Mastering Cardiovascular Longevity: Glycocalyx & Biohacking for Optimal Heart Health

Vascular health is fundamentally essential to longevity and health span, and that’s why I’m thrilled to be welcoming Dr. Michael Twyman to New Frontiers. Trained as an invasive cardiologist, Dr. Twyman has made the shift to a more preventative approach, moving beyond traditional cath lab results to focus on the health of the 60,000 miles of blood vessels that carry vital blood, oxygen and nutrients to every organ in the body, with hopes of reaching patients before they reach the end stages of disease.

In this episode we’ll look at endothelial glycocalyx dysfunction as the root cause of cardiovascular disease, and dive into the key roles of nitric oxide, circadian biology, and the oral microbiome on cardiovascular health. I know you’ll find this interview to be absolutely fascinating. Have a listen and leave me a comment let me know what you think. ~DrKF

The world of cardiovascular healthcare has long been dominated by a reactive mindset of waiting for symptoms and depending on cath labs, invasive procedures, and medications once the disease process has taken hold. However, a profound shift is taking place, reshaping the approach to cardiovascular health.

Dr. Michael Twyman joins us today to talk about this new era where prevention and early detection take center stage. A model that goes beyond conventional boundaries to address the health of the endothelial glycocalyx, which impacts the 60,000 miles of blood vessels that carry oxygen and nutrients to every organ in the body and is now recognized as the key to cardiovascular health. The focus expands to include intriguing areas like circadian biology and the influence of the oral microbiome on nitric oxide production and cardiovascular health.

It’s a proactive approach that could revolutionize how we perceive and prioritize heart health. Please welcome Dr. Michael Twyman to the show.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi everybody. Welcome to a new Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And of course, today is no exception. I am really excited to be here today with Dr. Michael Twyman. I’m going to give you his background and we’re going to jump right in. Dr. Twyman is a board certified cardiologist who has now become a preventative cardiologist.

In 2017, he discovered biohacking, and I’m really actually curious to hear about that journey, and has been using this modality of health optimization to help patients make incremental changes to their lifestyle and environment to improve their heart health and overall health over time, including using photo biomodulation, which I’d also like a couple of sentences on as well. Dr. Twyman, welcome to New Frontiers.

Dr. Michael Twyman: Thank you for the opportunity. Great to be here.

Dr. Kara Fitzgerald: All right. We’re going to jump in and talk about all things vascular health, but I do want a little bit of your background on how you made this transition in your own professional journey. And then do just introduce us to photobiomodulation and then we’ll move right into vascular health.

Dr. Michael Twyman: Sure. So the quick background is I’m a conventionally trained invasive cardiologist, and I basically decided to leave the matrix a few years ago because it wasn’t that I got tired of treating people at the end stage of cardiovascular disease, but I got much more interested in the prevention side of things. And it really starts with healthy endothelium, which I know we’re going to get deep into in today’s conversation. But discovered functional medicine back in 2013 or so, did some training with A4M, learned from Dr. Mark Houston, who’s done a lot of the seminal work with endothelial health, and then eventually discovered biohacking back in 2017. And that’s the reason for the blue blocking glasses.

I was taking a long trip over to Asia from St. Louis, and I knew the jet lag was going to be pretty severe, so found an article that talked about wearing these funny looking glasses on the plane and maybe your jet lag wouldn’t be so bad. So, I  got to Asia, the jet lag was maybe about a third as bad as I expected. And then when I got home, I was like, “I got to read up on that. How does that work?” And so then that led me down the pathway of discovering circadian biology and then a short detour into photo modulation. So how to use red light therapy to optimize your mitochondrial health. So that’s why there’s a big mitochondria behind me on my wall here in the office that I chat with my patients. We’ve got to keep your mitochondria healthy and photo biomodulation is one of those tools that can help with that.

Dr. Kara Fitzgerald: All right. Super cool. That is a great story. I just came back from Singapore, by the way, and I didn’t have my appropriate glasses with me, and I did hit some jet lag. That’s just awesome. Thank you for that background. So vascular health is to your biohacking and cardio background… Vascular health is fundamentally essential to longevity, to health span moving commensurate with a long lifespan. So just talk to me about why it’s so important and how you think about it in practice now that you’ve moved into preventative cardiology.

Dr. Michael Twyman: Sure. So it’s great that we have cath labs, I was trained in them. We could save people right up to the brink of death, but putting people on aspirin, beta blockers, and statins wasn’t enough. It didn’t stop all the heart attacks. And we’re still, every 40 seconds in the United States, somebody’s having a heart attack. There’s already 800,000 heart attacks in the US every single year, and it’s still the number one killer of men and women worldwide. So what are we potentially missing? I always break it down with the patients that I want to think about three buckets.

There’s vascular health by how healthy is the endothelial glycocalyx and the endothelium; how much inflammation, oxidative stress is going on, which you can monitor with blood work; and then you get into the lipoprotein side of the equation. Because sometimes traditional medicine will simplify too much where there’s quote “good cholesterol, bad cholesterol”, and I just stop in there, like, they’re just cholesterol, but there’s different things bearing the cholesterol through the system. And if cholesterol was the biggest problem, we can severely lower cholesterol through different agents and people are still having events. Again, what are we missing? It’s the endothelial health component of things.

Dr. Kara Fitzgerald: And glycocalyx.

Dr. Michael Twyman: Correct. The glycocalyx that sits on top of it.

Dr. Kara Fitzgerald: All right. So I’m just curious about if you can just give me a quick rundown of the labs that you’re thinking about as a cardiologist to evaluate these, and then I want to specifically talk a little bit about glycocalyx.

Dr. Michael Twyman: Sure. So there’s unfortunately not one lab you can point to. There’s a multitude of them, but a simple one that somebody could do today, it’s just a urine microalbumin and creatinine. We all check those for people with high blood pressure or diabetes. But if you’re leaking protein into your urine, you by definition have endothelial dysfunction and glycocalyx dysfunction to your kidneys, you likely have it somewhere else in the 60,000 miles of blood vessels that you have. So I always start with that, is the urine test. But again, breaking down into buckets, there’s multiple labs you can look at for oxidative stress.

