Vitamin K dependent protein activity and incident ischemic cardiovascular disease: The multi ethnic study of atherosclerosis

Authors: DANZIGER, JOHN - Beth Israel Deaconess Medical Center; YOUNG, REBEKAH - University Of Washington; SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TRACY, RUSSELL - University Of Vermont; IX, JOACHIM - Department Of Veterans Affairs; JENNY, NANCY - University Of Vermont; MUKAMAL, KENNETH - Beth Israel Deaconess Medical Center

Submitted to: Arteriosclerosis Thrombosis and Vascular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/14/2016
Publication Date: 5/1/2016
Citation: Danziger, J., Young, R.L., Shea, K., Tracy, R.P., Ix, J.H., Jenny, N.S., Mukamal, K.J. 2016. Vitamin K dependent protein activity and incident ischemic cardiovascular disease: The multi ethnic study of atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology. 36(5):1037-1042.

Interpretive Summary: This study evaluated the association between vitamin K-dependent protein activity and heart disease in a multi-ethnic group of community-dwelling adults. Higher circulating concentrations of the inactive form of the vitamin K-dependent protein prothrombin were associated with a higher risk for incident ischemic heart disease. Increasing vitamin K intake either through diet or supplements reduces the inactive forms of vitamin K-dependent proteins. Whether this affects heart disease remains to be determined.

Technical Abstract: 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-gamma-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-gamma-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-gamma-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-gamma-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.