title: Diastolic Left Ventricular Function in Relation to Urinary and Serum Collagen Biomarkers in a General Population.
abstract: Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e' decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e' increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e' decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p≤0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure.
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Zhen-Yu
authors.identifier: http://orcid.org/0000-0002-3785-7417
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Yang
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Thibault
authors.identifier: http://orcid.org/0000-0002-7720-8438
authors.initials: T
authors.lastname: Petit
authors.affiliation: Mosaiques Diagnostic and Therapeutics AG, Hannover, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-8029-5800
authors.initials: M
authors.lastname: Pejchinovski
authors.affiliation: Mosaiques Diagnostic and Therapeutics AG, Hannover, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Fang-Fei
authors.initials: FF
authors.lastname: Wei
authors.affiliation: Mosaiques Diagnostic and Therapeutics AG, Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pontillo
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.affiliation: Mosaiques Diagnostic and Therapeutics AG, Hannover, Germany.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-0379-5836
authors.initials: T
authors.lastname: Koeck
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0003-2238-2612
authors.initials: C
authors.lastname: Delles
authors.affiliation: Research Unit Cardiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Voigt
authors.affiliation: Centre for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.|Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.affiliation: Mosaiques Diagnostic and Therapeutics AG, Hannover, Germany.|BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.|R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
mesh_terms: D000328:Adult; D001530:Belgium; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003094:Collagen / Q000097:blood* / Q000737:chemistry / Q000652:urine; D003971:Diastole; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000652:urine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000652:urine; D016277:Ventricular Function, Left
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen