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

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.