Atherosclerotic Disease Clinical Trial
Official title:
Short Telomere in Patients at High Cardiovascular Risk: a Simple Marker or a Major Determinant of Accelerated Arterial Aging
The prevailing view in telomere epidemiology is that leukocyte telomere length (LTL) is
associated with atherosclerosis and accelerated aging since it serves as a biomarker of the
cumulative burden of inflammation and oxidative stress during adult life. Our recent results
however, indicate that telomere length (TL) is mainly determined at birth and childhood.
Since short telomeres ante cede atherosclerosis, the investigators hypothesize that TL is
not just a simple marker, but a real determinant of arterial aging. That is because TL
reflects cellular repair capacity and a short LTL denotes diminished repair reserves. This
hypothesis cannot be tested by measurements of LTL alone, since this parameter reflects TL
at birth and its age-dependent attrition thereafter. The investigators propose, therefore, a
model that makes it possible to examine different elements of TL dynamics in different
tissues: leukocytes, skeletal muscle, endothelial progenitor cells (EPCs), skin or
subcutaneous fat in patients with or without atherosclerosis.
Our model is based on the following premises, which are derived from observations that TL is
synchronized (equivalent) across somatic tissues/cells of the newborn:
- TL in skeletal muscle mainly reflects TL at birth
- The difference in TL between muscle and leukocytes in adults (approximately 1.5 Kbp)
mainly reflects LTL attrition during the growth period, i.e., childhood/adolescence
- TL in EPCs determines the cell proliferative ability and therefore capacity for vessels
repair during aging.
The general aim of the present project is to examine the links of arterial aging with TL, as
expressed in different tissues, and LTL dynamics, as expressed in the difference between TLs
of muscle and leukocytes.
Specific objectives:
1. To determine whether TL during early development, which is primarily reflected in
muscle TL, and LTL attrition during development, which is primarily expressed in the
difference between muscle TL and LTL, are associated with indices of arterial aging.
2. To examine the relation between EPC-TL to endothelial regenerative capacity and
endothelial function. In order to attain this objective the investigators will perform
two types of experiments:
- Measure TL in progenitor cells and relate it to clinical phenotypes of arterial
aging and atherosclerosis, as well as markers of endothelial dysfunction
- Generate in vitro progenitor cells with different TL induced by the environmental
factors (oxidative stress) and assess their phenotypes concerning inflammation and
microvesiculation, in order to show a possible mechanistic relationship between TL
in PC and the atherogenic and the regenerative capacities of these cells.
The project is composed of 6 tasks:
T1: Recruitment and sample collection (skeletal muscle, total blood) of 170 patients with
atherosclerosis and 170 controls. Performed by surgeons and cardiologists of Marseille and
Nancy University hospitals T2: Characterization of arterial aging in all patients (Geriatric
Dpt, Univ. hospital Nancy, Pr Benetos and AP-HM, Internal Medicine, Marseille, Dr Rossi) T3:
Characterization of early and late endothelial progenitor cells (EPC): laboratory of
hematology and vascular biology and in UMR_S1076 in Marseille (Prs Dignat-George and
Sabatier) T4: Measurements of TL in all samples (skeletal muscle, leukocytes and EPC):
UMR_S1116 Nancy (Dr Lacolley) in collaboration with Pr Aviv (University of Medicine of New
Jersey) T5: Characterization of inflammation markers in blood samples: UMR_S1116 and the
UMR_S1122 (Dr Siest-Visvikis, Nancy) T6: Database construction and statistical analyses
(UMR_S1116)
The results of this program could completely modify the present concept on the association
between TL and cardiovascular risk: Actually, if our concept of early determination of TL is
valid, therefore TL could be a true determinant of the arterial aging pace, through
limitation of repair capacity of cells.
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Observational Model: Case Control, Time Perspective: Cross-Sectional
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