16: The Hidden Dangers of High Cholesterol – What You Must Know with Dr. Thomas Dayspring

If you do not have cholesterol in your artery wall, you do not, exclamation point, have the disease called atherosclerosis. So it is cholesterol that is the causal agent for atherosclerosis, but your artery didn't over synthesize cholesterol. So obviously there is what I call an illegal dump job of cholesterol in your artery wall.

Welcome back everybody. It's great to be back again. I'm Here today with Dr. Dayspring is a world renowned lipid. So I'm going to read his introductory first and we'll kind of grab into it. So Dr. Asping is an internist who's a fellow of the American College of Physicians who also serves as a social media ambassador to the European Atherosclerosis Society and National Lipid Society. He's practiced internal medicine, lipidology, women's cardiovascular health for 37 years in New Jersey and then worked seven years as a scientific officer for two large cardiovascular biomarker labs in Richmond, Virginia. For the last five years he's been a lipid specialist or advisor for early medical which is Dr. Peter is practice. Great to have you here today to.

Talk to be chatting with a colleague in Richmond here.

I know, yeah. So it was interesting talking with you before and also watching some of your previous podcasts and things like that. So first I want to talk about how do you go because when I was in medical school at MCV here in Richmond, lipidology, like I didn't even know the word lipidologists so I didn't really hear that term until I started doing my integrative functional training back in 2012 and even practicing locally I had never like didn't know people actually did this and they come find out you've been doing it for decades. So kind of walk us through how do you go from internal medicine what your progress was to get to be like literally a world renowned lipidologist.

It's quite been quite a journey for me and I had no grand design to wind up where the heck I am. I joke. I went to medical school in the Dark Ages 1968-1972 and never mind the science of lipidology, we barely knew what lipid. The only lipid being measured in patients at time was total cholesterol and also triglycerides which were not understood at all. And there were virtually zero lipid therapy. So we were told at what level of cholesterol to worry about but there was nothing to do about it even if somebody had fh and back in those days, the worrisome level was if they're above 300 you got a problem and if they're not, don't worry about them. But somehow I got very interested in cardiology because at that time when you were a young stud resident and doing night call and moonlighting in ERs during your residency, the biggest crisis was acute coronary syndrome. They were rampant. They were coming in every night. And what did we do for them if they we didn't have to CPR them in the emergency room. We put them at bed rest, gave them oxygen, maybe heparin, treated ventricular premature contractions totally unnecessarily. So that's where I started. It's like before the Wright brothers invented their first airplane and now we're watching rockets fly around. So I went into the private practice of internal medicine, still very interested in cardiology because it was the primary pathology that was killing people. By that time we had cured bleeding ulcers with Tagamet. So that wasn't a problem anymore. So early in my career was get on the hypertension bandwagon that can do good to cardiovascular disease. Still no lipid management. And what the rudimentary lipids we're measuring, you didn't know what to do with them anyway. But sooner or later it was in the mid-1980s that some information started to come in that you can measure lipids and if you can reduce cholesterol in the blood. However you're mentioning by that time in the 80s we had the calculated LDL cholesterol. We had direct HDL C measurements, so we were a little smarter, had triglycerides. Still didn't know what to do, but at least we knew. Hey. Then the first drug that worked was bile acid sequestrans, cholesteiramine. Pretty much an unusable drug, but it did lower LDL cholesterol a bit and did reduce outcomes in a big clinical trial. Then the first FIBRI trial came in. Gemfibrizole, first primary prevention trial really done. The Helsinki Heart trial where GEM fib as a monotherapy reduced events. That was published in 1987. And what hit the market in 1987? Statins, Mevacor, Lovastatin being the first guys like me who started to delve into studying lipids in the 1980s of course became major statin users. Probably most of the internists and clinicians at time used statins very cautiously, if at all, because although they lowered cholesterol, there were no long term safety trials or even outcome Trials we were believing, hey, cholesterol lowered cholesterol. It worked. Statins lowered cholesterol more. And of course 1994, seven years after they hit the market, the 4s trial with Simvastatin outcomes beneficial very soon, within the year, a primary prevention trial west of Scotland with Pravicol worked. So statins came along. So I was boom, boom really being aggressive with lipid management by that time. Now back then when you somehow discovered yourself and it was all self studying lipids at dying, there certainly no society of lipids. You just try and delve into the literature and learn what you could. But interesting pharma understood. Here's a doctor up here, he's writing a lot of statins. What does he know? That doctors who aren't writing a lot of stands, so they sort of hang around with you and they interview you and listen to you and they get the feeling that you might know what you're doing. So they give you an opportunity. We would like you to speak to other doctors. Okay? So what they do is they send you out into your local community to basically speak to a few friends or colleagues who know of you, who might come to a lecture you're doing. And by luck my self study up to that time I sort of knew a little bit what I was talking about. And the doctors I talked to, better yet, they sort of liked the way I explained how I approach lipids, what I know about lipids. And it spreads like wildfire. If you get the reputation, you're a good lecturer and it's really the pharma people who are monitoring you. Early on at that time, back in the late 80s, early 90s, you start getting invitations to lecture here, there and everywhere. So I love doing it. I started to accept invitations and now you're traveling out of your local community, even out of state. And when you start doing that, and sooner or later you're lecturing at medical schools or through faculty doing grand rounds at a hospital, you start to meet the higher ups in lipidology and you get to interface with them a little bit. They get to know who you are and you start also when you're at that, you start attending more national meetings. Now there was no lipid meetings to attend, but American heart places like that, endocrine societies, and you'd meet more and more of those high level colleagues and before I know it, when I grabbed the high level colleagues and I annoyed the heck out of them, but they sort of like the way I do. By that time I had a reputation as being a Great illustrator of lipoproteins and lipids in visual, mostly powerpointers. So they all wanted to know how I did that. Long story short, I got to meet virtually everybody who's anybody in lipids, became friendly with him, and then you start getting invitations to speak at national meetings. Hey, write, publish a chapter here, help me co author this paper here, and here I am. And even when you get to a point where you're so busy doing the educational things, I had to bring in a colleague to assume much of my practice, keeping only the tough cases or some new cases. And then at a point, father time gets you. And yeah, I really can't keep doing this forever practicing myself. And I have so many opportunities to lecture, write and teach. And then I got the laboratories, wanted me to come down as a scientific officer. And it was a wonderful opportunity that I just fell into. And they recruited me because this guy can understand lipids. He explained lipids and he speaks to clinicians. The laboratorians are not always the greatest people to speak to. Clinical guys like yourself, I don't know, they just don't sort of speak the same language. But so I got for seven years to hang around with world class clinical laboratorians, became friendly with many of them, started attending their meetings, and it helped me better understand their part of the lipidology equation, translate it to real world guys. And so I just became even better at understanding lipid speaking. The National Lipid Society started just before 2000. By 2004, they decided, we want to start a journal and we want to start fellowships for lipid guys. And ultimately we want to create a lipid certifying examination. So the American Board of Clinical Lipidology was formed. I was a little bit in on the ground floor on that. I helped develop a lot of the self assessment programs. I would teach at their Masters of Lipidology course. And before you know it, so now they're going to start certifying lipidologists. So they brought a group, just under 100 of us together, believe it was in Chicago, and they had like, they put together the first beta trial examination. And so they brought in quotes from best and the brightest. We'll give you guys the exam and see how you do on it. Do you like it? Was it fair? Are you guys all going to fail this? So, and now one feature of that was, hey, if you took the exam, they would grant you certification in clinical lipidology. Now again, they were recruiting people who were likely going to pass the test, no matter. But I took the test I get an underground floor. I have certificate now 28 in the. As far as I don't know what to up there now but in the thousands or so just continued to teach and. But now I was into the lab. And the great thing about the lab, I'm called their scientific officer because I know a lot about this stuff. But these labs were very busy doing hundreds of thousands of assays and you get doctors calling up, I don't understand this, what can I do? So hey, dayspring will get that phone call to try and make it.