So I always look at either oxidized LDL or oxidized phospholipids on apoB, and then the urine test, [inaudible 00:05:20] creatinine. That’s like, how much are you going to rust? If that number is high, you’re likely to be oxidizing from the inside out. There’s a whole bucket of inflammatory labs. So start with high sensitivity CRP. If you can only get one, that’d be the one. And then looking at some of the lipoproteins, if I only could pick one, it’d be Apolipoprotein B, or ApoB for short. So I would start there. And then there’s some other labs that you can look at, asymmetric dimethylarginine, symmetric dimethylarginine, uric acid, homocysteine. All these are ancillary things that if they’re elevated, you’re very likely to have lower nitric oxide levels.

Dr. Kara Fitzgerald: I think anybody with any metabolic dysfunction, anybody with prediabetes type of picture is probably going to have problematic nitric oxide. We could even get that simple when fasting blood sugar. Do you agree?

Dr. Michael Twyman: Correct. It definitely checks all the markers of insulin resistance because that just one the biggest driver of glycocalyx dysfunction.

Dr. Kara Fitzgerald: Well, that’s a good list of labs. That’s just a really smart list of labs. And we’re fortunate that some of the more sophisticated lipid labs are available if you have basic insurance. So I think we’re getting better and better coverage for those, even ADMA. All right. So let’s talk about glycocalyx and why you, as a cardiologist, care about it so much.

Dr. Michael Twyman: Yeah, it’s the protective coating for the entire 60,000 miles of blood vessels that you got. And your organs, they need oxygen, they need nutrients. And how does it get there? Well, it’s a blood flow supply. So back to being an invasive cardiologist, we were looking at the major coronary arteries during an angiogram, your left main artery, your LAD, your circumflex, right  coronary. And then we’d say like, “Oh, you got a severe blockage of 70%. Okay, you get a stent.”

“It’s less than 70%. You don’t get a stent.” But 99% of the blood flow to the myocardium is coming through the microvasculature, and your blood vessels that are the micro vessels, I’ve seen numbers maybe up to a hundred to maybe a thousand blood vessels will fit in the diameter of one hair. So they’re microscopically small, but they all have this lining, this glycocalyx lining, which glycocalyx stands for… It’s like a sugarcoating or it’s a gel coat. When that gel coat gets impaired, then everything starts going downhill from there. So that is the most root cause thing I can look at for somebody who has cardiovascular disease is do they have healthy glycocalyx, do they have healthy endothelium?

Dr. Kara Fitzgerald: And now we talked about some of your labs at the beginning, but how else do you evaluate somebody… Who’s someone who’s at risk, barring the patients that you saw in the cath lab?

Dr. Michael Twyman: Sure. The short answer is everybody’s at risk, but to what degree? Aging is going to be one of the bigger ones because you tend to collect more chronic diseases as you age. But endothelial dysfunction, glycocalyx dysfunction, this can start in people’s teenage years, but it may be 10, 20, 30 years before they start presenting clinically to somebody’s office with high blood pressure or showing up with signs and symptoms of advanced cardiovascular disease. So chest pain, shortness of breath, those type of symptoms. So I think almost anybody should be worried about their endothelial function and their glycocalyx, but the older you are, the more you got to be mindful of it.

Dr. Kara Fitzgerald: I think you’re absolutely right that this starts incredibly early in life. Are you thinking about that when you’re talking to your patients these days? When are you really considering intervention, even if it’s just some tweaks in the diet?

Dr. Michael Twyman: It’s always going to be the four pillars of health that I talk about, and I know you speak many of the same language that I do. Yes, nutrition, exercise is important, but we’re also talking about your stress management, your sleep optimization. You got to get those pillars right, because then it doesn’t matter too much how many supplements you take or medications you take if you don’t get the basics right first. So the majority of my patients are generally going to be more longevity minded, preventative minded. So they’re going to be generally 45 years old and above, but that’s still younger than most cardiologists will see patients.

I tell people, “Yes, I did the conventional cardiology, but I understand how bad it can get. I’m trying to prevent you from meeting my colleagues essentially.” But I almost think I’m too late. I think it really should be pediatric cardiologists doing this type of work because metabolic syndrome is becoming an epidemic in teenagers. This is when the lifestyle habits that they need for longevity are really set in stone. I don’t want to wait until you’re 56 years old where you got advanced disease when we’re trying to reverse things. It’s a lot easier to teach a teenager, these are the big basic things you need to do to have a healthy glycocalyx as you live.

Dr. Kara Fitzgerald: Yeah, and healthy glycocalyx is healthy lifespan. I think you’re right. I think that all of us need to participate in this radical paradigm shift. You can’t do a sedentary McDonald’s life up until 45 and expect not to really sustain some significant damage from that. Yeah, I think you’re absolutely right. My work, I’ve been researching all things epigenetic, and when we look at when it’s important to think about optimizing gene expression, it’s in utero. Or when I ask David Perlmutter, when do you think about brain health? When do you start with Alzheimer’s prevention? And it’s in utero. And this is the same thing. There’s a radical paradigm shift just needs to take place.

Dr. Michael Twyman: 100%. We all have an expiration date, but we don’t all have the same health span. And that’s how I’m starting to think about things is that, I know Peter Attia’s book came out recently and he has what he calls the marginal decade, the last 10 years of your life. What do you want that to look like? I think that’s a good framework if you want to be a healthy 90-year-old or healthy 100+ year old, what do you need to do right now to get there? Well, one, don’t have a heart attack or stroke. Then you back your way up into like, that’s going to help prevent Alzheimer’s, that’s going to really reduce the risk of malignancies, and it really comes down to metabolic flexibility and preventing vascular disease.

Dr. Kara Fitzgerald: So therefore, with this backdrop, who are you thinking about with regard to vascular risk?  Who comes in your office?

Dr. Michael Twyman: Yeah, that’s the thing. There’s different cohorts of people that come see me. These people are coming in because they’ve got quote, “high cholesterol” and they’re wanting to talk about options for treatment. There’s people that have family histories that, “Hey, my dad had a heart attack at 55. I’m 45. I don’t go down the same pathway as my dad. What do I need to do?” But I basically always bring it back down to the basics, the four pillars of health. You got to optimize your mitochondrial function. But we’re testing everybody who walks in the door to look at the health of their arteries before they have something that’s going to be abnormal on a stress test.

