title: Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism.
abstract: OBJECTIVE
  Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF.
  
  
  METHODS
  One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts.
  
  
  RESULTS
  Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C.
  
  
  CONCLUSIONS
  In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.
authors.affiliation: aDepartment of Internal Medicine, University of Navarra Clinic bProgram of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra cIdiSNA, Navarra Institute for Health Research, Pamplona dDivision of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastián eDivision of Internal Medicine, Donostia University Hospital, University of the Basque Country, San Sebastián fDepartment of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain *Javier Díez and Arantxa González contributed equally to the study.
authors.forename: Ana
authors.initials: A
authors.lastname: Huerta
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.forename: Gorka
authors.initials: G
authors.lastname: San José
authors.forename: Ramón
authors.initials: R
authors.lastname: Querejeta
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Beloqui
authors.forename: Elena
authors.initials: E
authors.lastname: Zubillaga
authors.forename: Gregorio
authors.initials: G
authors.lastname: Rábago
authors.forename: Cristina
authors.initials: C
authors.lastname: Brugnolaro
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D055316:Cystatin C / Q000097:blood* / Q000494:pharmacology; D004452:Echocardiography; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology; D053495:Osteopontin / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D011669:Pulmonary Wedge Pressure; D013318:Stroke Volume; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D055316:Cystatin C; D010446:Peptide Fragments; D011347:Procollagen; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C042813:procollagen type I carboxy terminal peptide; D053495:Osteopontin; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1