Previously, I wrote about the use of Grape Seed Proanthocyanidin Extract (GSPE) to help ameliorate atherosclerosis, a main cause of cardiovascular disease (CVD), here:
https://www.earthclinic.com/cures/grape-seed-extract-atherosclerosis.html
I'd like to discuss another supplement that can also effectively combat atherosclerosis. Due to its unique mechanism of action, it may synergize well with GSPE.
First, I would like to discuss something that doctors don't often mention to you when they prescribe statins to lower cholesterol. Doctors often don't tell you the exact reason why they are prescribing statins, but rather tell you something like lowering cholesterol will help reduce your chances of getting cardiovascular disease (CVD) such as heart attack or stroke. Recently, my doctor told me that although my cholesterol and triglyceride levels were good, there was room for improvement.
I asked my doctor if the reason why he wanted to lower my cholesterol further was to reduce my chances of getting atherosclerosis and subsequent CVD, to which he said, yes. So I then asked him if the goal is to reduce atherosclerosis, why don't they test me for atherosclerosis instead of cholesterol? He said that they can test for atherosclerosis, but it is more than ten times more expensive than testing cholesterol levels and many insurance companies won't cover it, so they test cholesterol levels instead. So once he told me that I started reading studies on the topic.
Atherosclerosis is the main cause of CVD and CVD is the number one cause of death in the world, representing 32% of all global deaths. I also came across the following study that was done at UCLA in 2009 that came to an interesting and puzzling conclusion as discussed here :
Here is a relevant quote from the study:
A new national study has shown that nearly 75 percent of patients hospitalized for a heart attack had cholesterol levels that would indicate they were not at high risk for a cardiovascular event, based on current national cholesterol guidelines.
This study also suggested lowering the acceptable guideline targets for LDL cholesterol levels for those at risk for CVD and raising the HDL cholesterol level target range. Because of this study and others like it, the cholesterol level guidelines are continually updated, with the last update being in 2018.
My take on this study is that it makes more sense to test for atherosclerosis instead of cholesterol if the idea is to reduce atherosclerosis to help prevent CVD. So this makes me think that ideally, we should be lowering both cholesterol levels and atherosclerosis simultaneously because cholesterol may not be the most accurate indicator for atherosclerosis and preferably without the use of statins that do have significant side effects as discussed here:
Here are some relevant quotes from the above article on statin side effects:
One of the most common complaints of people taking statins is muscle pain. You may feel this pain as a soreness, tiredness or weakness in your muscles. The pain can be a mild discomfort, or it can be serious enough to make it hard to do your daily activities.
Occasionally, statin use could cause an increase in the level of enzymes in the liver. These enzymes signal inflammation. If the increase is only mild, you can continue to take the drug. Rarely, if the increase is severe, you may need to try a different statin.
It's possible that your blood sugar level, known as blood glucose, may increase when you take a statin. This may lead to developing type 2 diabetes. The risk is small but important enough that the Food and Drug Administration (FDA) has issued a warning on statin labels regarding blood glucose levels and diabetes.
It is important to note that although statins can lower cholesterol, it has been shown in studies that statins mainly only slow atherosclerosis progression, as discussed here:
Here are some relevant highlights from the above link:
This brings us to Nattokinase (NK), a supplement that is often suggested for cardiovascular health and, more specifically, to reduce atherosclerosis, triglycerides, and cholesterol levels. A potential problem with NK is that label-suggested dosing levels are frequently inadequate to reduce cholesterol or triglyceride levels and or significantly reduce atherosclerosis.
To add further confusion to the question of adequate dosing of NK, most retail suppliers of NK sell their products mainly in 2000 FU (Fibrinolytic Units) capsules and recommend one or two capsules per day. If you take the higher dose of two capsules per day at a total of 4000 FU/day, the dose is likely too low to be effective for the purpose, but as mentioned in this study, other studies have shown some benefit at 6,000 FU and 7,000 FU.