In conventional cardiology, you usually don’t do a lot of testing until people have symptoms. I’m testing asymptomatic people. I’m looking at their arterial elasticity. I’m looking at their blood pressure, not only their brachial blood pressure, but their central aortic blood pressure. There’s devices that can look at that. I’m looking at salivary nitric oxide, which is a tool that you can use to see is that person likely getting enough nitrates in their diet. So there’s a lot of little pieces they can put together. These all seem to rhyme. So they probably do actually have healthy arteries right now. And then you can confirm some of it with the blood work that we were talking about earlier.

Dr. Kara Fitzgerald: It’s interesting, talking about glycocalyx health has become very important to me as I’ve marched into my fifties, and I think even though I’m reasonably healthy now and putting some attention into remaining that way for as long as possible, taking some ownership over my health span being in step with my lifespan. Tending to my glycocalyx is something that’s a part of my daily supplement stack really at this point. I want to talk to you about these amazing sulfated polysaccharides, and specifically the remnant sulfate from monostroma nitidum, if I’m saying that. I know it as tending to my glycocalyx, but this is one of the interventions that we can take pretty easily that may really aid in optimizing our vascular wellness.

Dr. Michael Twyman: Correct. So the one way to think about the glycocalyx, again, it’s this protective gel coating lining all 60,000 miles of your blood vessels. You first want to try to remove the things that are damaging it. It’s always wise to start there. So if you’re smoking, stop smoking. If you have dysregulated glucose and insulin, work on that. If you have dyslipidemia, work on that. So remove the insults first, but then there are products that can support a healthy glycocalyx. So the glycocalyx is comprised of proteoglycans, glycoproteins, and these glycosaminoglycans.

Well, what the product rhamnan sulfate is, it’s a fiber component of the monostroma nitidum algae, and this rhamnan sulfate has been demonstrated to help regenerate or support the glycocalyx. So if you think of the gel coat being like hairs at the bottom of an ocean or a riverbed, if the glycocalyx gets damaged, those hairs basically got a buzz cut. Products that have rhamnan sulfate in it donate these sulfur units or sulfate units to the glycocalyx and can help regenerate or regrow it.

Dr. Kara Fitzgerald: What’s the science say? What kind of research is there on this?

Dr. Michael Twyman: There’s a lot of science behind it that it helps support healthy blood sugar regulation, prevents lipoproteins from sticking to the arteries. Because that’s the way I describe to patients is that if the glycocalyx gets impaired, then whatever’s floating through the blood is more likely to be sticking to the arteries.

They have studies where they’re looking at pulse wave velocity. There’s a device called the Max Pulse that I use in my office to assess it, but there’s other companies that make these pulse wave velocity devices. Essentially as blood’s coming through your arteries, the artery should expand quickly and snap back, kind of like an accordion, it should be really quick. If you have sick arteries, it’s more like a lead pipe. But there’s studies that show that within a couple hours of administration of these rhamnan sulfate products, bacteria elasticity is significantly improved and stays improved while the rhamnan sulfate is being circulated through the system. So I routinely use this in patients that have evidence of endothelial dysfunction or glycocalyx disruption.

Dr. Kara Fitzgerald: Are most of these studies in humans?

Dr. Michael Twyman: They’re a combination. There are some small trials in humans, and then there are some animal studies. As well as, I’m definitely not a binge scientist, but somehow they get endothelial cells and they hook them up into these wells and then they administer different compounds that will potentially damage the glycocalyx. One of the ones that typically is used is lipopolysaccharides, the LPS damages the glycocalyx, and then they give the products to see does it support the glycocalyx. So there’s studies in all areas. So bench research, animals, and humans, and ongoing humans once for sure.

Dr. Kara Fitzgerald: That’s awesome. It sticks around in the body sufficiently where you don’t have to dose it multiple times to the day. Is that correct?

Dr. Michael Twyman: Correct. Generally, it’s a twice a day product for most people, but if people’s glycocalyx is improving, then maybe once a day. Now sometimes I get the question, “How long should you use these products for?” Well, sometimes it’s lifetime. If you’ve got a lot of cardiovascular disease, probably lifetime’s the right answer. But in some people I think sometimes it’s like a probiotic. It’s like you’re supporting the body temporarily, getting things back online when the major insult is removed, and then when the glycocalyx has been regenerated and you’re doing the blood work testing or these noninvasive tests and it’s telling you the artery are really elastic and they’re making good nitric oxide levels, then maybe if the patient is wanting to at that point, then you start deescalating some of the support.

Dr. Kara Fitzgerald: Would a maintenance dose… It’s funny, I’m selfishly thinking of myself because I have incorporated this as just part of a reasonable longevity stack. But do you take it out of curiosity? Do you think having a little bit of background rhamnan sulfate is a good idea?

Dr. Michael Twyman: I believe so. I personally take Arterosil, so I’ve been taking it for over almost two years now. I’m a believer. I’ve read the data, I have the toys in my office. I’m a biohacker, I’m going to test myself and if things aren’t optimized, I reach for what I know. And it’s been helping my arteries stay healthy and it’s my stated goal. I had a great-grandmother who lived to 106 and I’m trying to beat that  record.

Dr. Kara Fitzgerald: Nice.

Dr. Michael Twyman: I have to have a healthy glycocalyx. So that is in one of my stacks is taking Arterosil, so I take it twice a day and I have no side effects from taking it.

Dr. Kara Fitzgerald: No, not at all. It’s easy to do. I’m once a day, I’m just not good doing twice a day. I generally fail on twice a day unless I take it before bed. But yeah, I’m pretty bullish on it being just a really fundamental, important part… Well, let’s turn our attention to… Although let me also say before we talk about nitric oxide, I appreciate you giving alternatives, like that we can do all of this underlying work, we can evaluate and if somebody’s healthy- I mean there’s plenty of folks out there who don’t feel like taking a stack of supplements every day. And I appreciate that. And the fact that we can do all the underlying work, the four pillars as you’re referring to them, and they can live relatively supplement free should they choose, is another option.

