Abstract 13951: Circulating Inactive Matrix Gla-protein, Warfarin Use and Large Artery Stiffness in Heart Failure With Reduced Ejection Fraction

Abstract

Background: large artery stiffness increases pulsatile afterload to the LV and is strongly predictive of adverse outcomes in heart failure and reduced ejection fraction (HFrEF). The identification of pathways related to arterial stiffness may provide novel therapeutic targets. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that inhibits arterial calcification. Vitamin K deficiency leads to production of inactive non-phosphorylated and uncarboxylated MGP (dp-ucMGP). We hypothesized that greater levels of dp-ucMGP, indicating impaired MGP activation, are related to arterial stiffness in human HFrEF. Methods: We studied 50 subjects with HFrEF and 279 control subjects without HF. dp-ucMGP MGP was measured with ELISA (VitaK; The Netherlands). In a subgroup of subjects (34 with HFrEF and 146 with no HF), carotid-femoral PWV (a measure of large artery stiffness) was measured with arterial tonometry (Sphygmocor Device). Carotid-radial PWV, a measure of medium-sized muscular artery stiffness, was also measured. Results: Subjects with HFrEF demonstrated markedly increased levels of dp-ucMGP (654.7 vs. 426.8; P=0.004). Among subjects with HFrEF, warfarin use (standardized Beta 0.66; P<0.0001) was the main predictor of dp-ucMGP. In turn, dp-ucMGP predicted carotid-femoral PWV (Beta=0.43; P=0.01) in HFrEF, even after adjustment for age, gender, mean arterial pressure and heart rate (Beta=0.43; P =0.007). In contrast, dp-ucMGP was not associated with carotid-radial PWV, a measure of muscular artery stiffness. Conclusions: HFrEF is associated with reduced levels of inactive dp-ucMGP, particularly in the setting of warfarin use. Circulating dp-ucMGP is independently associated with large artery stiffness in HFrEF, likely due to its role in vascular calcification. This suggests that deficient vitamin-K dependent activation of MGP may contribute to arterial stiffness in HFrEF and could be targeted with vitamin K supplementation and/or the use of anticoagulants other than warfarin. This hypothesis needs to be tested in future trials.