Still other suppliers recommend as much as 8,000 FU per day, but even if you take 8,000 FU daily, the dose may still be insufficient for optimal cholesterol, triglyceride, and atherosclerosis-lowering effects. The following August 2022 study used a low dose of NK at 3,600 FU and at a high dose of 10,800 FU in 1062 participants:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9441630/
The study above, because of its large size of 1062 participants and coverage of three major health issues of high cholesterol, high triglycerides, and atherosclerosis, delivered some very impressive and informative results on the use of NK for this purpose.
First off, it was shown that 3,600 FU/day had no effects on these three study parameters above. Secondly, they showed that the dose of 10,800 FU/day was statistically significantly effective at lowering the three main study parameters.
The rates of improvement were also very good.
The above improvement rates represent those who responded to NK compared to those who didn't. In many studies, they give a median or average number. The above numbers make it fairly clear that NK effectively improves these critical atherosclerosis and CVD parameters.
Here are some relevant study quotes :
After 12 months of NK consumption, both the size of CCA-IMT and the size of the carotid artery plaque decreased significantly (from 1.33 to 1.04mm on average, P < 0.001). The size of the plaque decreased by up to 36%, suggesting that NK is very effective in improving/reducing carotid atherosclerosis (Table 4). The overall improvement rates in CCA-IMT and CPS are not as high as those in blood lipids, with approximately 2/3 and 77.7% of the participants showing improvement in CPS and CCA-IMT, respectively (Table3).
The above quote clearly illustrates the efficacy of 10,800 FU/day of NK in lowering atherosclerosis parameters in humans.
As shown in Table 5, no differences in NK efficacy were found between male and female participants, although changes in female participants were marginally greater, but were not statistically significant. We found that NK at 3,600 FU dose was not effective in lowering lipids and suppressing atherosclerosis. Lipid levels and CCA-IMT and plaque size did not change after 12 months of NK consumption at that dose (Table 6).
The above quote clearly shows that 3,600 FU per day of NK has no effect on the three main parameters being tested.
Table 7 showed that the lipid lowering and antiatherosclerotic effects of NK were better in participants who exercise more compared to those who exercised less. Compared the effects of NK in obese participants with those of non-obese subjects, we found that the effects of NK in obese subjects were more prominent (Table 8).
This study also showed that Vitamin K2 had an additive effect to NK's positive effects mentioned above. It is also worth mentioning that vitamin K2 has blood-coagulating effects that may help to offset the blood thinning effects of NK.
This study also showed that Aspirin had a positive additive effect with NK, but low-dose aspirin in new users has shown significant potential for gastric ulcers as discussed here in this 2022 article :
https://onlinelibrary.wiley.com/doi/10.1111/apt.17050
Here is a relevant article quote:
This study shows that low-dose aspirin is an independent risk factor for both gastric and duodenal ulcers. The associations were not significant or weak in the prevalent-user design and strong and statistically significant in the new-user design in both cohorts. Thus, it is important to weigh risks against benefits when low-dose aspirin treatment shall be initiated and to monitor adverse gastrointestinal symptoms after the start of low-dose aspirin therapy.
More Relevant Quotes From The Main NK Study:
In this study, we present evidence to show that continued NK supplementation at the dose of 10,800 FU daily for 12 months significantly decreased TC, TG, LDL-C and increased HDL-C in hyperlipidemic participants. Administration of NK effectively improved atherosclerotic conditions by significantly reducing CCA-IMT and CPS. The study also investigated the factors surrounding the use of NK and contributing to improving clinical outcomes. The findings of this study are very important, as they demonstrate that NK at a dose of 10,800 FU, a high dose compared to the recommended dose of 2,000 FU for use in Europe (24), is highly effective in the treatment of hyperlipidemia and progression of atherosclerosis, two main contributors to the development of CVD.
An important finding from this study is that NK, when used in a high dose, is very effective both in controlling the progression of atherosclerosis and in lowering blood lipids. This is entirely consistent with previous findings in human clinical studies in which NK was used at doses of 6,000 FU and 7,000 FU (5, 19).