Let’s talk about nitric oxide and the nitric oxide relationship to the glycocalyx and why it’s so important. It’s another sexy molecule, if you will, or something that we’re really thinking about with regard to vascular health.

Dr. Michael Twyman: Sure. Nitric oxide was so important that they awarded the Nobel Prize in medicine for its discovery back in 1998 for its role in the cardiovascular system. And quick side note, that is the major reason why Viagra was such a commercial success is because it was keeping nitric oxide around longer and helping guys have better erections. They initially were studying it for high blood pressure, but they noticed the side effect was the erections, and they thought, “Oh, this is probably a better market.” But those type of medicines… And that’s actually on my intake question for patients is, do you use these type of medicines?

And it’s mostly as a canary in the coal mine type of question, is that if you’re using those medicines, you may have a nitric oxide deficiency problem. And so you got to figure out why do they have low nitric oxide to begin with. So how does nitric oxide get produced? Well, one of the major ways is directly on the endothelial lining. The endothelium is one cell thick and lines your entire lumen of your blood vessels. And sitting on top of the endothelium is the glycocalyx. So the glycocalyx is sensing what’s floating through the lumen, and you will have shear stress. So as the blood is flowing through there, it transduces that glycocalyx and sends a message down to the underlying endothelium.

Or I tell my patients that it tickles the glycocalyx and the underlying endothelium’s like, “We probably need to make more nitric oxide.” So the body will convert the amino acid arginine in the presence of oxygen, enzyme endothelial nitric oxide synthase or eNOS, will then convert over to citruline, and then nitric oxide is produced. And then the nitric oxide, which is the signaling molecule, diffuses down into the muscle and the wall of the artery and through a process eventually causes the smooth muscle to relax. And then when the smooth muscle relaxes, the blood flow rushes down into the downstream artery. And when nitric oxide is in sufficient levels, I talk about it being like a nonstick surface or when there used to be things with Teflon on it.

When you have high nitric oxide levels, the lipoproteins, the white blood cells, the platelets, they just slide on by the arteries. It’s when nitric oxide’s low, things start coming in and getting stuck to the artery walls like Velcro. But that pathway after the age of 40 or so, becomes less effective. The endothelial nitric oxide synthase enzyme just doesn’t work as well. So there’s this backup pathway, this inter salivary pathway. So when you eat nitrates, which are in green leafy vegetables and beets, if you have the right bacteria in your saliva, the nitrate reducing bacteria will break those nitrates down. You’ll swallow it, it’ll get converted into nitrites during that process. And then as long as you have stomach acid, the stomach acid will do the conversion and eventually nitric oxide will get produced.

But if people are using antiseptic mouthwash, they’re using high fluorinated products, they disrupt the oral microbiome. So people are aware of the gut microbiome, well the oral microbiome is also important. So this is the reason you want to mind your oral microbiome as well. But the other concern is some people are on long-term acid blocking medicines, the proton pump inhibitors, and without stomach acid, you don’t make enzymes as efficiently. So sometimes it’s about withdrawing things if you can. So withdrawing the mouthwash, withdrawing the acid blocking medicine, if it makes sense for the patient to do that, and often their salivary pathway comes back online and can help rescue their nitric oxide production.

Dr. Kara Fitzgerald: Are you going to see that using the salivary nitric oxide test? You’re just going to see it, it’ll be white because it’ll flash pink. It’s a colormetric change, but you’ll just see it white.

Dr. Michael Twyman: Yeah, it’s like a litmus paper. So you put slime on it. It’s either going to be white, mildly pink, or bright red. But I do have a little bit of a nuanced take on it, because there are different companies that make these nitrate strips. Some work better than others, and you just have to see which one works for you. I think they’re most useful for patients that when they do the strips, at some point they have an optimal level, and then when their levels start becoming less than optimal, then you got to figure out what changed.

But I’ve seen many patients and often myself included, taking products that are supposed to support nitric oxide, support the glycocalyx. And my salivary pathways are never optimal or they’re very rarely optimal. And so I don’t know what oral microbiome that I have. I’m not using products that are going to disrupt it, but I think that’s the next stage is having oral probiotics that can help generate these nitrate reducing bacteria. But that’s future looking and not ready for prime time yet. So I don’t put too much faith…

If your blood pressure’s normal and you do other testing that says your arteries are likely elastic, if your salivary nitric oxide test strip is white, that isn’t something to throw up a five alarm fire for. It’s just that you might not be somebody who can make that conversion happen. So as long as you get into the downstream effects, that the blood pressure’s normal and the arteries are elastic, you’re still getting the benefit right on the artery layer.

Dr. Kara Fitzgerald: So your eNOS is working, you’re still making nitric oxide in adequate supply systemically. You’re just not you utilizing the oral microbiome apparently. Is that correct? Is that what you’re saying?

Dr. Michael Twyman: Possibly. Or you’re just maybe not getting enough nitrates into the system. Some people just don’t eat enough. But if you’re supplementing with a high quality nitrate enriched product, you should be able to overcome that. So I think it’s, in my experience, probably some more with the oral microbiome than that we don’t know how to actually optimize just yet.

Dr. Kara Fitzgerald: So you could be taking a good eNOS product and still not change it to that bright pink?

Dr. Michael Twyman: Correct. And that’s why I take multiple data points. That’s why I do test like an arterial elasticity. I have an EndoPAT device in my office that actually tells you the percentage of how much your brachial artery will dilate in response to a vascular stressor. So I correlate all the data points, and if one data point doesn’t make sense, it’s not that I completely throw it out, but I’d be like, we’re just not going to get you freaked out at home if your levels never go to the bright red levels.

Dr. Kara Fitzgerald: Right. That’s cool. That’s nice. That’s nuanced. I want to go to your practice. It sounds like you’ve got a lot of fun instruments. First of all, cool. We need to underline and highlight the fact that you’re using a certain mouthwash and that’s why you’ve got high blood pressure or that’s a big contributing factor. You’ve completely trashed your oral microbiome, and probably you’re not making enough eNOS because of that. How many people actually think about their mouthwash or their toothpaste, and it’s such a huge deal.

