DOI: 10.1161/jaha.125.042370 ISSN: 2047-9980

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

Anna E. Bortnick, Mahim Naveed, Xueyan Fu, Kyla Shea, Bryan Kestenbaum, Ian de Boer, Joachim H. Ix, Ryung Kim, Emily Hamerton, Rohan Kankaria, Russell P. Tracy, Michael Tsai, Matthew Budoff, George Thanassoulis, Sarah Booth, Jorge R. Kizer
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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.

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