And which labs were those that you were doing that?

I started with Health Diagnostic Lab which was an incredible lab and again world class laboratorians. Ultimately laboratories get into trouble with third party payers because they're always going to be accused of unnecessary testing and third party payers don't like to pay for it. One of those third party payers is the government through Medicare and Medicaid and they surely when they see a lab is really creating a lot of bills, they come down with their investigators and hey, unnecessary testing. Every test was ordered by a doctor practicing medicine. It's not what laboratory but they'll say, hey, do you really need this many of those tests? So ultimately they stopped paying them and the labs fold. So HDL ultimately went into bankruptcy after a decade. But they were bought at biops at the bankruptcy sale by Truth Health Diagnostics who came in. They kept me. They wanted me to continue as the scientific officer. They kept a lot of the people, they narrowed down the group but ultimately ran into the same trouble. After four or five years they're being investigated for unnecessary testing. The screws are put on them and they have to fade away too. That was 2019. I joined HCL in 2012. And then my friend Peter Attia said, Tom, I know the labs are not there. What are you doing? I said, well, I guess I'm retired finally. And I was into my, I guess late 60s at that time, early 70s. And Peter says, well, I have this very specialized practice and I've leaned on you for the last decade. I knew Peter for a long time and we interacted on lipids a lot. Me trying to teach him and help him solve. So he gave me an opportunity to be the lipid specialist in his practice. Now I don't practice there but I look at lipids. He's got internists working for him who do the practicing and prescribing it himself. But I will talk to them. If they get a lipid thing, we'll talk in a group here's what I think is going on. Here are possible solutions to it. Peter does a lot of education with his podcasts, writing weekly emails, so I get involved in any of them that are lipid. If you go through his podcast library, you'll notice a dozen of the world's top lipid thought leaders. I've done eight of them with Peter, but there are many, many more. But I recruited most of those speakers to come and speak to because I know all the tough guys. And the last thing I'll tell you is at a certain point when I started to slow down a little before I left the labs, I got involved with social media. Twitter was invented and it was there ultimately LinkedIn. So I started going on Twitter and started publishing there, writing little tweets and put all my teaching slides, which people love. So before I know it, I got like 37,000 followers on Twitter. Not bad for somebody who just tweets all the time. LinkedIn. I only accept if you're a professional. There's a lot of laymen and who knows who following me on Twitter. But now all of a sudden, you're recognized far more globally than you were. I've done a number of talks around the world, but I still didn't have a high level recognition. But once I hit social media, you mentioned I'm a social media ambassador for the European Anthropology. I never heard that because they contacted me. And we love the way you're educating on social media and we'd like you to copy us on some of the tweets or help us with some of our endeavors. So why wouldn't I?

Yeah.

And now all of a sudden I way more collected connected globally with the top thought leaders in the world than I. I was mostly collected connected in the United States and now it's globally. So it's been wonderful.

That's a great summary. I haven't actually heard all those different things put together with your store. So it's really great to hear that. It's kind of interesting, the whole lab thing, because I as a practice clinician, I have the exact same issue where it's like, this lab is paid for by this insurance. This lab is not paid for by this insurance. This one is a cash base. And so I have to create my own ecosystem where it's like I want to do, you know, Cleveland Heart Labs, which has the NMRS and all the advanced stuff we'll talk about here in a little bit. And you realize, hey, that's going a different pathway if you use certain labs like doctor's data don't accept insurance. If I, if it's a certain carrier, I'll use it for that. And so I almost have to become like an insurance expert. And I've actually gotten some letters from certain carriers which I won't mention here just in case their representatives are listening, who have sent me cease and desist letters that if I keep on ordering this lab, they might drop me from their insurance. And so in the way my practice is set up right now, I do like a membership and insurance that allows me to use insurance for labs that are appropriate. It also allows me to use the patient's resources for labs that are outside their scope. But yeah, you gotta stay on your toes because if not, I don't know.

