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.

中文翻译：

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短的白细胞端粒长度先于动脉粥样硬化的临床表达的新颖性和意义

原理：白细胞端粒长度短（TL）与动脉粥样硬化性心血管疾病（ASCVD）相关。尚不知道这种关系是源于出生时固有的短白细胞TL（LTL）还是其后更快的LTL损耗。LTL代表高度增生的造血系统中的TL，而骨骼肌中的TL则代表最小复制性组织。

目的：我们测量了同一个体中的零担和肌肉TL（MTL），以期获得终身零担消耗的比较指标，并了解零担与ASCVD的时间相关性。

方法和结果：我们的发现队列包括259名年龄在63±14岁（平均±SD）的个体，他们接受（n = 131）或没有（n = 128）ASCVD临床表现的手术。在所有受试者中，针对肌肉活检部位（MTL _A）进行调整的MTL均比LTL长，而LTL-MTL _A的差距在ASCVD患者和对照组中也随着年龄的增长而扩大。ASCVD患者的年龄和性别调整后的LTL（ P = 0.005），而不是MTL _A（ P = 0.90），比对照组短。白细胞和肌肉之间的TL间隙（LTL-MTL _A）较宽（ P = 0.0003），白细胞和肌肉之间的TL比（LTL / MTL _A）较小（ P= 0.0001）在ASCVD中比在对照中。在包含143个个体的队列中复制了发现。

结论：这项首次应用血液和肌肉TL模型的研究显示，与对照组相比，ASCVD患者的LTL磨损更为明显。LTL减员的差异与成年期间的年龄无关，这表明早年磨损的增加更可能是ASCVD患者LTL缩短的主要原因。

临床试验注册： URL：http://www.clinicaltrials.gov。唯一标识符：NCT02176941。