TELomeres and ARTerial Aging

Suspended

• Conditions: Atherosclerosis of Artery

• Registration Number: NCT03928769
• Lead Sponsor: Central Hospital, Nancy, France

Brief Summary

The prevailing view in telomere epidemiology is that leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ACVD) since it serves as a biomarker of the cumulative burden of inflammation and oxidative stress during adult life. However, our recent results indicate that telomere length (TL) is mainly determined before adulthood, by TL at birth and TL attrition during growth. They also demonstrate that short telomeres precede the clinical manifestation of atherosclerosis. The investigators therefore hypothesize that LT is not a simple marker, but a major determinant of arterial aging.

Two mechanistic hypotheses may explain an active role of short telomeres in accelerated arterial aging and development of ACVD.

The first is that a short TL at the leukocyte level reflects a short TL in endothelial progenitor cells (EPC). Cell replicative capacity being TL-dependent, short telomeres in the EPC would therefore be responsible for diminished replication capacity and vascular repair potential, thereby increasing the vulnerability for developing age-related arterial diseases.

The second hypothesis is that a short LTL reflects short TL in arterial wall cells, leading to an increase in the number of senescent vascular cells. Senescent cells are known to alter their secretion pattern, a phenomenon called senescence-associated secretory phenotype (SASP), and thus contribute to tissue injury by promoting inflammation and tissue remodeling leading to lesion progression.

These assumptions cannot be tested by LTL measurements alone. The investigators propose, therefore, a model that makes it possible to examine different elements of TL dynamics in different tissues and cell types: leukocytes, circulating EPCs, in situ EPCs and arterial resident cells (mainly smooth muscle cells) in patients with or without atherosclerosis.

Our model is based on the following observations:

* TL is synchronized (equivalent) across somatic tissues/cells of the newborn: an individual with short telomeres (relative to his pairs) in one tissue should also have short telomeres (relative to his pairs) in other tissues.

* TL in EPCs (both circulating and in situ) determines the cell proliferative ability and therefore capacity for vessels repair during aging.

* TL in the cells of the arterial wall determines the number of senescent cells that therefore contribute to tissue injury through their change of phenotype.

The general aim of the present project is to examine the mechanistic links between arterial aging and TL in these different cell types.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-04-24
• Study First Submitted QC: 2019-04-24
• Study First Posted: 2019-04-26
• Study Start: 2019-05-08
• Status Verified: 2021-01
• Last Update Submitted: 2021-04-13
• Last Update Posted: 2021-04-15
• Primary Completion: 2021-04-20
• Study Completion: 2021-10-20

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Male or female ≥ 18 years
• Patient for whom a vascular surgery is programmed, and whose nature allows obtaining of arterial segment without any harm for the health of the patient
• Patient for whom a blood sample is planned on the day of the procedure
• Person who has received complete information on the organization of the research and who has not objected to his participation and the exploitation of his data
• Compulsory affiliation to social security

Exclusion Criteria

• Patient who has previously undergone radiotherapy at the sampling site
• Patient with cancer at the sampling site

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Circulating EPC levels	Inclusion visit	Circulating EPC levels measured from whole blood specimens after primary culture of peripheral blood mononuclear cells (PBMC) on fibronectin (in cells per million of PBMCs)
Tissue EPC levels	Inclusion visit	Tissue EPC levels measured from arterial wall cells in healthy and pathological zones obtained after enzymatic digestion, cell sorting and primary culture.

Secondary Outcome Measures

Name	Time	Method
TL in EPC	Inclusion visit	Description and comparison of telomere lengths in circulating and tissue endothelial progenitors in patients with atheromatous pathology and those with traumatic vascular disease.; The telomere length in the different cell types (expressed in kb) will be measured by Southern blot after DNA extraction.

Trial Locations

Locations (1)

Centre Hospitalier Régional Universitaire de Nancy; 🇫🇷 Nancy, France