How anybody practices the type of medicine you do, or even run of the mill internal medicine or family practice, because everybody's trying to put handcuffs on you with no recognition that you're a well trained physician, you have your own CV that shows you're not some dummy who's discovered testing here and there and you're doing it appropriately. But they don't want to pay for it. They want to maybe pay for a lipid profile, a glucose level, even fight some people on A1C's and good God.

Yeah, I first ran into that when I was in the military. And that was before this was before Medicare was paying for screening colonoscopies. And so the United States military followed the same standards as Medicare. And it's this common knowledge, if you're in the military, just being in the military increases your risk for Parkinson's, als, the chemicals you're exposed to. First Gulf, second Gulf, you're Vietnam. We know these veterans are getting bladder cancers, all these things. So. So like all my guys that came and see me, it's like everybody gets a colonoscopy. Insurance wasn't paying for it. So I have this colonel or general, a sergeant. Do you have blood in your stool? And they'd say, no, it's okay. Have you ever in your life ever had blood? When I was 12, bingo. And I get the insurance to pay for it. And all of a sudden it's this game where like, I know you're high risk because of your history. I know it's becoming more common. I have to massage the system. And then five years later, it's now considered okay for screening. And now as of like a year or two ago, now it's okay to screen a 45 year old to 40 for colon cancer.

They're catching up. What you knew 20 years ago. Yeah.

Well, that's kind of, that's a great transition because it sounds like your entry into this foray, so to speak, was a ton of self study. Like there was no board. You predated the board, you actually were part of the board, help form all this kind of stuff. And so now at this stage in your career, you have this history and we'll probably talk about what's cholesterol and you have this. But it's like interesting how like in the modern day of evidence based medicine, people forget there's a, sometimes a 20 year lag between data and clinical stuff. And you literally have lived that. That's been your experience.

It's funny, when I was working at the lab, one of my jobs was because they were calling up the lab all the time, stop offering this test. What the heck would you even look, why are you asking this? And I would be brought into those phone calls as somebody who had a high level knowledge of appropriate use of. But you'd be talking to a bunch of accountants, bean counters, somebody who they directed as medical director, who had a very limited knowledge on any of these things. And I would give them the scientific A, B, Cs and Ds as to why each test is very appropriate in one ear there and out the other. Finally I got to the point it's a waste of time being on these phone calls. My credentials mean nothing, my experience mean nothing. They don't want to hear it.

What's interesting.

So, so tough. One thing, last thing, I'll say I was one of the reasons I left medicine after 37 years. For most of my 37 years, I had nobody over my shoulder restricting me. They respected somebody's expertise. But then it got to the point where you had to have little algorithms for who can get this, who can, and that's it. If I have opportunities, people want to give me other employment, goodbye private practice. Yeah, it's unfortunate.

There's, there's, there's a whole generation of physicians like you. And actually it was pretty standard 25 years ago. That physician would work till they're 75, maybe 80. Sometimes they'd work until they're actually like you're kind of old. You come to work in a cane, you forget you should need to retire. And now we have people retiring. This happened with the pandemic where a lot of people in the local environment were like, I'm done. 55. A couple GI doctors retiring at 55. It's almost like you're removing 15 to 20 years of a Physician's career.

If I didn't get the lab opportunity and after the lab, Peter, I'd have been in a rocking chair a long time ago. Enjoying retirement. I sort of love my retirement now, which is still teaching lipids, because I love it. But that's. You were looking for ways to get.

Out of the private practice in medicine and heart disease. I lost interesting statistics like quoting Heart disease is the most common cause of death in our country. If you're a female diagnosed with breast cancer, heart disease is still the most common cause of. So it's one of those things that something as basic as cardiovascular disease and obviously lipids are one of the major risk factors. It's like a bigger deal, I think. In 1900 cardiovascular disease was uncommon. By the 50s it was the most common cause of death in our country. And 74 years later, it still is. So let's make a little transition. One other thing you mentioned when all, everything you mentioned where in that. Because there's a bunch of different credentialing societies now where in that does lifestyle, diet, exercise, where in your journey in lipid medicine do those? Because in the functional medicine world, the foundations are always diet, exercise kind of stuff.

And it has to be. But look, we're at the point in lipidology now where we believe anybody who does show up with a lipid disorder, there's an abnormal genetic process behind that. If you had a perfect genome, if that even exists, but at least say a perfect lipid genome, the genes that influence lipids, some of them minusculely, some of them disastrously, but we're created from billions of genes. So if you've got a few even more minor genes by themselves, but oh, they start pairing up in you, you will have what we call an abnormal lipid phenotype. That means the blood tests come back abnormal, whatever, they're measuring yourself. So like everything else. So if we all have genes that are sending us down to abnormal lipids, what it really influences a gene's, what it's going to do to that phenotype. It's the environment that a gene gets exposed to. So in the lipid world, what are the environments of concern that lipid drugs are going to be influenced by? And clearly you start with lifestyle. And what does lifestyle include? Well, of course it's your nutrition, but it's your activity, your exercise, it's your sleep patterns. God forbid you're exposing yourself to toxins like the soldiers you talk about or the smokers that we encounter all the time. So it's genes plus Environment, environment, lifestyle. Now part of the lifestyle is nutrition. So obviously if you have a lipid disorder, somebody should be advising you on if you're an expert in lipids, the type of nutrition you or the nutritionist that you influence or work with or respect might come up with a nutritional plan that would probably or likely be beneficial to a lipid disorder. The one thing you will find out, and I think you have to be open minded on nutrition. There is no such thing as I'm going to memorize one diet, that's it for everybody and I'm done. That is absurd. You know that. So you do have to individualize a nutritional plan based on not only whatever lipids, you get other biomarkers, you get other historical things, physical examination, you're assessing their activity and their muscles, blah blah, blah. And you're going to come up perhaps with solutions with all of them. You're certainly going to stop smoking. Despite no randomized bonded trial.

Evidence based medicine. There's no like, what's your evidence? Like common sense for parachutes.

No evidence but most of them. Did you read that?

Did you read that BMJ article about that?

Yeah, that's a great line. So anyway, nutrition is part of it. But you, no matter what, even if you're an expert and you say, huh, you're insulin resistant, you're not. Here's the nutritional plan. I'm coming up where you've been eating too much saturated fat. We're gonna, you have to try your nutritional plan addressing all the other things, sleep, muscles, blah blah, blah. But if it doesn't work, you have to be prepared to abandon your nutritional plan and try something else. Even though what you suggest might work in the majority of people, you're going to find out diets can be funny. As far as solving a lipid disorder, I will then go on to whatever lifestyle changes you do come up with and I've listed four or five that you'll approach to. If you still have a lipid disorder that puts the patient at cardiovascular risk, you must welcome pharmacology into the world. And now that we're realizing the lipid or lipoprotein concentrations that are really necessary to say with this amount of certain biomarkers, it is impossible to get atherosclerotic cardiovascular disease. Our goals of therapy over the years, I told you when I started it was 300 total cholesterol. Now we're into LDL cholesterol or APOB, LDLP if you're beyond lipid markers. Boy, every 5, 10 years the bar keeps getting lowered on what is an acceptable. What is an appropriate goal of therapy. Goals of therapy have always come in two directions for the very high risk and for those who are not at high risk, basically. And of course, you'd be more aggressive with the goal of therapy and the very high risk. But really those goals of therapy are merging. What's good for one is certainly probably good for the other. The one who's already had a heart attack, you're trying to prevent the next one. But in the other ones, primary prevention. We're now calling it primordial prevention. Let's get your lipids, lipoproteins in balance so we can take the leading global cause of morbidity mortality out of your picture. Concentrate on the other things I have to worry. Cancers in you or arthritic things in you. Bowel diseases in you. And you can zero in on that. But so the lipid management is nutrition and lifestyle and ultimately pharmacology. And the good thing, in the year 2024, there is almost nobody outside of rare genetic lipidosis that you cannot get to a pretty good goal of therapy to eliminate atherosclerosis. But those people do require drug treatment. We basically have four drugs that you can use other than we're not talking about pediatric homozygous fh, where they have drugs that you're never gonna use as an adult. Four drugs. So there's not a lot to master, even with the pharmacology nowadays. Have you ever lost trust in your own body or in the doctors who were supposed to help you heal? It happens to millions of people who are stuck in the cycle of prescriptions, tests, and more questions than answers. That's why Dr. Aaron Hartman wrote his new book Uncurable. As a physician and a parent, he's lived through the pain of being told there's nothing more we can do. But instead of accepting that, he built a new path, one that combines traditional and functional medicine to uncover what's really driving illness. Uncurable is more than a book. It's a roadmap to help you find the root causes your doctor might have missed, reactivate your body's natural healing systems, and finally believe in what's possible again. If you've lost hope or trust in the system, this book will help you take back control. Go to UncurableBook.com and grab your copy along with Dr. Hartman's free resources to help you start your healing journey today.

That's a great transition to the next thing I want to talk about, which is like lipids proper before you get to therapies because there's so much confusion. You know, you mentioned LDL and HDL. You mentioned APO. I don't think you mentioned A1B. We'll mention them here. You know, LP. And then is all these other metabolic markers, like fibrinogen levels, hscrp, homocysteine levels. A lot of people are confused about what these things mean. What's the most important one? Is it total cholesterol, Is it apoa? And then where do like these other metabolic markers like homocysteine, hs, crp, maybe that's how statins work. Is inflammation, all that kind of stuff? Could you kind of like, I know I threw your plate up, right, for the next three hours. Right. But could you like as briefly as possible, kind of go through that whole thing?

We'll try, of course, that would be an eight hour podcast.

I've heard a couple, I've heard a couple of those. And so we're trying not to.

So we're not going to go there. But yeah. And the first thing is to understand when you have a disease you're trying to eliminate. In this case it's atherosclerotic coronary disease or atherosclerotic vascular disease, because you can get it obviously in arteries apart from your coronary tree. You have to understand what are risk markers and, and what are risk factors. So there's a subtle definition. Many of the things you mention are risk markers. They're not risk factors. Risk factors. You should have solid data that the particular thing you're analyzing is causal of the disease you're trying to eliminate. And basically the causal risk factors for atherosclerosis are, look, apart from gender, male gender is a little higher risk than women. So we can't do anything with that age using major risk risk factor, Good luck trying to stop aging. But the ones that we can measure the number. Smoking is a major risk factor.

My smoking, obesity, diabetes, like all that.

Has to be eliminated from day one. Even obesity is not a risk factor per se, but obesity is associated with risk factors and a bunch of risk markers. So at the end of the day, you're very concerned about obesity, to be sure. But there are obese people who somehow escape the more severe forms of atherosclerosis and everything. So with risk, everything else that contributes to atherosclerosis is going to be in the risk marker category. To prove causality, you have to basically get to that by passing through three stages of proof. One is a ton of epidemiological proof. Now, as you know, they're mostly observational trials, which, when you have 20 or 30 of them, they're pretty believable. But you still can't say it's because of all the confounding things that go into epidemiologic observational trials. The next thing would be randomized control trials, almost all of which are done with a therapy where you take a group of people who have similar risk factors, risk markers, and you decide this group is going to get a placebo and this group is going to get some action. Maybe it's a diet, tough to do diet, randomized controlled therapies, because you pretty much know what group you're in. So it's really not blinded. But then you have the pharmacological treatments, which can be blinded, and you will prove, at least as a pharmacological agent, gonna reduce major adverse cardiovascular events or not. And then, as you know, in all of those trials, there's secondary and tertiary endpoints, and that's where they're looking, looking at some of these what things come into risk marker things ultimately. So in the randomized controlled trials, you can certainly prove that modifying certain biomarkers seemed to reduce it. So all of the early cardiovascular trials were aimed at lowering LDL cholesterol. Ultimately, those of us in the lipid world knew LDL cholesterol is just the poor man's way of doing apob, or LDL particle concentration. But when they started testing LDL cholesterol, APOB wasn't even known or invented. You certainly couldn't order it if you as a doctor. So those markers came in later in the game. So LDL cholesterol, hey. Because cholestyramine lowered LDL cholesterol and it worked. Probably everything that lowers LDL cholesterol is going to work. Didn't turn out that way.

Let me stop you there real quick. So am I hearing you correctly that you're. Even if your LDL is like 161, 70, if it's possible to have an elevated LDL that's that high with a normal APO B or elevated A1? What I'm hearing is that even with elevated LDL, if the APOB is lower or normal or optimal, that higher LDL is not really as much of a concern?

Yes, and we'll get to that. So the early trials, to be called causal epidemiological, the randomized control trials, and then in came the Mendelian randomization trials. They're Mother Nature's randomized Trials where you can take people, analyze their genes, look at a biomarker and say, hey, people who have these genes are probably going to have this, the biomarker. Let's see, how long did they live? Did they have heart attacks? So all of a sudden you had genetic causality. And that's pretty much the most definitive way to say something is causal or not. And LDL cholesterol has entered that world of epidemiologic data. Randomized controlled data in Mendelian rhythm randomization trial. Ultimately, so did APOB when they went back and looked at it, because they could go back to all those trials and almost all of the randomized controlled trials that were looking at LDL cholesterol, the researchers were doing APOB too. So that data does exist. And they could go back and look at that and say, aha, the APOB is also causal. Now we have several societies that have declared LDL cholesterol in APOB as causal. For atherosclerosis, triglycerides entered that group. But the data's a lot weaker on triglycerides, and they got it through the Mendelian pathway. There are certain triglyceride genes that are causal for atherosclerotic disease. Most of them are not, but some are. So H. Triglycerides is probably in the picture. It's something you better look at. Seriously funny. The HDL metrics, which are either HDL cholesterol or or measuring its structural protein, apoprotein A1, were not shown to be causal. And that really shook up the world a little bit because what was everybody measuring and putting high emphasis on HDL cholesterol, Not many were measuring APOA1. Some were, and we're betting the house on that too. Now we know you cannot. And if you're ordering those tests, you should know what they tell you and what they don't. So the causality in the lipid world right now is APOB. LDL particle count, which is an APOB. It's a different assay, but APOB is you're measuring all of the APOB containing lipoproteins, but 95% of them are LDLs. So APOB is really an LDL particle test. So those are your most superior tests that I wish everybody was doing, because then you wouldn't need any cholesterol metric, because in retrospect, it turns out total cholesterol was the first biomarker they're looking at. It proved to be, hey, this is in the causal range, but it's a weak Thing. Total cholesterol is just a very poor man's APOB test. If you came to me with a total cholesterol really above 250, I know when I get around to doing an APOB, it's going to be through the root. Total cholesterol alerts me to that. LDL cholesterol is a better predictor of APOB than is total cholesterol. Because total cholesterol, you're looking at HDL cholesterol plus LDL cholesterol plus VLDL cholesterol. But HDL cholesterol is out of the causal mix now. So that gives total cholesterol some weak variability. LDL cholesterol. Hey, you're just looking at the LDL particles. 95% of APOB is LDL particles. So LDL cholesterol. That's why it's important. Then they came up with this. Let's calculate non HDL cholesterol. Let's see a freebie. You take total cholesterol, a direct assay that's accurate, and you subtract from it HDL cholesterol. A direct assay that means nothing, but it's an accurate measurement. If I subtract HDL cholesterol, the cholesterol that we now know is irrelevant from total cholesterol, what's left? APOB cholesterol. Non HDL cholesterol is the best biomarker in a lipid profile of what your APOB level is.

So are you saying that having an elevated APOA1HDL is not protective?

No.

It's not protective.

No. And now why did we believe it was for so long? Because we were all preaching low HDL cholesterol. You're a dead man walking. I'm going to raise HDL cholesterol even though I have nothing but niacin, which ultimately proved to be a futile drug even though it raised HDL cholesterol.

Have you heard about the reception recent article put out about niacin dosing increasing heart disease? By chance, I've had several patients this past week send me messages. I looked at it.

Yeah. Personally, I believe it. And because I. I know the bad things that niacin does. Niacin? Totally. Even though we. The main reason we were drowning people with niacin was to raise HDL cholesterol. We now know it makes HDL particles dysfunctional.

It makes HDL particles dysfunctional.

So what we now know is HDL cholesterol. APOA1 is irrelevant because it doesn't tell us what the HDL particles are doing.

In Your body when you have dysfunctional versus functional, it's not a window.

