Nattokinase, Vitamin K2, and Cardiovascular Health

How Japan's fermented soybean superfood delivers nattokinase, vitamin K2, and Bacillus subtilis probiotics to support heart health, bone density, and longevity

Natto is a traditional Japanese food made by fermenting soybeans with Bacillus subtilis var. natto. Despite its distinctive smell and sticky texture, it has one of the most impressive nutritional profiles in the fermented food world. Natto is the richest known food source of vitamin K2 (as MK-7) — important for directing calcium into bones rather than arteries — and the only common dietary source of nattokinase, an enzyme with documented fibrinolytic and blood-pressure-lowering activity [1]. Japanese population studies consistently link regular natto consumption to lower rates of cardiovascular mortality and all-cause mortality compared to non-consumers [3][4].

What Makes Natto Unique

Natto is produced by inoculating whole cooked soybeans with Bacillus subtilis var. natto spores, then fermenting at around 40°C for 15–24 hours. This process does three things that ordinary soybeans cannot:

Nattokinase production. Fermentation generates a serine protease enzyme capable of dissolving fibrin clots, reducing platelet aggregation, and modestly lowering blood pressure. This enzyme is specific to natto — it is not found in other fermented soy products like miso or tempeh.

Extraordinary vitamin K2 (MK-7) content. A 50–80g serving of natto delivers 300–800 mcg of MK-7 — far exceeding any other food source, including cheese and other fermented foods. K2 activates osteocalcin (which binds calcium into bone) and matrix Gla protein (which prevents calcium from depositing in arteries).

Bacillus subtilis probiotic delivery. Unlike lactic acid bacteria in yogurt or sauerkraut, Bacillus subtilis is a spore-former that survives stomach acid reliably and reaches the intestine intact. It transiently colonizes the gut and has been shown to increase populations of beneficial bacteria, including Bifidobacterium and Blautia.

Nattokinase and Cardiovascular Health

Nattokinase was first characterized in 1987 when Japanese researcher Hiroyuki Sumi observed that natto could dissolve fibrin clots on a petri dish in a striking demonstration of fibrinolytic activity.

Fibrinolysis. Nattokinase degrades fibrin directly and stimulates the body's own plasminogen activator system, making blood less prone to dangerous clotting without the bleeding risk associated with pharmaceutical anticoagulants [1]. Its mechanism is complementary to — but distinct from — aspirin's antiplatelet action.

Blood pressure. A randomized, double-blind, placebo-controlled trial in 79 adults with elevated blood pressure found that 100 mg nattokinase daily for 8 weeks significantly reduced both systolic and diastolic blood pressure. Von Willebrand factor — an endothelial stress marker predictive of cardiovascular events — fell by 15% in the nattokinase group, with no consistent change in the placebo group [2].

Atherosclerosis. A large clinical study of 1,062 participants with confirmed atherosclerosis or hyperlipidemia tested nattokinase at 10,800 FU/day for 12 months. The high-dose group showed significant reductions in carotid artery intima-media thickness, plaque cross-sectional area, and lipid markers including LDL and total cholesterol. The lower dose tested (3,600 FU/day) produced no significant effect, pointing to a meaningful dose threshold [6].

Vitamin K2 (MK-7) and Bone Density

Most people in Western countries consume little to no vitamin K2, relying instead on vitamin K1 from leafy greens — which has limited conversion to K2 in the body. Natto sidesteps this entirely by providing preformed MK-7 in amounts that measurably raise circulating levels and activate bone-building proteins.

A clinical study confirmed that dietary natto reliably raises serum MK-7 and gamma-carboxylated osteocalcin — the functional, calcium-binding form of osteocalcin — in direct proportion to the MK-7 content of the natto consumed [5]. The long half-life of MK-7 (three days, compared to hours for K1) means that regular natto intake maintains steady circulating K2 levels throughout the week.

The cardiovascular benefit of K2 is mechanistically separate from nattokinase: activated matrix Gla protein (MGP) inhibits calcium deposition in arterial walls, potentially explaining why natto consumption correlates with lower cardiovascular mortality beyond what nattokinase alone would predict.

What Population Studies Show

Two large cohort studies have tracked natto consumption against mortality outcomes in Japanese adults:

The Takayama study followed 29,079 adults for 16 years and found that the highest quartile of natto intake was associated with a 25% lower risk of total cardiovascular mortality (HR 0.75, 95% CI 0.64–0.88, P-trend = 0.0004) compared to the lowest quartile. Reductions were seen for both stroke and ischemic heart disease mortality [3].

