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出境医 / 临床实验 / PROGENitors, TELomeres and ARTerial Aging (PROGENTELART)

PROGENitors, TELomeres and ARTerial Aging (PROGENTELART)

Study Description
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.


Condition or disease
Atherosclerosis of Artery

Study Design
Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 100 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Target Follow-Up Duration: 1 Day
Official Title: Role of Telomere Length in Arterial Smooth Muscle Cells and Circulating/Tissue Endothelial Progenitors in the Development of Atherosclerotic Lesions: Set up of the Experimental Model
Actual Study Start Date : May 8, 2019
Estimated Primary Completion Date : April 20, 2021
Estimated Study Completion Date : October 20, 2021
Arms and Interventions
Group/Cohort
Control Group
Patients with traumatic vascular injury, ultimately corresponding to control patients
Atheroma Group

Patients will be included either in the atheromatous group (patients with atheromatous pathology) or in the control group (patients without atheromatous pathology), according to the clinical evaluation.

In the atheromatous group, subjects must have a clinically significant atheromatous pathology.

The investigator must specify the site (s) affected by the atheroma: carotid artery, coronary artery, aorta, renal artery, mesenteric artery or lower limb artery.

Outcome Measures
Primary Outcome Measures :
  1. Circulating EPC levels [ Time Frame: 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)

  2. Tissue EPC levels [ Time Frame: 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 :
  1. TL in EPC [ Time Frame: 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.



Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Recruitment is expected in patients undergoing surgery giving access to arterial surgical residues.

Recruiter Service: Vascular Surgery at Nancy-Brabois University Hospital (Prof. Serguei Malikov)

As part of the clinical care, the samples available according to the groups are as follows:

  • for the group suffering from atheromatous pathology: lesion (pathological zone) and lesion border (healthy zone)
  • for the group with traumatic vascular injury: lesion (but non-atheromatous lesion, therefore considered as control) and lesion border.
Criteria

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
Contacts and Locations

Locations
Layout table for location information
France
Centre Hospitalier Régional Universitaire de Nancy
Nancy, France, 54000
Sponsors and Collaborators
Central Hospital, Nancy, France
Tracking Information
First Submitted Date April 24, 2019
First Posted Date April 26, 2019
Last Update Posted Date April 15, 2021
Actual Study Start Date May 8, 2019
Estimated Primary Completion Date April 20, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 24, 2019)
  • Circulating EPC levels [ Time Frame: 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 [ Time Frame: Inclusion visit ]
    Tissue EPC levels measured from arterial wall cells in healthy and pathological zones obtained after enzymatic digestion, cell sorting and primary culture.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: April 24, 2019)
TL in EPC [ Time Frame: 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.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title PROGENitors, TELomeres and ARTerial Aging
Official Title Role of Telomere Length in Arterial Smooth Muscle Cells and Circulating/Tissue Endothelial Progenitors in the Development of Atherosclerotic Lesions: Set up of the Experimental Model
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 Provided
Study Type Observational [Patient Registry]
Study Design Observational Model: Case-Control
Time Perspective: Cross-Sectional
Target Follow-Up Duration 1 Day
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population

Recruitment is expected in patients undergoing surgery giving access to arterial surgical residues.

Recruiter Service: Vascular Surgery at Nancy-Brabois University Hospital (Prof. Serguei Malikov)

As part of the clinical care, the samples available according to the groups are as follows:

  • for the group suffering from atheromatous pathology: lesion (pathological zone) and lesion border (healthy zone)
  • for the group with traumatic vascular injury: lesion (but non-atheromatous lesion, therefore considered as control) and lesion border.
Condition Atherosclerosis of Artery
Intervention Not Provided
Study Groups/Cohorts
  • Control Group
    Patients with traumatic vascular injury, ultimately corresponding to control patients
  • Atheroma Group

    Patients will be included either in the atheromatous group (patients with atheromatous pathology) or in the control group (patients without atheromatous pathology), according to the clinical evaluation.

    In the atheromatous group, subjects must have a clinically significant atheromatous pathology.

    The investigator must specify the site (s) affected by the atheroma: carotid artery, coronary artery, aorta, renal artery, mesenteric artery or lower limb artery.

Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Suspended
Estimated Enrollment
 (submitted: April 24, 2019)
100
Original Estimated Enrollment Same as current
Estimated Study Completion Date October 20, 2021
Estimated Primary Completion Date April 20, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries France
Removed Location Countries  
 
Administrative Information
NCT Number NCT03928769
Other Study ID Numbers 2019-A00143-54
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Central Hospital, Nancy, France
Study Sponsor Central Hospital, Nancy, France
Collaborators Not Provided
Investigators Not Provided
PRS Account Central Hospital, Nancy, France
Verification Date January 2021