So as much as I blast it in the year 2024, looking at HDL cholesterol, or APOA1, HDL particles are incredibly important for your cardiovascular health and probably many other aspects of chronic disease health that you have. Why? Because HDLs don't carry lipids. There's 45 molecules of cholesterol in an average mature HDL particle. LDL particles carry 15 to 1800 molecules of cholesterol. VLDLs carry 5 to 6000 molecules of cholesterol. But what do HDLs? Why are they the densest particle in a centrifuge? High density. They sink in a centrifuge because they don't carry lipids, they carry proteins. And it's the proteomics of an HDL particle that is brought to tissues. And if they're carrying good proteins, anti inflammatory antioxidant proteins, anticoagulant proteins, immunological proteins, they can do wonderful things. We have 28 times more HDL particles in our plasma than LDL particles. Remember an LDL particle count. If you are doing the NMRS you mentioned, you're maybe happy if it comes around 1000 nanomoles per liter, 1100. That's an average probably safe in most people. LDL particle count. LDL particles are reported in nanomoles. Now, if you're getting the nmr, you get an HDL particle count back. They're counting HDL particles in a very different way than Apoa1, which is faulty. But the HDL particle count is 38, maybe 40, 35. But it's not in animals. It's micromoles per liter. If I want to convert micro to nanomoles, I have to multiply by 1000. So if your HDL particle count is reported to you as 38 micromoles and your LDL particle count is 1000, you actually have 38,000 HDL particle nanomoles of particles. But so that would tell you. God, we got quadrillions of these HDLs floating around and we have distinct subpopulations of HDLs because each HDL can carry every protein. They each carry a couple of proteins. So we have groups of HDLs that do anticoagulant things. We have groups of HDLs that do antioxidant things. We got HDLs carrying tumor things, antibodies that can fight carcinogens. So you and I can't measure HDL function. There's no such thing as a total HDL functionality tests. We have one or two Things that you can order experimentally that check one aspect of what HDLS do. But we're never going to know what HDLS do until we do advanced proteomics coming but years away. So that's why HDLs are out of the picture. An HDL cholesterol level or an APOA one can tell you zero about the functionality of our HDL particles.

But the particle number, that can be helpful for protection if you have.

Because NMR reports have functional HDLs, but if you don't having a high HDL particle number, I can show you articles where They've measured both APOA1 and HDL particle count. And these people had very high HDL cholesterol. That means above 75-80mg of HDL cholesterol. And yet a bunch of them got coronary artery disease. And when they analyzed it came down to other. Other proteins that the HDL was carrying.

I'd read some things where they, you know, obviously the HD number in males and females is a little different. Optimal.

There's a gender difference like there is with HDL cholesterol.

But you get to a point where as it gets higher, it's more likely to have dysfunctional hdl. Does that hold true or is that still.

There's just no way to predict. There are people with very low HDL cholesterol now. Most of them are at risk for atherosclerotic heart disease. And I'll tell you, has nothing to do with their low HDL cholesterol. Low HDL cholesterol is a signal that something else is floating around and that's what's causal. Turns out to be guess what apob. The first thing you should do if you see a person with low HDL cholesterol before you say, oh my God, you're at risk for some cardiovascular complication is measure apob. And if it's normal, you can pretty much ignore their low HDL cholesterol unless it's extreme Low HDL under 20. That could be a certain genetic disorder. But if it's in the 30s, virtually all of them will have a high APOB. All those early studies, Framingham, Mr. Fit, you name it. Which suggested to us that low HDL cholesterol is so dangerous they never adjusted for apob. Once we have gone back and done that. Now HDL cholesterol disappears as a risk factor and HDLP emerges.

And where do you. From a clinician's perspective, because I'm ultimately a clinician, that kind of information. Where do you find that is that going back to like, is that in one of your lipidology journals that comes out or is that just you? You're in, you're still self studying, self learning and you're digging into stuff.

All I can tell you is self learning is a lot easier than it was in my day where I had, you know, spent hours in libraries in stacks. There was no Internet where I could look up stuff real quick. So it was a lot of unnecessary reading and reading things I couldn't understand because I wasn't a laboratorian or deep reader. So but now there are great textbooks. You can understand this stuff very rapidly. So maybe you buy one textbook, Valentine's Quiddervich and then when you understand lipids, you can buy the therapeutic lipidology textbook. Or even those textbooks would ultimately get into therapeutics and you will understand. Here's. And this came out in 1960s in a five part treatise in the New England Journal of Medicine. Been around a long time. I don't remember the New England Journal ever publishing a five part treatise on anything. But it was done by the guys working at the nih. They published five Part Lipid Disorder or Understanding Lipids. And all you have to know about that five part thing was they said and they knew it in 19, they knew it in the 50s, but they're publishing this in the mid-60s. We have to transfer our knowledge from lipids and start analyzing lipoproteins. Atherosclerosis is ultimately the end of the day. It is a lipid mediated disease and it's one lipid called cholesterol. But lipoproteins is what traffics lipids in our bloodstream. So if lipids are causing a pathology in anything outside of the brain, because what's floating in lipids in your bloodstream has zero to do with the brain. The brain's got its own lipid and lipoprotein system, but the lipids get trafficked in the bloodstream inside of lipoproteins. And unless a lipoprotein either invades a particle and dumps its lipids or is delipidated by a certain lipid receptor, what the lipoproteins are carrying is never going to get into any tissue. We know the arterial wall lipoproteins have a way of saying it's time for me to leave plasma. The liver didn't clear me, so I'm going to invade a tissue. And the most common tissue that lipoproteins carrying cholesterol invade that it's going to result in A disease is the walls of our organization, arteries. And it's the apob particles that invade, leave plasma, invade the artery, get trapped, and through a multi, multi, multi step process, you have cholesterol plaque, you have atherosclerosis.

