Vitamin K Status, Warfarin Use, and Arterial Stiffness in Heart Failure

Abstract

Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K–dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444–721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455–643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377–475 pmol/L; ANCOVA P =0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized β, 0.31; 95% CI, 0.19–0.42; P <0.0001), which was also true in analyses restricted to patients with HF (standardized β, 0.34; 95% CI, 0.16–0.52; P =0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized β, 0.13; 95% CI, 0.004–0.26; P =0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein

“…In the general population, dp-ucMGP has been repeatedly and strongly correlated with various markers of arterial calcification (35)(36)(37)(38), arterial stiffness (39) and CVD (40)(41)(42). Similar results were reported in cohorts characterized by high atherogenic status, such as patients with heart failure and CVD (30,(43)(44)(45). Since CKD is a state of accelerated calcification of both intimal and media layer as well as soft tissues, several investigators explored the association between dp-ucMGP and VC /CVD in these patients.…”

“…In HD and renal transplant recipients, in vitro and clinical data suggest that phosphate binders might enhance vitamin K bioavailability, through undesired binding of K2. Thirdly, it is not yet determined whether dp-ucMGP is a marker of accelerated arterial calcification (32), arterial stiffness (39,45) or both. Finally, the side-effects and the toxicity of vitamin K supplementation need to be further clarified.…”

Vitamin K–Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity

“…42 In patients with heart failure with preserved ejection fraction (n=96) and heart failure patients with reduced ejection fraction (n=53) and controls without heart failure (n=199), carotid-femoral pulse wave velocity with adjustment for confounders was positively associated with circulating dp-ucMGP (standardized β, 0.18; CI, 0.03–0.34; P =0.023). 40 In analyses restricted to participants with heart failure, the association remained significant (standardized β, 0.32; CI, 0.04–0.61; P =0.026). Carotid-femoral pulse wave velocity also increased with warfarin use (standardized β, 0.13; CI, 0.004–0.26; P =0.043), but this association lost significance with additional adjustment for circulating dp-ucMGP, 40 indicating that dp-ucMGP incorporates information on vitamin K antagonism.…”

“…40 In analyses restricted to participants with heart failure, the association remained significant (standardized β, 0.32; CI, 0.04–0.61; P =0.026). Carotid-femoral pulse wave velocity also increased with warfarin use (standardized β, 0.13; CI, 0.004–0.26; P =0.043), but this association lost significance with additional adjustment for circulating dp-ucMGP, 40 indicating that dp-ucMGP incorporates information on vitamin K antagonism.…”

“…Carotid-femoral pulse wave velocity is the gold standard for the assessment of arterial stiffness. In patients with hypertension, 38 diabetes mellitus, 39 renal dysfunction, 17 or heart failure, 40 this index was associated with circulating dp-ucMGP. These observations were replicated in 2 population studies.…”