People want simple answers to complex problems. Atherosclerotic plaquePlaque is the buildup of cholesterol, immune cells, scar tissue, and calcium inside an artery wall.—that fatty, inflammatory buildup inside arteryAn artery is a blood vessel that carries blood away from the heart to the rest of the body. walls—feels like something you should be able to “clean out” like a clogged pipe. That hope fuels massive interest in supplements that promise to “dissolve plaque,” “unclog arteries,” or “reverse heart diseasePlaque regression means existing plaque actually gets smaller, rather than just growing more slowly. naturally.”

NattokinaseA fibrinolytic enzyme extracted from natto (fermented soybeans) that breaks down fibrin, the protein scaffold of blood clots; it is widely sold as a supplement for circulation, blood pressure, and—controversially—plaque reduction. is currently one of the most popular supplements in this category. An enzyme derived from natto (fermented soybeans), it is widely marketed for circulation, blood pressureBlood pressure is the force of blood pushing against your artery walls. It is written as two numbers, like 120/80. The top number is the pressure when your heart squeezes, the bottom is when it relaxes., and plaque reversal. But marketing is not evidence.

To understand the reality, we need to look at what human clinical research actually shows: what doses were used, what outcomes were measured, and how it compares to other supplements with plaque-relevant data, such as aged garlic extract, omega-3s, and vitamin K2Vitamin K2 (menaquinone) is a fat-soluble cofactor required to activate Matrix Gla-protein, which inhibits vascular calcification; statin therapy may reduce vitamin K2 bioavailability as a byproduct of mevalonate pathway suppression, potentially influencing how calcium is deposited in plaques..¹–¹¹

(Disclosure: This is educational information, not medical advice. If you have known plaque or take blood thinners, consult your clinician before adding supplements.)

1. What “Plaque Reversal” Actually Means

AtherosclerosisAtherosclerosis is the disease behind most heart attacks and many strokes. Cholesterol particles get stuck in the wall of an artery, the body sends immune cells to clean up, and over years that mess hardens into plaque. isn’t just cholesterolCholesterol is a waxy substance your body needs. It goes into cell walls, hormones, vitamin D, and the bile that digests your food. You would die without it. stuck to an artery wall; it is a living lesionIn cardiology, a lesion refers to a discrete area of atherosclerotic plaque narrowing a coronary artery, typically described by the percentage of luminal obstruction it causes. The article describes four residual lesions too small in vessel diameter to accept a stent after the most critical one was treated. containing immune cells, fibrous tissue, and often calcium. “Reversing” it doesn’t just mean shrinking it—it also means stabilizing it so it is less likely to rupture.

When researchers measure reversalREVERSAL compared moderate and intensive statin therapy, using intravascular ultrasound to measure what happened to coronary plaque., they don’t rely on how a patient “feels.” They use reproducible imaging:

• Carotid ultrasound: Measuring the thickness of the artery wall (CIMT) or the size of the plaque.
• Coronary CT AngiographyCoronary CT angiography, or CCTA, is a CT scan done with dye in your veins that produces detailed pictures of your heart's arteries. (CCTA): Measuring plaque volume and composition (e.g., is it soft and dangerous, or calcified and stable?).
• Coronary Artery Calcium (CAC)Coronary artery calcium is a measure of calcified plaque deposits in the walls of the coronary arteries, quantified by CT scan and expressed as an Agatston score; higher scores indicate greater cumulative plaque burden and predict future cardiovascular events.: A risk score, though not always a perfect proxy for regression.

Real claims of regression require this kind of hard data, ideally from randomized controlled trialsA randomized controlled trial assigns people to a treatment or a comparison group purely by chance, then follows both groups. (RCTs).

2. The Mechanism: Fibrin vs. Plaque

Nattokinase is a fibrinolytic enzymeA protein that catalyzes the breakdown of fibrin, dissolving blood clots; fibrinolytic activity is distinct from plaque removal, because arterial plaque is embedded in the vessel wall rather than circulating in the bloodstream.—it breaks down fibrin, a proteinProtein is the nutrient your body uses to build and repair muscle and tissue. that forms the mesh of blood clotsA blood clot is a clump of blood cells and protein that forms to stop bleeding.. This often confuses people.

