title: CCL21 is associated with fatal outcomes in chronic heart failure: data from CORONA and GISSI-HF trials.
abstract: OBJECTIVE
  Chronic heart failure (HF) is in part characterized by immune activation and inflammation, and factors that regulate lymphocyte trafficking and inflammation may contribute to the progression of this disorder. The homeostatic chemokine CCL21 is a potent regulator of T-cell migration into non-lymphoid tissue and may exert inflammatory properties and influence tissue remodelling. We therefore investigated CCL21 levels and association with fatal outcomes in patients with chronic HF.
  
  
  RESULTS
  Plasma CCL21 was measured at randomization in 1456 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and in 1145 from the GISSI-HF trial. Association between CCL21 levels [given below as hazard ratio (HR) with 95% confidence interval (CI) for 1 SD increase] with all-cause (n = 741) or cardiovascular (CV) mortality (n = 576) was evaluated with multivariable Cox proportional hazard models, adjusting for clinical risk factors, C-reactive protein, and NT-proBNP. In multivariable Cox models, CCL21 was associated with higher risk of all-cause mortality (HR 1.16, 95% CI 1.02-1.32; P = 0.020) and CV mortality (HR 1.20, 95% CI 1.08-1.33; P < 0.001). When the two trials were analysed separately, CCL21 had a similar influence on risk prediction. Finally, CCL21 had a modest but significant impact on the discriminatory properties of the model (all-cause mortality, change in Harrell's C-statistic 0.004, P = 0.001; CV mortality, change in C-statistic 0.002, P = 0.002).
  
  
  CONCLUSIONS
  Circulating CCL21 was associated with all-cause and CV mortality in two large populations of contemporary patients with chronic HF.
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. r.ueland@medisin.uio.no
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Ståle H
authors.initials: SH
authors.lastname: Nymo
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.forename: John
authors.initials: J
authors.lastname: Kjekshus
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fucili
authors.forename: Aurelia
authors.initials: A
authors.lastname: Grosu
authors.forename: Serge
authors.initials: S
authors.lastname: Masson
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D000368:Aged; D054421:Chemokine CCL21 / Q000097:blood*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use*; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D009664:Norway / Q000453:epidemiology; D011379:Prognosis; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000627:therapeutic use*; D012307:Risk Factors; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium
keywords: CCL21; Heart failure; Inflammation; Survival analysis