Dr. Michael Twyman: And usually it’s mind opening to people that are like, “I’ve been doing this forever.” I’m like, “Well, let’s just see what happens if you don’t do it for a while.” And often, you’ll see a response.

Dr. Kara Fitzgerald: And then on the flip side, well I don’t know if it’s quite the flip side, but we see just all of the various diseases, gingivitis and periodontal disease, and contributing to cardiovascular disease. And certainly a piece of that has to be just disrupting nitric oxide synthesis.

Dr. Michael Twyman: Yes. It’s anti-inflammatory it’s antimicrobial, so there’s a huge oral systemic link. If you have periodontal disease, you often have vascular inflammation.

Dr. Kara Fitzgerald: Yeah, that’s right. So even that could be a phenotype flag just starting at oral health. Fascinating. Okay, what did I want to say about this? The half-life of nitric oxide? It’s like, what, a few seconds?

Dr. Michael Twyman: It’s a few seconds, yes. And that’s a challenge because it acts locally, but glutathione is a storage form for it. So a biohacker way to do is check a GGT level on your labs. And if you have excessively high GGT levels, you’re likely going to have low glutathione levels and nitric oxide probably more of an issue for you because you’re not going to be able to have the storage forms.

Dr. Kara Fitzgerald: And going back to ADMA, you’re shutting nitric oxide down if you’re making a bunch of asymmetric dimethyl arginine.

Dr. Michael Twyman: Correct.

Dr. Kara Fitzgerald: So that would be… Although in my experience, I was at the first lab in the US to release ADMA, and it wasn’t high routinely. So in my experience, it wasn’t the most sensitive marker, but valuable nonetheless, if it is high there’s a big problem there. All right. So it’s got a really fast half-life, which I think lends weight to the idea of the whole being approach: diet, lifestyle, sleep, stress, et cetera, to optimize our ability to make it as we get older because we’re declining in our ability to make it efficiently. Would you agree?

Dr. Michael Twyman: Correct.

Dr. Kara Fitzgerald: So treatment, working with nitric oxide, what are you doing in practice? Are you prescribing a nitric oxide product?

Dr. Michael Twyman: Yes, I am. And again, always start with what can you withdraw first? If they have high glucose, are you going to be using berberine, metformin, in addition to the lifestyle modifications? Are you dealing with their high stress job and their high cortisol? Start there first. But if you’re going to support nitric oxide, there’s multiple products on the market. Some of the original ones, those are like Neo40, used to use that routinely, but that’s dosed twice a day. And some people just don’t like using dissolving lozenges in their mouth, they don’t like the taste or they have a burning sensation.

So there are other products that can help support nitric oxide production that are in capsule form. And then depending on other markers, then we’ll also support the glycocalyx with products that have the rhamnan sulfate, such as the products like Arterosil]. So those are the baselines, support the glycocalyx and nitric oxide, they are synergistic. And I know they’re doing studies to see how well they work together. But my practice, I routinely do that for patients and monitor, and people are getting good results with it, more elastic arteries and such. So those are the base marks for that. And then they need to do all the inflammatory markers and figure out what’s causing the inflammation and start pulling those things back.

Dr. Kara Fitzgerald: The reality is if there’s evidence for poor nitric oxide, your glycocalyx has to be toast by definition, doesn’t it?

Dr. Michael Twyman: Essentially, yes. The glycocalyx is the first thing that gets impaired.

Dr. Kara Fitzgerald: And then accumulation of all of the various pro-inflammatory compounds and lipids, et cetera. So the nitric oxide product you’re using now?

Dr. Michael Twyman: So if I use the capsule, I tend to use Vascanox. Dr. Mark Houston, who was a mentor and did a lot of training with, had recently done a study utilizing it. The study was done in 12 people who had mild hypertension or more requiring antihypertensive medications. Or if they were, they did not adjust the doses of the antihypertensive medications. And it was shown that this product helped lower systolic blood pressure, I think on the average around 10 to 11 millimeters of mercury with no episodes of any hypertension or untoward side effects. So shown to be relatively safe in supporting healthy nitric oxide levels, which then could promote arterial elasticity and improving blood flow and blood pressure.

Dr. Kara Fitzgerald: That’s a nice drop. Yeah, that’s pretty impressive. How did he dose it in the study?

Dr. Michael Twyman: It was two tablets once a day because it has a longer… I don’t know the exact half-life, but they’re still in the effect of it over 24 hours later after the administration.

Dr. Kara Fitzgerald: That’s very impressive because I think that’s a pain in the butt with our current selection of nitric oxide products out there.

Dr. Michael Twyman: Because most of those had to be dosed BID or twice a day.

Dr. Kara Fitzgerald: And what makes this one different?

Dr. Michael Twyman: It also has hydrogen sulfide precursors in it. So my understanding is that hydrogen sulfide also has some vasodilatory effects. Doesn’t work exactly this way, but in my mind it works like sildenafil where it’s just helping nitric oxide be around longer so it has better function. So earlier we talked about nitric oxide is a signaling molecule. It’s around for a couple seconds, it’s gone. Hydrogen sulfide just tends to make things dilate better.

Dr. Kara Fitzgerald: Cool. And it’s impressive that they just did one time a day dosing. What else did I want to ask you on this? I had another question. So I had a good question that’ll come back to me in a second. But I want to know who your appropriate candidate is for nitric oxide supplement. It’s huge in the bodybuilding community. There’s a lot of people experimenting with that. And I will say that I’ve used Vascanox myself. I actually take it and do notice it is helpful before a workout or something like that. I do like it, even though I’m able to make it, my oral microbiome, I can turn the strip pink. I turn it more pink after Vascanox But who’s an appropriate candidate for it? In your office, when are you thinking about using it?

Dr. Michael Twyman: Almost anybody is a candidate for it, but it’s a test don’t guess philosophy. Person comes in and they have uncontrolled high blood pressure, dyslipidemia, diabetes. They’ve already had a previous stent, by definition they had some really bad glycocalyx dysfunction, endothelial dysfunction in the past. Have they recovered that or not? And if they haven’t, then you can support them with products like Vascanox and Arterosil so that those things may have a better chance.

