Short Leukocyte Telomere Length Precedes Clinical Expression of AtherosclerosisNovelty and Significance: The 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 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 (MTL A ) was longer than LTL and the LTL-MTL A gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL ( P =0.005), but not MTL A ( P =0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTL A ) was wider ( P =0.0003), and the TL ratio between leukocytes and muscle (LTL/MTL A ) 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.