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Phenotyping of myocardial fibrosis in hypertensive patients with heart failure. Influence on clinical outcome

Ravassa, Susana; López, Begoña; Querejeta, Ramón; Echegaray, Kattalin; San José, Gorka; Moreno, María U.; Beaumont, Francisco J.; González, Arantxa; Díez, Javier

doi: 10.1097/HJH.0000000000001258

Objective: Myocardial fibrosis is associated with alterations in the cross-linking and deposition of collagen type I (CCL and CD, respectively). We aimed to evaluate whether the combination of circulating biomarkers of CCL [the carboxy-terminal telopeptide of collagen type I to matrix metalloproteinase-1 ratio (CITP : MMP-1)] and CD [the carboxy-terminal propeptide of procollagen type I (PICP)] identifies myocardial fibrosis phenotypes with distinct clinical outcome in hypertensive patients with heart failure.

Methods: Endomyocardial biopsies and blood samples from 38 patients (small cohort), and blood samples from 203 patients (large cohort) were analyzed. Myocardial CCL and CD were assessed by histological methods. Serum PICP, CITP, and MMP-1 were determined by ELISA.

Results: Small cohort: CITP : MMP-1 cutoff 1.968 or less and PICP cutoff at least 110.8 ng/ml were used for predicting high CCL and severe CD, respectively. Large cohort: as defined by the above thresholds, patients were categorized into four subgroups based on the presence (+) or absence (−) of high CCL and severe CD. Compared with CCL−CD−, the adjusted hazard ratios for a composite end point of heart failure hospitalization or cardiovascular death over 5 years in CCL−CD+, CCL+CD−, and CCL+CD+ were 1.11 (P = 0.79), 1.99 (P = 0.07), and 2.18 (P = 0.04), respectively (P for trend = 0.005). In addition, the categorization based on CCL and CD yielded integrated discrimination (P = 0.03) and net reclassification (P = 0.01) improvements for the mentioned outcome.

Conclusion: The combination of low serum CITP : MMP-1 ratio and high serum PICP identifies hypertensive patients with heart failure presenting with a phenotype of myocardial fibrosis characterized by the concurrence of excessive CCL and CD and associated with poor outcome.

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aProgram of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra

bIdiSNA, Navarra Institute for Health Research, Pamplona

cDivision of Cardiology, Donostia University Hospital, University of the Basque Country, and Biodonostia Research Institute, San Sebastian

dDepartment of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain

Correspondence to Javier Díez, PhD, Program of Cardiovascular Diseases, CIMA, Avenida Pío XII 55, 31008 Pamplona, Spain. Tel: +34 948194700; fax: +34 948194716; e-mail:

Abbreviations: CCL, collagen cross-linking; CD, collagen deposition; CITP, carboxy-terminal telopeptide of collagen type I; CT-1, cardiotrophin-1; Gal-3, galectin-3; HF, heart failure; HHF, hospitalization for heart failure; IDI, integrated discrimination improvement; MF, myocardial fibrosis; MMP-1, matrix metalloproteinase-1; NRI, net reclassification index; NT-proBNP, amino-terminal propeptide of brain natriuretic peptide; OPN, osteopontin; PCWP, pulmonary capillary wedge pressure; PICP, carboxy-terminal propeptide of procollagen type I

Received 20 October, 2016

Revised 24 November, 2016

Accepted 15 December, 2016

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