Nattokinase Atherothrombotic Prevention Study
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Cognitive Studies, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 55 - 100 |
| Updated: | 5/9/2018 |
| Start Date: | April 2014 |
| End Date: | September 2019 |
The potential for nattokinase to "thin" blood and to reduce blood clotting by positive
antithrombotic and fibrinolytic effects presents a unique opportunity to safely study such
effects on cardiovascular disease and cognition. Unfortunately, such studies of
antithrombotic and fibrinolytic pathways of prevention have been limited due to lack of safe
compounds and the adverse reactions associated with current agents such as Coumadin.
Nattokinase, an over-the-counter supplement used for cardiovascular health, is the most
active functional constituent of natto, a fermented soy product. Natto has been consumed
primarily by the Japanese for over 1000 years, a population with one of the lowest risks for
cardiovascular disease and dementia. Cardiovascular disease and dementia remain the most
challenging age-related health risks of the 21st century for Americans necessitating
development of further effective preemptive strategies. Whether reducing the propensity for
thrombus formation and/or increasing fibrinolytic activity can prevent the progression of
atherosclerosis and cognitive decline has not yet been determined.
Using nattokinase under primary prevention conditions, the investigators propose to conduct a
randomized, double-blinded, placebo-controlled trial to determine whether decreasing
atherothrombotic risk can reduce the progression of atherosclerosis and cognitive decline.
The investigators propose to randomize 240 healthy non-demented women and men to nattokinase
supplementation or to placebo for three years. The primary trial end points will be
measurement of carotid arterial wall thickness and arterial stiffness, early changes of
atherosclerosis that can be measured safely by non-invasive imaging techniques. The secondary
trial end point will be ascertained through change in cognition measured by a
neuropsychological battery. In addition, biochemical blood measurements and in vitro studies
will be conducted to compare the effects of nattokinase relative to placebo on blood
coagulation and thrombus break-down capabilities, blood flow properties, inflammation and
inflammatory activation of endothelial cells that line blood vessels.
At the conclusion of this trial, the investigators expect to have sufficient evidence as to
whether reducing the propensity for thrombus formation and/or increasing fibrinolytic
activity can prevent the progression of atherosclerosis and cognitive decline. These results
will provide novel and important data that will be informative concerning primary prevention
through the atherothrombotic pathway. Providing evidence for a reduction in atherosclerosis
progression and cognitive decline with nattokinase is likely to shift the current clinical
paradigm for the prevention of these chronic age-related processes. In addition, such
evidence will serve to create a new field of discovery and opportunity for prevention of
cardiovascular disease and dementia.
antithrombotic and fibrinolytic effects presents a unique opportunity to safely study such
effects on cardiovascular disease and cognition. Unfortunately, such studies of
antithrombotic and fibrinolytic pathways of prevention have been limited due to lack of safe
compounds and the adverse reactions associated with current agents such as Coumadin.
Nattokinase, an over-the-counter supplement used for cardiovascular health, is the most
active functional constituent of natto, a fermented soy product. Natto has been consumed
primarily by the Japanese for over 1000 years, a population with one of the lowest risks for
cardiovascular disease and dementia. Cardiovascular disease and dementia remain the most
challenging age-related health risks of the 21st century for Americans necessitating
development of further effective preemptive strategies. Whether reducing the propensity for
thrombus formation and/or increasing fibrinolytic activity can prevent the progression of
atherosclerosis and cognitive decline has not yet been determined.
Using nattokinase under primary prevention conditions, the investigators propose to conduct a
randomized, double-blinded, placebo-controlled trial to determine whether decreasing
atherothrombotic risk can reduce the progression of atherosclerosis and cognitive decline.
The investigators propose to randomize 240 healthy non-demented women and men to nattokinase
supplementation or to placebo for three years. The primary trial end points will be
measurement of carotid arterial wall thickness and arterial stiffness, early changes of
atherosclerosis that can be measured safely by non-invasive imaging techniques. The secondary
trial end point will be ascertained through change in cognition measured by a
neuropsychological battery. In addition, biochemical blood measurements and in vitro studies
will be conducted to compare the effects of nattokinase relative to placebo on blood
coagulation and thrombus break-down capabilities, blood flow properties, inflammation and
inflammatory activation of endothelial cells that line blood vessels.
At the conclusion of this trial, the investigators expect to have sufficient evidence as to
whether reducing the propensity for thrombus formation and/or increasing fibrinolytic
activity can prevent the progression of atherosclerosis and cognitive decline. These results
will provide novel and important data that will be informative concerning primary prevention
through the atherothrombotic pathway. Providing evidence for a reduction in atherosclerosis
progression and cognitive decline with nattokinase is likely to shift the current clinical
paradigm for the prevention of these chronic age-related processes. In addition, such
evidence will serve to create a new field of discovery and opportunity for prevention of
cardiovascular disease and dementia.
Objectives and Hypotheses: The goal of the proposed study is to determine under randomized
controlled trial (RCT) conditions whether nattokinase reduces subclinical atherosclerosis and
cognitive decline in healthy women and men. The investigators' hypotheses are: 1) Compared to
placebo, nattokinase 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 will be correlated; and, 3) The reduction in
progression of subclinical atherosclerosis and cognitive decline with nattokinase 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 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:
1. To determine the effect of nattokinase on the 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.
2. To determine the effect of nattokinase 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.
2a. To determine the effect of nattokinase on cognitive decline according to apolipoprotein
(Apo) E e4 genotype.
3. To determine the association of subclinical atherosclerosis progression with cognitive
decline.
4. To determine whether the effects of nattokinase 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, expression of adhesion molecules VCAM-1 and ICAM-1 in
cultured human aortic endothelial cells) factors as well as blood pressure.
controlled trial (RCT) conditions whether nattokinase reduces subclinical atherosclerosis and
cognitive decline in healthy women and men. The investigators' hypotheses are: 1) Compared to
placebo, nattokinase 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 will be correlated; and, 3) The reduction in
progression of subclinical atherosclerosis and cognitive decline with nattokinase 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 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:
1. To determine the effect of nattokinase on the 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.
2. To determine the effect of nattokinase 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.
2a. To determine the effect of nattokinase on cognitive decline according to apolipoprotein
(Apo) E e4 genotype.
3. To determine the association of subclinical atherosclerosis progression with cognitive
decline.
4. To determine whether the effects of nattokinase 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, expression of adhesion molecules VCAM-1 and ICAM-1 in
cultured human aortic endothelial cells) factors as well as blood pressure.
Inclusion Criteria:
- Age >55 years
- Male or postmenopausal female (no uterine bleeding for >6 months)
Exclusion Criteria:
- Clinical signs, symptoms, or personal history of CVD
- Diabetes mellitus or fasting serum glucose >140 mg/dL
- Plasma triglyceride levels >500 mg/dL
- Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood
pressure >110 mmHg)*
- Uncontrolled tachycardia or irregular heart rates (i.e., atrial fibrillation)
- Thyroid disease (untreated)
- Renal insufficiency (defined as serum creatinine >2.0 mg/dL)
- Life threatening illness with prognosis <5 years
- Current use of lipid-lowering medication
- Current use of food supplements containing soy, soy protein, isoflavones or other
phytoestrogens
- Known sensitivity or allergy to soy or nuts
- Regular aspirin or other antiplatelet medication use
- Use of anticoagulants
- Bleeding diatheses or tendencies
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