• Fibrin clots form in the bloodstream and can block flow acutely.
• Plaque is embedded in the artery wall itself.

While nattokinase may improve blood flow by affecting clotting factors, that does not automatically mean it “scrubs” plaque out of the vessel wall. The real question is: Does this biological mechanism translate to shrinking plaque in humans?

3. The Strongest Evidence: The NAPS Trial

The most critical study for anyone considering this supplement is the Nattokinase Atherothrombotic Prevention Study (NAPS).²,¹⁰ This was a randomized, double-blind, placebo-controlled trial—the gold standard of research.

• Dose: 2,000 Fibrinolytic Units (FU)The standard unit used to measure the clot-dissolving activity of nattokinase supplements; 2,000 FU per day is the dose found on most commercial bottles and is the dose tested in the NAPS trial. per day (the standard dose in most bottles).
• Outcome: They measured the progression of subclinical atherosclerosisSubclinical atherosclerosis means plaque is present but has not yet caused any symptoms or events. using carotid ultrasound (CIMT) and arterial stiffness.

The Result: At the standard 2,000 FU dose, the study did not find that nattokinase slowed the progression of atherosclerosis compared to placeboA placebo is a dummy treatment — a sugar pill or a saline injection — given so researchers can tell what a real drug actually does..²

This doesn’t mean nattokinase is useless, but it is a reality check. The best-designed trial we have at the most common dose failed to support the “plaque reversal” narrative.

4. The “Positive” Studies: Context Matters

You will often hear about other studies that claim positive results, such as the trial by Ren et al. (2017).³ This study focused on patients with carotid atherosclerosis and hyperlipidemia and reported benefits.

Why the discrepancy? In supplement research, we often see a pattern where smaller, pilot studies or those using higher doses show promise, while larger, more rigorous trials show null results. While the positive data exists, it has not been consistently replicated in multi-center trials with standardized imaging.³

The Verdict: While there are signals of benefit in specific populations, we lack the definitive, high-quality evidence needed to claim it works for everyone.

5. Blood Pressure and Other Risk Factors

While plaque regression is unproven, nattokinase is not an inert pill. It has measurable effects on physiology.

• Blood Pressure: A randomized trial (Kim et al., 2008) showed nattokinase could lower blood pressure in patients with pre-hypertensionA blood pressure category, defined by JNC 7 as systolic 120–139 mmHg or diastolic 80–89 mmHg, indicating elevated pressure that is not yet classified as hypertension but still carries increased cardiovascular risk. or stage 1 hypertensionHypertension is the medical term for high blood pressure..⁴
• Lipids & Clotting: A 2023 meta-analysisA meta-analysis statistically combines the results of many separate studies into one overall estimate. suggested it may favorably impact cardiovascular risk factorsA risk factor is something that raises your chance of developing a disease — high cholesterol particles, high blood pressure, smoking, diabetes, family history., though the effect sizes varied widely depending on the dose.⁵

If your goal is modulating risk factors like blood pressure, the evidence is stronger than it is for dissolving plaque.

6. Safety: The “Natural” Blood Thinner?

Because nattokinase influences the clotting system, “natural” does not mean “risk-free.”

• Bleeding Risk: Theoretical and case-report evidence suggests a risk of bleeding, particularly if combined with aspirinAspirin makes blood platelets less sticky, so clots are less likely to form., Plavix, Xarelto, Eliquis, or even high-dose fish oil.
• Drug Interactions: It should be treated with the same caution as a mild medication. If you are having surgery or take anticoagulantsAn anticoagulant reduces the blood's ability to clot by interfering with clotting proteins. Warfarin and apixaban are examples., this is not a supplement to take casually.

7. How It Compares to Other Supplements

If your main goal is stabilizing or reducing plaque, how does nattokinase stack up against the competition?

