title: Relation of peripheral collagen markers to death and hospitalization in patients with heart failure and preserved ejection fraction: results of the I-PRESERVE collagen substudy.
abstract: BACKGROUND
  Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined.
  
  
  RESULTS
  This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-μg/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-μg/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185).
  
  
  CONCLUSIONS
  Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.
authors.affiliation: Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University/Alfred Hospital, Melbourne, Victoria, Australia. henry.krum@monash.edu
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Maros
authors.initials: M
authors.lastname: Elsik
authors.forename: Hans G
authors.initials: HG
authors.lastname: Schneider
authors.forename: Agata
authors.initials: A
authors.lastname: Ptaszynska
authors.forename: Marion
authors.initials: M
authors.lastname: Black
authors.forename: Peter E
authors.initials: PE
authors.lastname: Carson
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
authors.forename: Robert S
authors.initials: RS
authors.lastname: McKelvie
authors.forename: John J
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: Inder S
authors.initials: IS
authors.lastname: Anand
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003094:Collagen / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy / Q000401:mortality* / Q000503:physiopathology*; D006760:Hospitalization; D006801:Humans; D000077405:Irbesartan; D053208:Kaplan-Meier Estimate; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D011347:Procollagen / Q000097:blood*; D013318:Stroke Volume / Q000502:physiology*; D015996:Survival Rate; D013777:Tetrazoles / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D011347:Procollagen; D013777:Tetrazoles; C047202:procollagen Type I N-terminal peptide; C041876:procollagen Type III-N-terminal peptide; D053495:Osteopontin; D003094:Collagen; D000077405:Irbesartan