NAPSNattokinase Atherothrombotic Prevention Study

Objectives and Hypotheses: The goal of the proposed study is to determine under randomized controlled trial (RCT) conditions whether nattokinase supplementation reduces subclinical atherosclerosis progression and cognitive decline in healthy women and men. The investigators' hypotheses are: 1) Compared to placebo, nattokinase supplementation will show less subclinical atherosclerosis progression and cognitive decline in healthy women and men; 2) The reduction in subclinical atherosclerosis progression and cognitive decline with nattokinase supplementation will be correlated; and, 3) The reduction in progression of subclinical atherosclerosis and cognitive decline with nattokinase supplementation will be mediated through hemostatic, fibrinolytic, and hemorheological factors as well as attenuation of inflammation, monocyte activation, vascular endothelium injury, and activation of vascular endothelium by circulating monocytes. Specific Aims: To conduct a RCT to determine the effect of nattokinase supplementation on the progression of subclinical atherosclerosis (primary trial end point) and cognitive decline (secondary trial end point). Healthy non-demented women and men >55 years old without pre-existing symptomatic CVD and diabetes mellitus will be randomized over a 2-year period to oral nattokinase (2,000 fibrinolysis units) daily versus placebo in this double-blind, placebo-controlled trial; randomized treatment will be 3-years. The following 5 major specific aims will be completed: To determine the effect of nattokinase supplementation on progression of subclinical carotid artery atherosclerosis determined as the rate of change of the common carotid artery intima-media thickness (CIMT) and arterial stiffness in computer image processed B-mode ultrasonograms. To determine the effect of nattokinase supplementation on cognitive decline determined with a neuropsychological battery designed to evaluate 7 cognitive domains including: attention, concentration, working memory, executive function; visuospatial/visuoconstructive skills; naming/semantic memory; and verbal and nonverbal episodic memory. To determine the effect of nattokinase supplementation on cognitive decline according to apolipoprotein (Apo) E4 genotype. To determine the association of subclinical atherosclerosis progression with cognitive decline. To determine whether the effects of nattokinase supplementation on subclinical atherosclerosis and cognitive decline are mediated through hemostatic (fibrinogen, factor VIII, platelet activity), fibrinolytic (tPA, PAI-1, D-dimer), hemorheological (plasma and blood viscosity, red blood cell aggregation), and inflammatory (MCP-1, IL-8, TNFα, IL-1β, IL-10, monocyte cell surface markers CD11b/CD11c and VLA-4, and cellular adhesion molecules VCAM-1 and ICAM-1) factors as well as blood pressure.