I always dig into, withdraw the insults and give the body the building blocks it needs to help repair itself. Because the body is wiser than we’re ever going to be. So I always think about the glycocalyx and endothelium being like the root cause problem in cardiovascular health. If you can support that, things don’t go downstream. I talked earlier about being an invasive cardiologist, and now when they come to the cath lab, it’s kind of like when Humpty Dumpty fell on the ground and you’re rushing around trying to save them. How about we keep them up on the wall to begin with? And that’s supporting the glycocalyx.

Dr. Kara Fitzgerald: Don’t even go on the wall Humpty. It’s a bad idea.

Dr. Michael Twyman: Well, I think just being alive puts you on the wall. But that’s the other way I can try to think about things.

Dr. Kara Fitzgerald: What I was thinking about, so you’ve pretty clear you’ve got this continuum of remove first, that’s very functional of you. That’s very strong functional thinking. And then you can start your interventions. I’m not always that strict, but I was thinking a little bit, there’s different nitric oxides. We have got endothelial, inducible, and neuronal. And inducible is pro-inflammatory by definition, that’s its role. So I’m wondering, this would be a time to be doing the remove phase, those lifestyle interventions before introducing Vascanox]? Or is that just not a concern?

Dr. Michael Twyman: I’ve not seen data that the nitric oxide promoting supplements are increasing eNOS or iNOS. And that’s just how I speak socially is nitric oxide is good in the cardiovascular system. But there are definitely roles where nitric oxide is used for the immune system to knock out infections. We talk about mitochondria.

Well, the mitochondria at the four cytochrome, nitric oxide acts as a hand break. It slows down electron flow. Is that necessarily bad? No. It’s decreasing oxidative stress because you’re not necessarily making a lot of energy at that point. But then using things like photo biomodulation, photo dissociates the nitric oxide out of that space, and then electron flow increases. So it does depend where the nitric oxide is at, but we’re mostly speaking… This situation’s more like we’re talking about the actual artery lining.

Dr. Kara Fitzgerald: So you could introduce it concurrent to your remove period.

Dr. Michael Twyman: For sure.

Dr. Kara Fitzgerald: All right. And so again, I’m curious about the candidate you’re starting on the product.

Dr. Michael Twyman: It’s going to be people who have abnormal carotid intima media thickness scans, abnormal CT coronary calcium scans, or if they’ve had a CT angiogram or if they’ve ever had a stent, they’re good candidates to think about supporting. Those are the people that are top of mind for me.

Dr. Kara Fitzgerald: And what about the biohackers, the early adopters? What might be some signals that it could be beneficial, although they’re not frankly down to cardiovascular disease? Yeah, go ahead.

Dr. Michael Twyman: I think you were saying is the bodybuilder community, the fitness people is because if you can get more oxygen nutrients into a muscle, you probably are going to have a better performance with it and you can get waste products away faster. So I know there are ongoing studies in humans looking at improving VO2 max with products like Vascanox. I don’t know enough of the details to speak on it eloquently, but there are those studies ongoing.

And then just anecdotally, yes, people who are on these type of products tell you exercise seems to be a little bit easier. And it’s probably not placebo, but even if it was placebo, if exercise is easier, great. Because exercise is the number one drug at improving nitric oxide production. If you’re improving blood flow down the arteries, you’re transducing that glycocalyx to tell the underlying endothelium, “Make us more nitric oxide.” So exercise is the best drug at promoting nitric oxide.

Dr. Kara Fitzgerald: That’s cool. What isn’t exercise the best drug for? That’s cool. Is it difficult? So for the patient who’s not psyched to use a supplement, is it difficult to really restore their ability or improve their ability to make nitric oxide? We talked about a compromised oral microbiome, but beyond that. And can you really bring that back?

Dr. Michael Twyman: Yes. I’ve definitely seen patients who have had severe endothelial dysfunction get back to normal. I saw somebody earlier today had a calcium score of over 700, which is a high risk finding. And we did an EndoPAT on this individual and they had a RHI reactive hyperemia index over four. This indicates that this person’s arteries can dilate 400% over baseline. So whatever damage to arteries in the past, they’ve improved it. And their arteries are very elastic at this stage. So it’s definitely reversible. I see it pretty much every day.

Dr. Kara Fitzgerald: That’s awesome. And their calcium score, that’s not going to really change?

Dr. Michael Twyman: That’s why I can’t I help you, because I get that question a lot, “Can my calcium score test go down?” It can, but that’s not necessarily the goal. Calcium, in my mind, is a marker that the artery had been damaged, so the glycocalyx got damaged, the underlying endothelium is damaged, and now the lipoproteins, which are carrying the cholesterol, they’ve stuck to your artery like Velcro. That kicks off an inflammatory response, the body basically thinks bacteria is attacking it, the white blood cells come in to investigate and they start gobbling up the lipoproteins. The cholesterol now gets stuck in the artery wall, kicks off more inflammatory cascade, and the plaques start building up little pimples on the artery wall.

And the body eventually will try to scar that pimple down with different fibrotic tissue, but it eventually will calcify it. So the calcium is a stabilizing factor, but it’s always going to be present with soft plaque. And that’s what you’re really concerned about because it’s the soft plaque, that tends to be the stuff that ruptures and causes the cardiovascular events. So if your calcium score is X, often it’s going to go up as you do treatment because you’re possibly changing the soft plaque to more hard plaque. Rarely should you see the calcium go down. If it goes down, that’s probably good, but nobody really knows if it’s good if it’s going down.

Dr. Kara Fitzgerald: That’s an interesting pearl that it may actually go up as you succeed in your intervention. All right, so what else do we want to be thinking about in optimizing vascular health long term?

Dr. Michael Twyman: I think it’s always going back to the four pillars. Stress management. People want to put a bad word that stress is always bad. It’s not. Without stress we’re not going to survive as a species. We’re going to have to do physical stress, ideally through exercise, and you’re going to do mental stress, but how well do you recover from that? That is tricky for some people.

