Regulators of Mineralization and Long-Term Progression of Aortic Valve and Mitral Annular Calcification: MESA.

BACKGROUND: Aortic valve calcification (AVC) and mitral annual calcification (MAC) may progress to aortic and mitral stenosis in older adults. The role of major mineralization regulators MGP (matrix Gla protein), FGF-23 (fibroblast growth factor-23), and fetuin-A in long-term progression of AVC and MAC remains unexamined. METHODS: We measured blood levels of dp-ucMGP (n=2663) at study baseline and evaluated these concurrently with prior baseline measures of FGF-23 (n=6547) and fetuin-A (n=2550) in relation to AVC and MAC quantified on ≤3 serial computed tomography scans over 9.4 (interquartile range, 9.0-9.8) years in MESA (Multi-Ethnic Study of Atherosclerosis). We used linear mixed-effects models to simultaneously assess the incidence and progression of AVC and MAC. RESULTS: Our objective was to investigate the association of circulating dephosphorylated-uncarboxylated (dp-uc) MGP, reflecting vitamin K deficiency/diminished MGP anticalcific capacity; FGF-23, a phosphaturic hormone; and fetuin-A, a calcium-phosphate solubilizer, with long-term incidence and progression of AVC and MAC. After adjustment for demographic and clinical characteristics, dp-ucMGP was associated with higher annual incidence/progression of AVC (0.94 [95% CI, 0.42, 1.46] Agatston units/y) and MAC (3.90 [95% CI, 1.06, 6.74] Agatston units/y); FGF-23 with higher annual incidence/progression of MAC (2.61 [95% CI, 0.50, 4.72] Agatston units/y); and fetuin-A with lower annual incidence/progression of AVC (-0.89 [95% CI, -1.55, -0.23] Agatston units/y (all per SD increment in regulator). CONCLUSIONS: In this multiethnic sample, dp-ucMGP and FGF-23 were associated with higher, and fetuin-A with lower, long-term incidence/progression of valvular or annular calcification. This has implications for therapeutic trials of calcific valvular disease, particularly targeting vitamin K supplementation to individuals with higher dp-ucMGP levels.