A 2020 BMJ cohort study of 92,915 participants followed for a median of 14.8 years found that fermented soy intake — primarily natto and miso — was associated with approximately 10% lower all-cause mortality. Crucially, total soy intake (including tofu and soy milk) showed no significant mortality association, suggesting that fermentation-specific factors rather than soy protein content drive the benefit [4].

Practical Notes

Natto's strong, ammonia-like smell and stringy texture are an acquired taste. The easiest approach is to start with small amounts mixed into warm rice, scrambled eggs, or avocado — the sticky strings break up more easily when stirred vigorously. Traditional Japanese serving includes soy sauce and hot mustard packets. Natto is typically sold frozen in small packs; freezing preserves it well without significant loss of enzyme activity.

Nattokinase is heat-sensitive, so avoid frying or boiling natto if you want to preserve its enzyme content. Eating it cold or at room temperature is ideal.

People taking warfarin or other vitamin K-interacting anticoagulants should consult their prescriber before adding natto regularly, as its very high MK-7 content can substantially affect INR values.

See also our tempeh page for a related fermented soy food with a milder flavor profile, and our vitamin K2 page for more on K2's role in calcium metabolism.

Evidence Review

Nattokinase: Mechanisms and Pharmacology

The most comprehensive review of nattokinase pharmacology (Chen et al., 2018, PMID 30013308) describes its mechanism through several parallel pathways. As a serine protease, nattokinase degrades fibrin directly and cleaves the cross-linked fibrin network formed during clot consolidation. It also upregulates endogenous fibrinolytic activity by enhancing tissue plasminogen activator (t-PA) expression and suppressing plasminogen activator inhibitor-1 (PAI-1) — the primary brake on the body's fibrin-dissolving system. In animal studies, orally administered nattokinase appears in the bloodstream with detectable fibrinolytic activity, though the extent of human gastrointestinal absorption and oral bioavailability remains incompletely characterized. The enzyme measures approximately 28 kDa and 275 amino acids. Its stability across a broad pH range and partial resistance to gastric degradation support the plausibility of oral activity [1].

Blood Pressure RCT

Jensen et al. (2016, PMID 27785095) conducted a randomized, double-blind, placebo-controlled, multicenter North American trial in 79 adults with elevated blood pressure, stratified by sex and enrollment site. Participants received either 100 mg nattokinase per day (as NSK-SD, a vitamin K2-removed concentrate) or placebo for 8 weeks. The nattokinase group showed statistically significant reductions in systolic blood pressure in both sexes, and diastolic blood pressure in males. Von Willebrand factor (vWF) — a glycoprotein secreted by stressed vascular endothelium and a marker of clotting risk and endothelial injury — declined by an average of 15% in nattokinase-treated participants versus no consistent change in the placebo group [2]. This trial is methodologically rigorous and establishes that nattokinase (not vitamin K2 from natto) is the active hypotensive agent, since K2 was removed from the supplement used.

Atherosclerosis: Large-Scale Clinical Study

Chen et al. (2022, PMID 36072877) recruited 1,062 participants with diagnosed atherosclerosis or hyperlipidemia from cardiology clinics and assigned them to nattokinase at 3,600 FU/day or 10,800 FU/day for 12 months. All participants had baseline carotid artery imaging to quantify intima-media thickness (IMT) and plaque size. At the 12-month mark, the high-dose (10,800 FU/day) group showed significant reductions in carotid IMT, plaque cross-sectional area, LDL cholesterol, total cholesterol, and triglycerides. The low-dose group showed no statistically significant change in any of these measures. Co-administration of nattokinase with vitamin K2 or aspirin produced synergistic improvements. Adverse events were rare and not significantly different between groups [6].

Notable limitation: the study compared two active doses rather than nattokinase against placebo, meaning regression-to-the-mean and placebo effects cannot be fully excluded. However, the dose-dependence finding — a clear threshold between 3,600 and 10,800 FU — provides internal biological plausibility and is consistent with prior pharmacokinetic data.

