title: Interleukin-6 and activin A are independently associated with cardiovascular events and mortality in type 2 diabetes: the prospective Asker and Bærum Cardiovascular Diabetes (ABCD) cohort study.
abstract: BACKGROUND
  Novel and robust cardiovascular (CV) markers are needed to improve CV morbidity and mortality risk prediction in type 2 diabetes (T2D). We assessed the long term predictive value of 4 novel CV risk markers for major CV events and mortality.
  
  
  METHODS
  We included patients with T2D who had cytokines (interleukin [IL]-6 and activin A [actA]), a maximum stress ECG test (evaluated by the normalization pattern in early recovery phase) and echocardiography (evaluated by a measure of the left ventricular filling pressure - E/Em) assessed at baseline. The primary endpoint was time to first of any of the following events: myocardial infarction, stroke, hospitalization for unstable angina pectoris and death. All outcomes were adjudicated by independent experts. We used Cox proportional hazard modeling, Harrell C-statistic and the net reclassification improvement (NRI) to assess the additional value beyond conventional markers (age, gender, prior CV disease, HDL, creatinine, diastolic BP, microalbuminuria).
  
  
  RESULTS
  At baseline the study cohort (n = 135, mean age/diabetes duration/HbA1c: 59 yrs/7 yrs/7.6% [59 mmol/mol], 26% females) had moderate elevated CV risk (42% microalbuminuria, mean Framingham 10 year CV-risk 9.6%). During 8.6 yrs/1153.7 person years, 26 patients experienced 36 events. All 4 novel risk markers were significantly associated with increased risk of the primary endpoint, however, only IL-6 and actA improved C-statistic and NRI (+0.119/43.2%, +0.065/20.3% respectively) compared with the conventional CV risk factors.
  
  
  CONCLUSIONS
  IL-6 and actA may provide prognostic information on CV events and mortality in T2D beyond conventional CV risk factors.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00133718.
authors.affiliation: Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, N-1309 Rud, Bærum, Norway. Annepernille@hotmail.com.
authors.forename: Anne Pernille
authors.initials: AP
authors.lastname: Ofstad
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.forename: Elsa
authors.initials: E
authors.lastname: Orvik
authors.forename: Svend
authors.initials: S
authors.lastname: Aakhus
authors.forename: Knut
authors.initials: K
authors.lastname: Endresen
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Morten W
authors.initials: MW
authors.lastname: Fagerland
authors.forename: Kåre I
authors.initials: KI
authors.lastname: Birkeland
authors.forename: Odd Erik
authors.initials: OE
authors.lastname: Johansen
mesh_terms: D028341:Activins / Q000097:blood*; D000368:Aged; D000789:Angina, Unstable / Q000097:blood / Q000401:mortality; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000401:mortality* / Q000503:physiopathology; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000401:mortality* / Q000503:physiopathology; D018450:Disease Progression; D025401:Echocardiography, Stress; D004562:Electrocardiography; D005260:Female; D006760:Hospitalization; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000401:mortality; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; C422405:activin A; D028341:Activins; D002097:C-Reactive Protein