Cardiovascular (CV) diseases are the leading cause of morbidity and mortality throughout the world. In the last decades, considerable attention is given to the prevention of CV diseases, and also to modification of risk factors. Modifiable risk factors can be changed, such as diet, body weight, physical activity, blood pressure and diabetes, while genetics, age and gender represent non-modifiable risk factors.
Different epidemiological studies have pointed to the Asian population, especially the people of Japan, having surprisingly lower CV mortality and lower risk of coronary artery disease compared to the rest of the world population. Possible explanation of their longevity and lower CV risk may be the food they regularly consume. Besides the lower content of saturated fatty acids and frequent consumption of fish in their diet, it is possible that the consumption of soybeans contributes to lower CV morbidity and mortality in Japan. This also refers to nattō, traditional Japanese breakfast made from fermented soybeans.
In 1987 one interesting enzyme was isolated from nattō, and named nattokinase. It was observed that this enzyme has multiple beneficial effects that can be used in CV prevention and therapy. Most important effects were fibrinolytic and anti-thrombotic, followed by antihypertensive and neuroprotective effect of this powerful and natural enzyme.
Nattokinase dissolves fibrin, a protein important for stabilization of blood clots. Oral administration of nattokinase in experimentally induced thrombosis led to the degradation of blood clots, with restoration of normal blood flow after only five hours. Afterwards, it was observed that in experimentally induced pulmonary thrombosis in mice, nattokinase stopped the thrombotic proccess by mechanism similar to the mechanism of aspirin. Animal model of carotid thrombosis showed better fibrinolytic effect of nattokinase compared to plasmin. Administration of nattokinase restored 62% of initial blood flow in coronary artery, compared to 15.2% with plasmin administration. Additionally, nattokinase confirmed to be four times potent than plasmin in thrombus dissolution.
Clinical trials confirmed fibrinolytic effect of nattokinase. Oral administration of nattokinase in humans showed gradual increase in plasma fibrinolytic activity. Maximum concentration of nattokinase in blood was observed after 13 hours of oral administration of just one dose of nattokinase. Subsequent trials showed that after two months of oral administration of nattokinase, plasma levels of fibrinogen, coagulation factor VII, and factor VIII were significantly reduced. Decrease in these hematologic parameters was noted in healthy people, in people with elevated CV risk, and also in patients on dialysis.
Oral administration of only one dose of nattokinase is sufficient for fibrinolytic effect. This was observed in clinical study that enrolled 12 healthy people who took only one capsule of nattokinase (2000 FU) or capsule containing placebo. Significant increase in antithrombin blood concentration was noted only two hours after taking nattokinase. After four hours of nattokinase administration there was increase in concentration of fibrin degradation products, while after six hours there was increase in D-dimer concentration. Additionally, four hours after oral administration of nattokinase decrease in coagulation factor VIII activity was recorded, which pointed to different fibrinolytic mechanisms of this enzyme. Although the changes of these parameters were significant, they were still in the reference range.
In 2008 first randomized trial analyzing the effects of nattokinase on arterial blood pressure in humans was published. This trial enrolled 86 subjects with prehypertension or stadium I hypertension, who received nattokinase (2000 FU once daily) or placebo per os, for eight weeks.
Nattokinase reduced systolic blood pressure for mean -5.55 mmHg more than placebo, as well as diastolic blood pressure (mean difference -2.84 mmHg).
Another similarly designed study explored the antihypertensive effect of nattokinase in patients with elevated arterial blood pressure, but for the first time in non-Asian population. This study included patients from USA and Canada, who’s dietary and lifestyle habits significantly differ from the Asian population. After eight weeks of oral administration of nattokinase, there was decrease in systolic blood pressure from mean 144± 1.5 mmHg to 140 ± 2.1 mmHg. However, observed reduction in systolic blood pressure showed no significant difference between patients taking nattokinase vs. placebo-group. However, decrease in diastolic blood pressure was significantly higher in patients taking nattokinase compared to patients in placebo-group, but affecting only male gender (from initial 86 mmHg to 81 ± 2.5 mmHg after eight weeks). Patients taking placebo had constant diastolic blood pressure throughout the study period (mean 88 ± 2.6 mmHg). Different results could be explained by the different study population included. Namely, non-Asian subjects had no prior contact with nattokinase, nor they have consumed nattō. It is possible that longer administration of nattokinase is necessary for antihypertensive effect to be registered.
Antihypertensive effect can partially be explained by the inhibition of angiotensin-converting enzyme (ACE). Such mechanism was observed on animal models with administered nattokinase.
Experimental studies, followed by clinical trials in humans, showed that nattokinase reduced the intima-media thickness in carotid artery, along with the reduction in atherosclerotic plaque size. Underlying mechanism of the anti-atherosclerotic effect may be the synergistic fibrinolytic, antithrombotic, and anticoagulant effect of this enzyme. Additionally, nattokinase administration was associated with larger plaque reduction compared to subjects taking simvastatin.
Although experimental studies showed that nattokinase is associated with significant reduction in total cholesterol, LDL-cholesterol and triglycerids, clinical testing in humans pointed to reduction in these parameters, which was statistically non-significant. It is possible that higher doses of nattokinase are required for its hypolipemic effect.
Nattokinase inhibits platelet aggregation in vitro and in vivo, with mechanism similar to the mechanism of aspirin. Namely, nattokinase inhibits thromboxane B2 production by the activated platelets, which results in decrease in platelet aggregation and antithrombotic effect. It was also observed that nattokinase might reduce aggregation of red blood cells, and therefore improve rheological characteristics of blood.
Experimental studies showed that nattokinase is capable of degrading amyloid fibrils. Further research on neuroprotective effect of nattokinase was initiated, focusing on amyloid-related diseases, such as Alzheimer disease. Potential neuroprotective effect might be explained by the proteolytic, anti-inflammatory, and anti-apoptotic activity of nattokinase.
Neuroprotective effect was also registered in the experimental model of acute ischemic stroke. Observed decrease in infarction volume may be interpreted by the effect of nattokinase on vascular smooth muscle cells (myorelaxation and vasodilatation), and also by endothelial protection (via enhanced fibrinolysis and stimulation of endogenous thrombolysis).