So what are, what are some triggers, like before? I also want to ask you about LP because we haven't talked about that.

Yes, that would be the third thing I was going to do on the causal list.

Like what are some triggers that trigger the lipoprotein carrying particles to invade me here at this part of this. Maybe, maybe that gets into endothelial dysfunction, maybe it gets into some other issues like that.

Sure. So every little avenue you talk about is, oh, now here's the 42 steps that I'm looking at, but we'll dumb it down a little bit. So first of all, it is cholesterol deposition in the artery wall. If you do not have cholesterol in your artery wall, you do not, exclamation point, have the disease called atherosclerosis. So it is cholesterol that is the causal agent for at atherosclerosis. But your artery didn't over synthesize cholesterol. So obviously there is what I call an illegal dump job of cholesterol in your artery wall over years, resulting in plaque. The illegal dumping didn't occur last week, it occurred for the last 20 or 30 years. So how is cholesterol a hydrophobic lipid? How are triglycerides a hydrophobic lipid trafficked in your plasma? Because they are. If nobody was bringing triglycerides to your muscles, you would have no fatty acids to oxidize and create ATP. Try moving a muscle without ATP. So triglycerides have to be brought to muscles, but cholesterol here is what is not taught. Has to be brought to almost no tissue in your body, because every tissue in your body. Even if we wanted to talk about the brain, which has nothing to do with your plasma, lipids synthesizes all the cholesterol molecules it needs. So your what is the primary carrier of cholesterol in the plasma? It's the APOB particles, 95% of which are LDLs. So it doesn't take much imagination to realize it's the apob particles that carry the most cholesterol, that if they crash your artery wall, they're going to initiate atherogenesis. And the most common apob particle is LDLs. So we could know how many LDLs are floating in your plasma by two and only two tests. If you want a Measurement of it, I don't want to guess it anymore by using LDL cholesterol or non HDL cholesterol. And that would be apob, or the LDL particle count, which for decades was only brought to us through nuclear magnetic resonance. But Quest probably 10 years ago brought a secondary apparatus that can count APOB particles and it's called ion mobility transfer. The first, I got to get a little history here. The first back in the 30s the way we knew there were particles that carrying cholesterol because it used to be thought cholesterol was like potassium, just a solute in the blood that floated around by itself. And in 1930s electrophoresis was invented to separate proteins. So let's study proteins. And they discovered alpha and beta proteins and gamma proteins. And they did an electrophoretic with a more advanced type of electrophoresis. In 1940, when they separated the alpha and beta proteins, they looked at other things as good God, there's cholesterol associated with the beta proteins and there's cholesterol with the alpha. Twenty years later, the alpha proteins turned out to be your HDLs. The beta proteins turned out to be the VLDLs and LDLs. So we no longer used alpha and beta lipoproteins. It was now we can put them in the centrifuge, high density, low density, and that's where we are today. Many of us still use the beta lipoprotein because it is APOB. But it was only the 70s when somebody said, hey, there is APOA1 and APOB. Separate them and measure, analyze them and sequence them. So the APO proteins came much later. So it is the APOB particles that leave plasma and enter the artery wall. Why do they leave plasma? To create pathology. Evolution didn't want it that I guess for most of human existence, evolution didn't care about atherosclerosis because you were going to die or something long before you were going to hit age 6 but or 70 and have a heart attack or stroke, some infection or trauma was going to take you out. So ultimately it did become important. So we now know once your APOB concentration, your LDL particle concentration crosses a certain threshold, which we can measure, they will leave plasma and start inverting the artery wall. The higher that level, the more that will leave plasma and invade the artery wall and the sooner you will get atherosclerosis. Depending on the intensity of your escalation of apob, that should make sense. But what is the cause of high APOB in plasma? And it's one thing, your liver's function is to grab circulating apob particles and pull them into the liver. Because what are the apob particles delivering to the liver that the liver must have for a crucial thing that it does? They need cholesterol. So the liver can de novo synthesize cholesterol and it's good at it, but it cannot synthesize all the cholesterol it needs. So it must remove cholesterol carrying particles or delipidate them in plasma to get the cholesterol pool that it needs. So how does the liver get LDL particles or apob particles? Vldl. Because remember, once a vldl delivers triglycerides to the muscles, its primary function, it's only carrying cholesterol, which it delivers to no cell in your body. The LDL is out there floating around for several days full of cholesterol, which it doesn't deliver to any cell in your body. The VLDLs and LDLs are waiting for the liver to express a couple of receptors, mostly the LDL receptors, which is stoichiometrically designed to recognize the apob peptide on these particles. So the LDL receptor grabs apob, internalizes that particle into the liver. It goes into an endosome that turns into what we call a lysosome that digests the particle. And whatever was in those particles, mostly lipids and a big protein, gets dissolved the protein into amino acids, triglycerides, any that are left, fatty acids and glycerol cholesterol ester into free cholesterol and more fatty acids. And then the liver uses those molecular lipid species for whatever it wants to do. But why does the liver need cholesterol? What are the three major things the liver needs so much cholesterol for? The one should be obvious, but you got to go back probably college physiology, early med school, nursing school physiology. You need to make bile acids in the liver and send them down to the gut if you would like to absorb a lot of things, malnutrition, if you don't send bile acids down, cholesterol gets converted to bile acids, by the way. And then bile acids are reabsorbed at the ileum. And most are reabsorbed and reused, but some are not. If bile acids are not reabsorbed at the ileum, they go out. Your bacteria rear end into the toilet bowl. That is the primary way the human