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Vitamin K-Dependent Protein Activity and Incident Ischemic Cardiovascular Disease: The Multi-Ethnic Study of
John Danziger1, Rebekah L Young2, M Kyla Shea2
1From the Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (J.D., K.J.M.); Department of Biostatistics, University of Washington, Seattle (R.L.Y.); Human Nutrition Research Center on Aging, Tufts University, Boston, MA (K.M.S.); College of Medicine (R.P.T.) and Department of Pathology (N.S.J.), University of Vermont, Burlington; and Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.). jdanzige@bidmc.harvard.edu.
Insights
Vitamin K-dependent protein (VKDP) activity, indicated by lower des-γ-carboxy prothrombin, is linked to a higher risk of cardiovascular disease events. This association holds true even when considering traditional risk factors and vitamin K intake.
Area of Science:
- Cardiovascular Science
- Biochemistry
- Nutritional Science
Background:
- Vitamin K-dependent proteins (VKDPs) play roles in thrombosis, vascular calcification, and vessel stiffness.
- The prospective association between VKDP activity and incident cardiovascular disease (CVD) has not been established.
Purpose of the Study:
- To investigate whether VKDP activity is prospectively associated with the risk of incident ischemic cardiovascular disease.
Main Methods:
- Assessed VKDP activity by measuring des-γ-carboxy prothrombin concentrations in 709 multiethnic adults without prevalent CVD (Multi-Ethnic Study of Atherosclerosis).
- Followed participants for a median of 11.0 years for incident ischemic CVD events (coronary heart disease, stroke, fatal CVD).
- Analyzed the association between des-γ-carboxy prothrombin quartiles and CVD risk, adjusting for traditional risk factors and vitamin K intake.
Main Results:
- A total of 75 ischemic CVD events occurred.
- Ischemic CVD incidence increased progressively with higher des-γ-carboxy prothrombin levels.
- A doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53-fold increased risk of incident ischemic CVD (95% CI, 1.09-2.13; P=0.008), consistent across subgroups.
Conclusions:
- VKDP activity is associated with incident ischemic cardiovascular events in middle-aged and older adults.
- Further research is warranted to elucidate the role of VKDPs in cardiovascular disease pathogenesis.
Objective:
Vitamin K-dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular disease has not been studied.
Approach And Results:
VKDP activity was determined by measuring circulating des-γ-carboxy prothrombin concentrations in a random sample of 709 multiethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA). Lower des-γ-carboxy prothrombin concentrations reflect greater VKDP activity. Subjects were followed up for the risk of ischemic cardiovascular disease (coronary heart disease, stroke, and fatal cardiovascular disease) for 11.0 years of follow-up. A total of 75 first ischemic CVD events occurred during follow-up. The incidence of ischemic cardiovascular disease increased progressively across des-γ-carboxy prothrombin quartiles, with event rates of 5.9 and 11.7 per 1000 person-years in the lowest and highest quartiles. In analyses adjusted for traditional cardiovascular risk factors and measures of vitamin K intake, a doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53 (95% confidence interval, 1.09-2.13; P=0.008) higher risk of incident ischemic cardiovascular disease. The association was consistent across strata of participants with diabetes mellitus, hypertension, renal impairment, and low vitamin K nutritional intake.
Conclusions:
In this sample of middle-aged and older adults, VKDP activity was associated with incident ischemic cardiovascular events. Further studies to understand the role of this large class of proteins in cardiovascular disease are warranted.
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