Tier 1: Strongest Human Imaging Data

• Aged Garlic Extract (AGE)A standardized supplement produced by prolonged cold aging of raw garlic, which concentrates water-soluble organosulfur compounds; randomized CT imaging trials have shown it can reduce low-attenuation (soft, rupture-prone) coronary plaque in patients with metabolic syndrome.: This has perhaps the most impressive imaging data. A randomized trial (Matsumoto et al., 2016) used cardiac CT scans and found that AGE reduced “low-attenuation plaqueA vulnerable plaque is one at high risk of cracking open: a thin cap, a large greasy core, active inflammation, and often outward bulging of the artery.”—the soft, dangerous type of plaque prone to rupture.⁶,¹¹
• Omega-3s (EPA/DHA): Specific formulations (often high-dose EPA) have been shown in RCTs using CCTA to affect coronary plaque volume and composition.⁷,⁸

Tier 2: Mechanism-Based or Mixed Data

• Red Yeast RiceA dietary supplement made from rice fermented with Monascus purpureus that naturally contains monacolin K, a compound chemically identical to the prescription statin lovastatin; it lowers LDL cholesterol through the same HMG-CoA reductase pathway as pharmaceutical statins.: Contains monacolin KThe active cholesterol-lowering compound in red yeast rice; it is chemically identical to lovastatin and inhibits HMG-CoA reductase, the same enzyme targeted by prescription statin drugs. (natural lovastatin), so it works via the proven LDL-lowering pathway.⁹ It works, but quality control is a nightmare.
• Nattokinase: Good for blood pressure and flow, but the direct plaque-shrinking evidence is weak at standard doses.²,⁵
• Vitamin K2: Promising for preventing arterial calcificationThe deposition of calcium crystals within the arterial wall, which stiffens the vessel and in coronary arteries is used as a marker of atherosclerotic burden; some evidence suggests vitamin K2 may help inhibit its progression., particularly studied in kidney diseaseKidney disease means the kidneys have lost some of their ability to filter waste from your blood. patients, but the data on reversing existing hardening in healthy people is less established.¹⁰

Summary: The Strategic Approach

If you are taking nattokinase 2,000 FU expecting it to scour your arteries clean, the best science we have (the NAPS trial) suggests you may be disappointed.

However, if you view it as part of a broader strategy to manage blood pressure and blood viscosity, it has a role. But for those strictly focused on coronary plaque, the human imaging data for Aged Garlic Extract and pharmaceutical-grade Omega-3s is currently superior.

References

1. Chen H, McGowan EM, Ren N, et al. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomark Insights. 2018;13:1177271918785130. Published 2018 Jul 5. doi:10.1177/1177271918785130
2. Hodis HN, Mack WJ, Meiselman HJ, et al. Nattokinase atherothrombotic prevention study: A randomized controlled trial. Clin Hemorheol Microcirc. 2021;78(4):339-353. doi:10.3233/CH-211147
3. Ren NN, Chen HJ, Li Y, Mcgowan GW, Lin YG. Zhonghua Yi Xue Za Zhi. 2017;97(26):2038-2042. doi:10.3760/cma.j.issn.0376-2491.2017.26.005
4. Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res. 2008;31(8):1583-1588. doi:10.1291/hypres.31.1583
5. Li X, Long J, Gao Q, et al. Nattokinase Supplementation and Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Rev Cardiovasc Med. 2023;24(8):234. Published 2023 Aug 15. doi:10.31083/j.rcm2408234
6. Matsumoto S, Nakanishi R, Li D, et al. Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study. J Nutr. 2016;146(2):427S-432S. doi:10.3945/jn.114.202424
7. Alfaddagh A, Elajami TK, Ashfaque H, Saleh M, Bistrian BR, Welty FK. Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial. J Am Heart Assoc. 2017;6(12):e006981. Published 2017 Dec 15. doi:10.1161/JAHA.117.006981
8. Feuchtner G, Langer C, Barbieri F, et al. The effect of omega-3 fatty acids on coronary atherosclerosis quantified by coronary computed tomography angiography. Clin Nutr. 2021;40(3):1123-1129. doi:10.1016/j.clnu.2020.07.016
9. Cicero AFG, Fogacci F, Banach M. Red Yeast Rice for Hypercholesterolemia. Methodist Debakey Cardiovasc J. 2019;15(3):192-199. doi:10.14797/mdcj-15-3-192
10. Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, et al. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5. Pol Arch Med Wewn. 2015;125(9):631-640. doi:10.20452/pamw.3041
11.  Efendy JL, Simmons DL, Campbell GR, Campbell JH. The effect of the aged garlic extract, ‘Kyolic’, on the development of experimental atherosclerosis. Atherosclerosis. 1997;132(1):37-42. doi:10.1016/s0021-9150(97)00078-6