So I know you’ve done research on having people doing mindfulness and doing it 20 minutes twice a day. How do you balance that autonomic nervous system, that is key to teach people. And then that’s the big thing too, is the sleep management. America has a pandemic of not being able to sleep well. And if you do not sleep well, then you can take all the supplements you want, all the medications you want, you can eat a perfect clean, organic diet. You’re not going to get the same results because the mitochondria, that’s when they repair themselves. You have to sleep well to age well.

Dr. Kara Fitzgerald: Yeah, that’s right. That’s a good quote. So how are you motivating your patients to engage in this? You can say, “I’ll see you in a couple of years in the cath lab then.” You know could do that, you could try the threatening approach, the threatening fear-based approach. But I’m here in Connecticut and I’m in Fairfield County, I’m close to New York. People live here who commute into the city. There’s a preponderance of high stress humans here. And one of the things that I’ve found in my years of treating people is that their willingness to work with this, to really take the impact of toxic stress, not the hormetic stress that you’re talking about, but that toxic stress seriously, it’s often the last thing.

They’re willing to do diet, they’re willing to do exercise. They’ll take any supplement that I think is needed. But to slow down and really engage in mindfulness that moves the needle, that’s impactful is the last thing. One patient comes to mind who couldn’t, her final 10 pounds… Her life was fabulous. We dialed in everything we could, but it was that. And the only thing that we needed to do, this has been multiple cases in different patients, was with stress.

It’s like you’re facing this. So I’ll bring it up every session. We’ll keep that conversation alive. I think that’s essential, and I think it’s motivating, maybe it goes somewhere subconsciously. But here I tend to see people really having a struggle with embracing it and taking it seriously. What about you and how do you get people to engage in that conversation and take action?

Dr. Michael Twyman: I think it’s the Vince Lombardi way, the only way to lead is by example. And that’s the only thing I really can motivate people with. Because the fear-based approach can work for some, but telling people, “Stop smoking because always you’re going to have a heart attack.” Doesn’t get them necessarily to quit smoking. You have to give them a bigger why. And so do I think vascular health’s important for everybody? Of course I do. But if it’s the person who’s looking for longevity, you have to have healthy arteries to age well. That’s always where I start.

And so I’m going to basically teach people along the way, what am I doing for myself? As a good biohacker, you’re going to test not guess. You’re going to try things. And that seems like it works, that doesn’t work. And then when something works, then you get curious. Then you go reading all the research like, holy cow, I didn’t realize there was a thousand articles on the glycocalyx. I didn’t know about this word three years ago. Where was I?

And I think that’s just being constantly curious and exploring things that like, mitochondria might be really important for longevity. Well, how does photo biomodulation work? Oh, it’s the mitochondria. And just adding things onto your armamentarium. I’m always going to have this basis as an invasive cardiologist. I still know how that gets done. I’m just trying to prevent myself or any of my patients ever from going back down that pathway. And so, just lead by example is the best way.

Dr. Kara Fitzgerald: Well, we need more of you. We do need more of you doing just this and preventing,  putting the cath labs out of business. I know, it’s not going to be anytime soon.

Dr. Michael Twyman: No, but I’ve joked about that. That’d be great. I know people are concerned that AI is going to replace everybody. I would love to replace the cath labs, give those guys skills and they can go do something else.

Dr. Kara Fitzgerald: What’s some of the research? I know we’ve touched upon quite a bit of it, and for show notes purposes, folks, we’ll park some of the citations. Certainly that Mark Houston paper will put into the show notes. But what are some of the studies out there that are just really lighting you up these days?

Dr. Michael Twyman: I know they’re researching other ways to look at the health of the glycocalyx because there’s right now no direct way to assess it.

Dr. Kara Fitzgerald: What about GlycoCheck?

Dr. Michael Twyman: It’s an interesting technology. It’s a intravital microscope. So it’s a microscope that you put under the tongue and you can look at the sublingual blood vessels and you can look at the perfused boundary region, which is just how much do the red blood cells penetrate into this region? The more it penetrates, the worse off the glycocalyx is. But I have not yet seen convincing evidence that what’s going on in your oral circulation is exactly the same that’s going on in your coronary circulation.

So I think it’s probably at this point useful for more of a sepsis type of picture. So somebody in ICU, put the probe in and see what’s going on. They could probably be in disseminated shock. Makes sense. But until they show me the research that it truly correlates with the coronaries, I don’t know exactly what to make of it just yet, but I think that is a coming type of technology is that do they have enough research to pinpoint that these glycocalyx promoters are actually promoting improved glycocalyx throughout the entire system and not just in the oral cavity. So I think that is an interesting way. And then I had recently given a talk to the PLMI organization and I was doing some research on it, and I know those organizations looking at MRI, trying to find a tracer that the glycocalyx would be traced with.

And then you would do an MRA and you’d be able to subtract out the volume and tell the person, “This is your entire volume of glycocalyx throughout your entire system.” So that would be super, super fascinating when that technology, if it gets developed, would be online. Because then people could basically go in for a yearly GlycoCheck or whatever they’re going to call it, GlycoScan or something and say like, “Is my glycocalyx healthy? Yes or no?” Because right now everything is a downstream effect. We’re doing markers of endothelial health, we’re looking at biomarkers like ADMA. Those all give you a signal, but you’re not directly looking at the glycocalyx. So I think that is the future.

And then I also had seen that there is articles that are talking about the glycosaminoglycan, like the GAGOme is what they were calling it, which is quite a funny term. But the GAGOme is looking at, how much heraran sulfate and hyaluronic acid should be normal in your bloodstream or in your urine. I think it’s going to take AI and machine learning to really figure out what is the exact normal level of degradation that the glycocalyx is supposed to be doing, and then offer an intervention and then retest, and then have AI be like, “Yes, that’s actually improving that.” But I think that is probably the thing that I’d be most excited for, is that we’d have some test that we can do really routinely be like, “Do this intervention. The glycocalyx got better, yes or no?”

Dr. Kara Fitzgerald: But you would anticipate seeing some phenotypic change as well.

Dr. Michael Twyman: Correct.

