What is nattokinase and its effects on cardiovascular health in adults?

What is Nattokinase?

Nattokinase is a fibrinolytic enzyme derived from natto, a traditional Japanese fermented soybean food, that demonstrates blood pressure-lowering effects but lacks established cardiovascular mortality or morbidity benefits and is not recommended in any major cardiovascular guidelines.

Basic Characteristics

Nattokinase is a serine protease enzyme produced during the fermentation of soybeans by Bacillus subtilis (or Bacillus amyloliquefaciens) to create natto, a traditional Asian food 1, 2. The enzyme has gained popularity as a dietary supplement marketed for cardiovascular health, though it remains absent from evidence-based cardiovascular treatment guidelines 3.

Proposed Mechanisms of Action

Fibrinolytic and Antithrombotic Properties

• Nattokinase exhibits direct fibrinolytic activity, meaning it can break down fibrin clots in laboratory and animal studies 4, 5
• The enzyme decreases plasma levels of coagulation factors including fibrinogen (by 7-10%), factor VII (by 7-14%), and factor VIII (by 17-19%) after 2 months of supplementation 5
• These effects suggest potential antithrombotic properties, though clinical outcomes related to thrombosis prevention have not been established 6, 4

Anti-inflammatory and Antioxidant Effects

• Recent studies suggest nattokinase may modulate molecular pathways related to inflammation and oxidative stress 4
• These properties are proposed as adjuvant strategies for non-communicable diseases, though clinical validation is lacking 4

Clinical Evidence on Cardiovascular Risk Factors

Blood Pressure Effects

Nattokinase supplementation significantly reduces blood pressure, with systolic blood pressure decreasing by 3.45 mmHg (95% CI: -4.37 to -2.18) and diastolic blood pressure decreasing by 2.32 mmHg (95% CI: -2.72 to -1.92) compared to placebo 6. This represents the most consistent cardiovascular benefit demonstrated in clinical trials.

Lipid Profile Effects

• Low-dose nattokinase supplementation (specific threshold not defined in studies) paradoxically increased total cholesterol by 5.27 mg/dL (95% CI: 3.74 to 6.81), decreased HDL cholesterol by 2.76 mg/dL (95% CI: -3.88 to -1.64), and increased LDL cholesterol by 6.49 mg/dL (95% CI: 0.83 to 12.15) 6
• High-dose nattokinase increased total cholesterol by 3.18 mg/dL (95% CI: 2.29 to 4.06) but showed no significant effects on HDL or LDL cholesterol 6
• No significant effect on triglycerides was observed 6
• These lipid effects are unfavorable and contradict the proposed cardiovascular benefits

Glucose Effects

• Nattokinase supplementation led to a slight increase in blood glucose of 0.40 mg/dL (95% CI: 0.20 to 0.60) 6
• The clinical significance of this small increase is uncertain

Pharmacokinetics

• Following oral ingestion of a single 2000 FU dose, nattokinase can be detected in human serum with peak levels occurring at approximately 13.3 ± 2.5 hours post-dose 1
• The enzyme remains detectable in blood for up to 24 hours after ingestion 1
• Bioavailability and complete pharmacokinetic parameters remain incompletely characterized 1

Safety Profile

• No notable adverse events were reported in clinical trials of nattokinase supplementation 6, 5
• The enzyme was well-tolerated in healthy volunteers, patients with cardiovascular risk factors, and patients undergoing dialysis 5

Critical Limitations and Clinical Context

Absence from Evidence-Based Guidelines

Nattokinase is not mentioned in any major cardiovascular guidelines, including ACC/AHA heart failure guidelines, ESC cardiovascular toxicity guidelines, ADA diabetes cardiovascular risk guidelines, or stroke management guidelines 3. This absence is notable given these guidelines comprehensively address cardiovascular risk reduction strategies.

Lack of Hard Outcome Data

• No randomized controlled trials have demonstrated that nattokinase reduces cardiovascular mortality, myocardial infarction, stroke, or heart failure hospitalizations 6, 4
• Studies have only examined surrogate markers (blood pressure, coagulation factors) rather than clinical outcomes that affect morbidity and mortality 6, 5

Unfavorable Lipid Effects

The paradoxical increase in total cholesterol and LDL cholesterol with low-dose supplementation, combined with decreased HDL cholesterol, represents a potentially harmful lipid profile that could theoretically increase cardiovascular risk 6. This contradicts the proposed cardiovascular benefits.

Comparison to Guideline-Recommended Therapies

Established cardiovascular therapies with proven mortality benefits include:

• ACE inhibitors and ARBs for heart failure and hypertension 3
• Beta-blockers for heart failure and post-myocardial infarction 3
• Statins for lipid management 3
• SGLT2 inhibitors for heart failure and diabetes 3

These therapies have demonstrated reductions in cardiovascular mortality and morbidity in large randomized trials, unlike nattokinase 3.

Clinical Recommendation

Nattokinase should not be recommended as a primary or adjunctive therapy for cardiovascular disease prevention or treatment. While it demonstrates modest blood pressure-lowering effects, the magnitude is small (3-4 mmHg systolic), the lipid effects are potentially harmful, and most importantly, there is no evidence that it reduces cardiovascular events, mortality, or improves quality of life 6.

Patients seeking cardiovascular risk reduction should be directed toward guideline-recommended therapies with established mortality benefits, including lifestyle modifications (Mediterranean diet, exercise), antihypertensive medications, statins, and diabetes management as appropriate 3. The absence of nattokinase from all major cardiovascular guidelines reflects the insufficient evidence base for its clinical use 3.