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

Fang‐Fei Wei ,Pierre Monney,Michel Burnier,Menno Pruijm,Peter Verhamme,Murielle Bochud,Stefan Janssens,Lutgarde Thijs,Cees Vermeer,Georg Ehret,Jan A Staessen,Karel Allegaert,Sander Trenson,Yassine Bouatou,Tatiana Kuznetsova,Zhenyu Zhang ,Pierre‐Yves Martin ,Belén Ponte ,Wenyi Yang ,Qi‐Fang Huang

doi:10.1371/journal.pone.0193967

Abstract

ObjectivesA 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.MethodsWe measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss.ResultsAmong 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).ConclusionsOur 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.

Highlights

In view of the demographic transition, heart failure (HF) is a major public health problem [1]
We hypothesized that left ventricular (LV) filling pressure–a measure of diastolic LV dysfunction–increases with higher plasma level of inactive desphospho-uncarboxylated Matrix Gla protein (MGP)
We studied the distribution of active and inactive MGP in human myocardium

Summary

Introduction

In view of the demographic transition, heart failure (HF) is a major public health problem [1]. Diastolic HF, referred to as HF with preserved ejection fraction, accounts for 50% of cases [2]. Mortality of diastolic HF is 30% within one year of the first hospital admission [3]. Matrix Gla protein (MGP) is a small protein (11 kD) synthesized by vascular smooth muscle cells and the endothelium [7]. Activation of MGP requires two posttranslational modifications: vitamin-K dependent γ-glutamate carboxylation and serine phosphorylation [7]. Activated MGP is a potent locally acting inhibitor of calcification in large arteries [8] and protects against macrovascular complications [9,10]

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