Dr. Kara Fitzgerald: But you could have plenty of glycocalyx damage perhaps without much phenotypic obvious presentations, obvious signs. What is the tracer that they’re testing for glycocalyx? I’m so curious, have they come up with it?

Dr. Michael Twyman: I don’t think they have one yet. I think that was the thing that they’re trying to figure out. I can’t remember, one that would bind to albumin, but there’s other components in the glycocalyx other than just albumin. So they don’t have one yet.

Dr. Kara Fitzgerald: Wow, that’s really interesting. Fascinating. And I appreciate your opinion on GlycoCheck. It seemed like a really cool technology, but it makes sense that it’s assessing locally, and is it reflective of systemic. All right, so you’ve got your grandma who’s 106? Or she lived to be 106. Is she still alive?

Dr. Michael Twyman: She passed away in 2000, but she was born in 1893. So she made it three centuries.

Dr. Kara Fitzgerald: That’s incredible. Wow. I’m curious if she gave you any interesting tidbits about life back then. But so what are the most important hacks on your journey and what you share with your patients? Just in our wrapping up, what do we really need to do?

Dr. Michael Twyman: It always sounds counterintuitive, but I always start with circadian biology. Yeah, it’s that important. Our body craves consistency. So I just walk people through what an optimal day would be is you’d be up around sunrise. The first light that hits your eyes would be natural sunlight. That light hits the melanopsin receptor in the back of your retina, that sends a message to the super cosmetic nucleus in the brain and tells your body it’s daytime. And you start making cortisol and all your sex hormones.

The color of the light or the wavelength of light change throughout the day. So when UVA light comes out later in the morning when UVA hits your skin, it’s going to liberate nitrates from your bloodstream. You’re going to release nitric oxide with UVA light hitting your skin. Later in the day, UVB comes out, you’re going to sulfate the cholesterol and make vitamin D, and then it goes in reverse. The sun sets and the receptors in the back of the eye would realize it must be nighttime because there’s no more blue photons hitting the back of my eye. And you would go to bed in a couple hours after that, or you’d have a fire and maybe delay it a little bit.

But now with our backlit technologies, this blue light coming off our devices that we’re chatting with right now, this is set at 5,500 kelvin. This is the exact same color temperature as solar noon. So every time you’re looking at your devices, you get a hit in your brain that it’s still noontime and that’s messing people’s circadian rhythms up dramatically. And so then people don’t sleep well, which leads to all the cascades of insulin resistance. And they can’t change their body composition and their brain is foggy. You have to start with your light cycles first. So I always start with circadian rhythm biology first, and then we layer in your nutrition, your exercise, your stress management.

Dr. Kara Fitzgerald: That’s really interesting. Wow, that’s so cool. And once you’re not sleeping, and once you kick in insulin resistance, then it’s just the slippery slope? You’re going to stop making nitric oxide, and you’re endothelial and endothelium and you’re Glycocalyx are going to just stick together and just all of that. And you accelerate your aging journey. Anything from your grandma, any cool little factoids you can share? I’m so curious.

Dr. Michael Twyman: She lived alone until she was a hundred, and then she did end up developing dementia in her later years and went into a facility. But she was a very happy-go-lucky lady.

Dr. Kara Fitzgerald: What did she do?

Dr. Michael Twyman: She did nothing. She did not exercise. She ate hot dogs, diet coke, Post Toasties. She did not sleep well. She lived literally under the flight path of the airport here in St. Louis. She did literally nothing health-promoting. So she was probably one of those lucky people. I eventually figured out a little bit why. I tested my dad’s genes, because he has excessively low lipoproteins. My dad has an APOE2 gene, I’m sure she had this. My dad has a loss of function PCSK9 gene. So he basically has built in Repatha or Praluent. So basically his LDL receptors are just always out there clearing APOE particles from the bloodstream.

So his LDL particle count’s like 500, 600, no medications. Calcium score’s like 10. So he’s not heart attack proof, but his risk of atherosclerosis is extremely low for people of his age. So I think she was one of those people that had some lucky genes that got her to 106. I’ve already done my own test. I know I don’t have those same cardiovascular protective genes, so I have to do more. So I have to do the biohacking, I have to do all the functional medicine I learned. So that’s why I say it’s lead by example, because I’m learning and I’m implementing as fast as I can because I have a large gap to close with her. So 107 is a long time from now, but it’ll come quick.

Dr. Kara Fitzgerald: You can do it. I think that’s wonderful. And my family, we have high LPA. I don’t, LP(a), but my grandfather, the opposite of your mom, of your grandma. He died in when he was 60. And I’m sure a massive heart attack. And I’m sure that LP(a) was leading the charge for him and we didn’t understand it back then. But we have plenty of interventions that we can do. Like LP(a) does not have to be a death sentence. So poor genes or not having the longevity genes that your dad and your grandma have does not mean you won’t hit 106 healthy and happy.

Dr. Michael Twyman: Yes.

Dr. Kara Fitzgerald: Well, listen, thank you so much Dr. Twyman. It was a really fun conversation with you today and keep up the good work.

Dr. Michael Twyman: Thank you so much for having the opportunity. This was definitely a fun conversation.

Dr. Michael Twyman is a Board-Certified Cardiologist who has now become a preventive cardiologist. In 2017 he discovered “biohacking” and has been using this modality of health optimization to help patients make incremental changes to their lifestyle and environment to improve their heart health and overall health over time, including photobiomodulation.

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Dr. Michael Twyman, MD

Endothelial Glycocalyx Research

Rhamnan sulfate from Monostroma nitidum research

Vascanox HP research: An Open-Label Study to Evaluate the Safety and Efficacy of a Novel Oral Nitric Oxide Supplement

OUTLIVE: The Science & Art of Longevity by Peter Attia

Max Pulse test

Arterosil by Calroy – monostroma nitidum supplement

EndoPAT device

Vascanox HP by Calroy – Nitric oxide supplement

Chen, YH., Narimatsu, Y., Clausen, T.M. et al. The GAGOme: a cell-based library of displayed glycosaminoglycans. Nat Methods 15, 881–888 (2018)

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