Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: Blood-and-Muscle Model
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 and/or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, while TL in skeletal muscle (M) represents a minimally replicative tissue.
Objective: We measured LTL and 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, MTLA (MTL adjusted for muscle biopsy site) 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: NCT02176941
- Received July 20, 2017.
- Revision received December 3, 2017.
- Accepted December 13, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.