Abstract
Objectives:
A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure-a measure of diastolic LV dysfunction-increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the distribution of active and inactive MGP in human myocardium.
Methods:
We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss.
Results:
Among Flemish and Swiss, E/e' (6.78 vs. 6.73) and dp-ucMGP (3.94 μg/L vs. 4.20 μg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e' increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P≤0.026); the odds ratios for having E/e' ≥ 8.5 were 1.99, 3.29 and 2.36, respectively (P≤0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P≤0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 μm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field).
Conclusions:
Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Calcium-Binding Proteins / metabolism*
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Cardiomyopathy, Dilated / diagnostic imaging
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Cardiomyopathy, Dilated / metabolism
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Cardiomyopathy, Dilated / pathology
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Cardiomyopathy, Dilated / surgery
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Cohort Studies
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Electrocardiography
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Extracellular Matrix Proteins / metabolism*
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Female
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Heart / diagnostic imaging
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Heart Transplantation
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Humans
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Male
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Matrix Gla Protein
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Middle Aged
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Multivariate Analysis
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Myocardial Ischemia / diagnostic imaging
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Myocardial Ischemia / metabolism
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Myocardial Ischemia / pathology
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Myocardial Ischemia / surgery
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Myocardium / metabolism*
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Myocardium / pathology*
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Netherlands
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Switzerland
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Ventricular Dysfunction, Left / diagnostic imaging
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Ventricular Dysfunction, Left / epidemiology
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Ventricular Dysfunction, Left / metabolism*
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Ventricular Dysfunction, Left / pathology*
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Young Adult
Substances
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Calcium-Binding Proteins
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Extracellular Matrix Proteins
Grants and funding
The European Union (HEALTH-F7-305507 HOMAGE and the European Research Council (Advanced Researcher Grant 2011-294713-EPLORE and Proof-of-Concept Grant 713601-uPROPHET) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and 11O3416N) currently support the Studies Coordinating Centre in Leuven. The Swiss National Science Foundation funded the Swiss Kidney Project on Genes in Hypertension (FN 33CM30-140331/1). G Ehret is supported by the Fondation pour Recherches Médicales, Geneva, Switzerland. The EPLORE grant paid for the plasma dp ucMGP measurement at R&D Group VitaK (Maastricht University, The Netherlands). Jan A. Staessen was a scientific adviser to R&D Group VitaK, but did never receive any monetary or other compensation from VitaK. Cees Vermeer was an employee of and received a salary from R&D Group VitaK, but this did not influence the study design, decision to publish or the preparation of the manuscript. Likewise the funders providing support to the Academic Partners in the form of authors’ salaries (FFW, ST, WYY, ZYZ, QFH, LT) did not have any role in the study design, data collection and analysis, decision to publish, or in preparation of the manuscript.