Vitamin K2 and Bone Biomarkers

Tsukamoto et al. (2000, PMID 10874601) conducted one of the earliest controlled studies of natto's effect on vitamin K status and bone metabolism in humans. Eight male volunteers consumed natto formulations with varying MK-7 content (from 0 to approximately 1,765 mcg per 100g serving) in a sequential crossover design. Serum MK-7 rose dose-dependently following natto consumption, and gamma-carboxylated osteocalcin — the active, calcium-binding form — increased in parallel [5]. This study established the functional relevance of natto's MK-7 content: it is absorbed, retained in circulation, and drives measurable activity in bone metabolism.

The clinical significance of osteocalcin carboxylation extends beyond bone: fully carboxylated osteocalcin is required to attract calcium toward bone matrix. Undercarboxylated osteocalcin is released into circulation when K2 is inadequate, and elevated undercarboxylated osteocalcin has been associated in population studies with both fracture risk and cardiovascular calcification.

Mortality Cohort Studies

Takayama Study (Nagata et al., 2017, PMID 27927636): A prospective cohort of 13,355 men and 15,724 women aged 35 or older, followed from 1992 for 16 years. Natto intake was assessed by validated food-frequency questionnaire at baseline. After adjustment for confounders including age, BMI, smoking, physical activity, and total energy intake, the highest versus lowest quartile of natto intake was associated with HR 0.75 (95% CI 0.64–0.88, P-trend = 0.0004) for total cardiovascular mortality, HR 0.77 for stroke mortality, and a non-significant trend for ischemic heart disease [3]. The association was present in both sexes but slightly stronger in women.

Japan Public Health Center Study (Katagiri et al., 2020, PMID 31996350): 92,915 Japanese adults aged 45–74, followed for a median of 14.8 years, with 14,384 deaths recorded during follow-up. Fermented soy intake (primarily natto and miso combined) was inversely associated with total mortality (HR approximately 0.90 comparing highest to lowest intake quartile). Nonfermented soy products including tofu and soy milk showed no significant association with mortality [4]. This dissociation between fermented and non-fermented soy is a key finding: it implies that fermentation-specific compounds — nattokinase, MK-7, bioavailable isoflavones, or probiotic organisms — rather than soy macronutrients explain the observed benefit.

Both studies are observational and cannot rule out residual confounding, particularly from dietary and lifestyle patterns that co-vary with traditional Japanese food choices. Natto is more commonly eaten by older, rural, and nutritionally traditional Japanese adults — populations that may differ in other unmeasured health behaviors.

Confidence Assessment

Across five distinct mechanistic and outcome domains, the evidence for natto's health benefits is unusually consistent for a traditional whole food:

Fibrinolytic and antithrombotic activity: well-established biochemically (strong)
Blood pressure reduction: supported by a rigorous multicenter RCT (moderate-strong)
Atherosclerosis management: supported by a large dose-ranging clinical study, though without placebo arm (moderate)
Vitamin K2 and bone/vascular metabolism: mechanistically well-characterized with human biomarker data (strong)
Mortality reduction: two large independent cohort studies show consistent direction and magnitude (moderate, observational)

The convergence of mechanistic, clinical, and epidemiological evidence across five domains, combined with millennia of traditional safe use, places natto among the most evidence-supported fermented foods available.

References

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular DiseasesChen H, McGowan EM, Ren N, Lal S, Nassif N, Shad-Kaneez F, Qu X, Lin Y. Biomarker Insights, 2018. PubMed 30013308 →
Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trialJensen GS, Lenninger M, Ero MP, Benson KF. Integrated Blood Pressure Control, 2016. PubMed 27785095 →
Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama studyNagata C, Wada K, Tamura T, Kawachi T, Konishi K, Tsuji M, Nakamura K. American Journal of Clinical Nutrition, 2017. PubMed 27927636 →
Association of soy and fermented soy product intake with total and cause specific mortality: prospective cohort studyKatagiri R, Sawada N, Goto A, Yamaji T, Iwasaki M, Noda M, Iso H, Tsugane S. BMJ, 2020. PubMed 31996350 →
Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individualsTsukamoto Y, Ichise H, Kakuda H, Yamaguchi M. Journal of Bone and Mineral Metabolism, 2000. PubMed 10874601 →
Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participantsChen H, Chen J, Zhang F, Li Y, Wang R, Zheng Q, Zhang X, Zeng J, Xu F, Lin Y. Frontiers in Cardiovascular Medicine, 2022. PubMed 36072877 →