Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction

Fang-Fei Wei, Sander Trenson, Pierre Monney, Wen-Yi Yang, Menno Pruijm, Zhen-Yu Zhang, Yassine Bouatou, Qi-Fang Huang, Belen Ponte, Pierre-Yves Martin, Lutgarde Thijs, Tatiana Kuznetsova, Karel Allegaert, Stefan Janssens, Cees Vermeer, Peter Verhamme, Michel Burnier, Murielle Bochud, Georg Ehret, Jan A. Staessen*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    8 Citations (Web of Science)

    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-uncar-boxylated 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 mu g/L vs. 4.20 mu g/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 mu m2 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.
    Original languageEnglish
    Article numbere0193967
    Number of pages20
    JournalPLOS ONE
    Volume13
    Issue number3
    DOIs
    Publication statusPublished - 12 Mar 2018

    Keywords

    • BONE MORPHOGENETIC PROTEIN-4
    • PRESERVED EJECTION FRACTION
    • K-DEPENDENT PROTECTION
    • VITAMIN-K
    • HEART-FAILURE
    • MENAQUINONE-7 SUPPLEMENTATION
    • ARTERIAL STIFFNESS
    • POWERFUL PREDICTOR
    • GENERAL-POPULATION
    • FILLING PRESSURE
    • Multivariate Analysis
    • Humans
    • Middle Aged
    • Male
    • Ventricular Dysfunction, Left/diagnostic imaging
    • Myocardial Ischemia/diagnostic imaging
    • Young Adult
    • Netherlands
    • Extracellular Matrix Proteins/metabolism
    • Aged, 80 and over
    • Electrocardiography
    • Adult
    • Female
    • Heart Transplantation
    • Switzerland
    • Heart/diagnostic imaging
    • Calcium-Binding Proteins/metabolism
    • Myocardium/metabolism
    • Aged
    • Cardiomyopathy, Dilated/diagnostic imaging
    • Cohort Studies

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