Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC)

Abstract

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.

Keywords: cardiovascular disease; hypertension; matrix Gla protein; phylloquinone; vitamin K.

FIGURE 1

Diagram of Health ABC participants included in this analysis. CVD, cardiovascular disease; (dp)ucMGP, (desphospho)uncarboxylated matrix Gla protein; Health ABC, Health, Aging, and Body Composition Study.

FIGURE 2

Fully adjusted cumulative hazards for incident CVD in Health ABC participants with plasma vitamin K <0.2 and ≥0.2 nmol/L, according to hypertension status, in participants treated for hypertension (n = 490; 135 events) (A), participants with untreated hypertension (n = 153; 48 events) (B), and participants free of hypertension (n = 414; 82 events) (C). Values were adjusted for age, sex, race, site, education, TGs, LDL cholesterol, HDL cholesterol, fasting glucose, insulin, BMI, systolic blood pressure, diastolic blood pressure, IL-6, estimated glomerular filtration rate, lipid-lowering medication use, diabetes medication use, anti-inflammatory medication use, Healthy Eating Index, walking time per week, smoking (pack-years), season, serum 25-hydroxyvitamin D, alcohol use, knee pain, and lower extremity function. CVD, cardiovascular disease; Health ABC, Health, Aging, and Body Composition Study.