Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model

Athanase Benetos, Simon Toupance, Sylvie Gautier, Carlos Labat, Masayuki Kimura, Pascal M Rossi, Nicla Settembre, Jacques Hubert, Luc Frimat, Baptiste Bertrand, Mourad Boufi, Xavier Flecher, Nicolas Sadoul, Pascal Eschwege, Michèle Kessler, Irene P Tzanetakou, Ilias P Doulamis, Panagiotis Konstantopoulos, Aspasia Tzani, Marilina Korou, Anastasios Gkogkos, Konstantinos Perreas, Evangelos Menenakos, Georgios Samanidis, Michail Vasiloglou-Gkanis, Jeremy D Kark, Serguei Malikov, Simon Verhulst, Abraham Aviv, Athanase Benetos, Simon Toupance, Sylvie Gautier, Carlos Labat, Masayuki Kimura, Pascal M Rossi, Nicla Settembre, Jacques Hubert, Luc Frimat, Baptiste Bertrand, Mourad Boufi, Xavier Flecher, Nicolas Sadoul, Pascal Eschwege, Michèle Kessler, Irene P Tzanetakou, Ilias P Doulamis, Panagiotis Konstantopoulos, Aspasia Tzani, Marilina Korou, Anastasios Gkogkos, Konstantinos Perreas, Evangelos Menenakos, Georgios Samanidis, Michail Vasiloglou-Gkanis, Jeremy D Kark, Serguei Malikov, Simon Verhulst, Abraham Aviv

Abstract

Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue.

Objective: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD.

Methods and results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals.

Conclusions: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.

Keywords: aging; atherosclerosis; biopsy; leukocytes; muscle; telomere.

© 2017 The Authors.

Figures

Figure 1.
Figure 1.
Leukocyte telomere length vs telomere length in the Discovery Cohort. Dotted line represents line of identity. LTL indicates leukocyte telomere length; MTL, muscle telomere length; and MTLA, site-adjusted muscle telomere length.
Figure 2.
Figure 2.
Telomere length models vs age in the Discovery Cohort. Difference between leukocyte telomere length (LTL) and site-adjusted muscle telomere length (MTLA) (left); ratio of leukocyte telomere length and site-adjusted muscle telomere length (right). ASCVD indicates atherosclerotic cardiovascular disease.
Figure 3.
Figure 3.
Four telomere length models in subjects of the Discovery Cohort. Values are adjusted for age and sex. ASCVD indicates atherosclerotic cardiovascular disease; LTL, leukocyte telomere length; and MTLA, site-adjusted muscle telomere length.
Figure 4.
Figure 4.
Four telomere length models vs the number of atherosclerotic sites in the Discovery Cohort. 0=Control; 1, one site; ≥2, two or more sites. Values are adjusted for age and sex. ASCVD indicates atherosclerotic cardiovascular disease; LTL, leukocyte telomere length; and MTLA, site-adjusted muscle telomere length.
Figure 5.
Figure 5.
Atherosclerotic cardiovascular disease (ASCVD) prevalence in the sample as a function of telomere length and sex for ages 50 and 80 years. Lines were computed for leukocyte telomere length (LTL) and LTL/site-adjusted muscle telomere length (MTLA) using the coefficients in Table 2. Lines drawn over 95% TL range in the data for the 2 sexes. Note that ages 50 (dashed lines) and 80 (solid lines) were chosen for illustration purpose only; age was entered as continuous variable in the analyses.

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