title: Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure.
abstract: BACKGROUND
  Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function.
  
  
  OBJECTIVE
  This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded.
  
  
  METHODS
  Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples.
  
  
  RESULTS
  Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ≤1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (≤1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death.
  
  
  CONCLUSIONS
  Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.affiliation: Department of Internal Medicine, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Zubillaga
authors.affiliation: Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bonavila
authors.affiliation: Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Magda
authors.initials: M
authors.lastname: Bergés
authors.affiliation: Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Kattalin
authors.initials: K
authors.lastname: Echegaray
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Beaumont
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: María U
authors.initials: MU
authors.lastname: Moreno
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: San José
authors.affiliation: Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Larman
authors.affiliation: Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Querejeta
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain. Electronic address: jadimar@unav.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D024042:Collagen Type I / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D053208:Kaplan-Meier Estimate; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood*; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D010446:Peptide Fragments / Q000097:blood; D012372:ROC Curve; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013030:Spain / Q000453:epidemiology; D013223:Statistics as Topic; D013318:Stroke Volume
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D010446:Peptide Fragments; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: biomarker; cardiovascular death; heart failure of hypertensive etiology; myocardial fibrosis