title: Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity.
abstract: OBJECTIVE
  Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown.
  
  
  RESULTS
  One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01-1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02-1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1β and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10.
  
  
  CONCLUSIONS
  Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Calvert
authors.forename: Tze-Vun
authors.initials: TV
authors.lastname: Liew
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gorenne
authors.forename: Murray
authors.initials: M
authors.lastname: Clarke
authors.forename: Charis
authors.initials: C
authors.lastname: Costopoulos
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Obaid
authors.forename: Michael
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Shapiro
authors.forename: Duncan C
authors.initials: DC
authors.lastname: McNab
authors.forename: Cameron G
authors.initials: CG
authors.lastname: Densem
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schofield
authors.forename: Denise
authors.initials: D
authors.lastname: Braganza
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Clarke
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Ray
authors.forename: Nick E J
authors.initials: NE
authors.lastname: West
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D016922:Cellular Senescence; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000209:etiology* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007962:Leukocytes / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000209:etiology* / Q000276:immunology; D012306:Risk; D012307:Risk Factors; D016615:Telomere; D018084:Ultrasonography, Interventional
chemical_list: D016207:Cytokines