The observation that co-administration of vitamin K2 and aspirin with NK led to a synergistic effect is interesting. In support of our findings, previous studies found that NK and aspirin share similar pathways and mechanisms of action in their interaction with platelets leading to inhibition of platelet aggregation (16, 34). Furthermore, the positive in vitro hemorheological effects of NK worked well with aspirin (35). These shared actions might contribute to a better clinical outcome. It is unknown why the use of vitamin K2 improved the action of NK. It could be related to the positive effect on bone, muscle and cardiovascular health associated with the administration of vitamin K2 (36, 37).
Safety Of Nattokinase
The use of the dose of 10,800 FU daily is based on previous studies demonstrating that NK is very safe without concerns of toxicity. In addition to the long history of the use of natto and purified NK in the diet in Asian countries, especially Japan, it has been shown that there is no concern for toxicity when adults take 1,000–14,000 FU daily (32), and no toxic side effects have been observed in rats using significantly higher doses of 22,000 FU/kg/day, equivalent to 1.43 million FU daily in humans (32). Importantly, there are no cases of toxic effects or serious side effects reported using this high dose in the literature, even though NK has been widely used and studied over many years. However, a side effect-related report showed that a patient with mechanical valve developed thrombus, but underwent a successful repeat valve replacement when using NK (100 mg daily, equivalent to 2,000 FU/day) as a replacement for warfarin (33). Again, this thrombus development problem may be related to the inefficiency of the low-dose used.
Conclusion
In summary, our data from this largest clinical study involving 1,062 participants suggest that NK at the daily dose of 10,800 FU, which is higher than the recommended dose of 2,000 FU, is significantly effective in the management of atherosclerosis progression and hyperlipidemia. No adverse effects associated with the use of NK is observed. The study advances our understanding of the action of NK and the importance of the dosage of NK. We also demonstrate that other factors, including lifestyle and co-use of vitamin K2 and aspirin, could contribute positively to the clinical outcome. Our findings provide evidence that promising and positive clinical outcome in the management of atherosclerosis progression and hyperlipidemia can be achieved safely by using NK at a dose of 10,800 FU per day. The outcome of this report warrants further randomized control clinical trials using increased doses of NK.
I am of the opinion that because of the different mechanisms of action involved between Nattokinase (NK) and Grape Seed Proanthocyanidin Extract (GSPE), the two together have the potential for synergy together. In addition, GSPE offers other potential health benefits because of its potent antioxidant effects as well as its known anti-inflammatory effects. Vitamin K2 (180 mcg), as used in this study, showed that it improved the effects of NK as did aspirin at 100mg/day.
Nattokinase is known to have potential blood-thinning effects, as does Aspirin, and Grape Seed Proanthocyanidin Extract (GSPE) is also known to have potential blood-thinning effects. If you are considering using one, two, three, or all of these supplements, check with your doctor first to ensure they will be safe for you in your particular situation and compatible with all medications you are taking.
On a positive note, Vitamin K2 is known to have blood-coagulating effects, which may help to offset some of the blood thinning effects of the others. It seems safer to start dosing low and work upwards toward the desired dose since there is always the possibility that a person can have an allergic reaction to almost anything.
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We searched Amazon for the highest amount of FU per capsule and found that most capsules provide 2,000 FU per capsule or less. However, a few offer higher dosages.
Nattokinase 4,000 FU PER CAPSULE: Arthur Andrew Medical, Nattovena, Pure Nattokinase Supplement, 4,000 FUs per Capsule, 90 Capsules
Nattokinase 4000 FU Per Capsule: BoostCeuticals Nattokinase Supplement 200mg 100 Vegan Capsules Pure No Stearates
Nattokinase 3,000 FU PER CAPSULE: PHARMAKON Nattokinase, Bioavailable Soft Capsules, Organic Fermented Soybean Extract, 6000 FUs per 2 Capsules - Made in Germany
Nattokinase 2000 FU PER CAPSULE: Nattokinase Supplement 4,000 FU Servings, 120 Capsules (Derived from Japanese Natto) Systemic Enzymes for Cardiovascular and Circulatory Support (Manufactured in The USA) by Double Wood
Grape Seed Proanthocyanidin Extract: Bronson Grape Seed Extract 400 mg - Antioxidant & Immune Support - Standardized Extract with 95% Proanthocyanidins- Non GMO, 180 Vegetarian Capsules