body gets rid of cholesterol, changes it to a bile acid, and do not reabsorb the bile acid in the ileum. And there Are forces at play to determine how much reabsorption you get. Number two, what does the liver do with cholesterol? People are going to be shocked if I ask anybody. Tell me what your HDL cholesterol is, and they'll give me a number. Where did that come from, the cholesterol that's in an hdl? Oh, it pulled it out of my artery wall. Well, maybe if you have atherosclerosis, it pulled a few molecules of cholesterol out of your artery wall, which have zero influence on your total HDL cholesterol level, Even though that may be a good process, pulling some cholesterol out of your artery wall. But it doesn't contribute to your HDL cholesterol. So where does most of your HDL cholesterol come from? 40% of it. The liver lipidates your HDL particles. There's a receptor, the scavenger receptor B1, that pumps out cholesterol ester into HDLs. There's another receptor called ABCA1, which pumps out free, unosterified cholesterol into your HDLs. So your HDLs fill up at least halfway with cholesterol. They have another source of cholesterol, which I'll tell you about. Two other sources. HDLs make a pit stop at your small intestine. Your intestine is absorbing cholesterol from your gut, and it absorbs free cholesterol. And some of that free cholesterol, we all think it's going into a chylomicron and going to be brought into the circulation. A large part is efflux into HDL particles that make a pit stop at the blood barrier to the side of an enterocyte. So a significant amount of your HDL cholesterol comes out of your gut. A clue for any practicing physicians or laymen listening to this. If you have high LDL cholesterol but also high HDL cholesterol, you might be an overabsorber of cholesterol. Because if the intestine is over absorbing cholesterol, it gotta get rid of it, because too much cholesterol will kill that enterocyte. It puts some of it in an hdl. All right, so your HDL is filling up with mostly liver cholesterol, maybe 20, 30% from the gut. Where does the rest come from? HDL particles can stop at any cell in your body that says, I have too much cholesterol. Too much cholesterol in any cell will crystallize and kill that cell. So evolution has given our cells great power to efflux Cholesterol, but it has to efflux cholesterol to a cholesterol acceptor protein, APOA1. So if I'm a nose cell or a kidney cell that says I got too much cholesterol, it's going to crystallize and kill me. I upregulate ABCA1, a membrane cholesterol efflux protein, so that free cholesterol can come out of the cytosol of the cell and join into a baby HDL particle. The HDL pulls unwanted cholesterol out of cells, a source of cholesterol. The HDL then has an enzyme that rapidly esterifies the free cholesterol to a fatty acid. Cholesterol ester goes into the core of the particle. Hydrophobic makes the particle get bigger. The amount of cholesterol being effluxed out of your peripheral cells is trivial. It contributes a little bit, but not much, just like pulling out of your artery wall, because most cells are not over producing that much cholesterol that they have to get rid of of. But it is mother nature's protective way to avoid cellular cholesterol toxicity. So where is the other significant part of your hdl? Cholesterol has come from? Wow. So if an HDL now has accepted cholesterol and is a big, fat, large mature hdl, it can go back to the liver, be delipidated, it can go back to the intestine, be delipidated. But before it gets dilipidated, it's got that final source of cholesterol floating around. There are, like I said, 28 times more HDLs than LDL. So they crash into one another. And once they align, there's a protein carried by HDLS that gets activated. It's almost, it sticks straight up and it's almost like a needle sticking off of the HDL and it penetrates the LDL particle. It's a lipid transfer protein. So the cholesterol ester, which your HDL is full of in its core, gets transferred out of the HDL into the LDL to make room for the cholesterol in the ldl. The LDL says to the hdl, wait a minute, if I'm taking your cholesterol, you have to take my triglycerides. So it's a one for one swab. Cholesterol exits the HDL, goes into the LDL triglycerides, which is about 20% of the core of an LDL. So an LDL has a lot of triglycerides and HDL has none. So to Speak. But before you know it, all of the cholesterol in the HDL is now in an ldl. Oh, and you mean the good cholesterol suddenly became bad cholesterol? That demonstrates the absurdity of those terms. So the LDL says, thank you, hdl, I'll bring it back to the liver and save you a trip. The primary function of LDLs in our plasma is to return cholesterol to the liver. That's a major part of the reverse cholesterol transport process. Now, look, it's a combination. HDLS pulled it out of the cells. Without that, cells would be dying of cholesterol excess. But the HDL said to the LDLs, you complete the touchdown, it's like a forward pass to a tight end. He carries the football into the end zone. The LDLs carry the cholesterol that used to be in the HDLs into the liver. That is called indirect reverse cholesterol transport. 40 to 50% of reverse cholesterol transport. By the way, the HDLs can also be delipidated at the liver. That's direct RCT. So total RCT, reverse cholesterol transport is direct HDL mediated, indirect LDL, a little bit VLDL mediated. So you have to remove the apob particles from plasma, and that is the sole bailiwick of LDL receptors.

So let's transition to the lp, which you said is, I think, the third causative agent for disease.

Atherosclerotic.

Yes.

Yeah.

And so where does that fit into everything that you just mentioned? Or is it its own creature that has a different.

Oh, it's its own creature, but it's a lipoprotein. So they were right in the 1960s when they said atherosclerosis is a lipoprotein mediated disease, and it's because of what lipoproteins carry that disease results with the regular apob particles. It's the cholesterol they're carrying. Has nothing to do with the triglycerides they're carrying, or certainly not the apoa one that they're carrying and everything. By the way, the last part of my APOB story was clearance of APOB particles is mediated by the liver manufacturing and expressing at its plasma surface an LDL receptor which grabs the apob particles and pulls them in, completing the indirect reverse cholesterol transport process. If, for whatever reason, your liver has not manufactured enough LDL receptors, or guess what your plasma apob level is going to be. It's going to be high, then where are the particles going into your artery wall. So if you want to, yes, cholesterol is causal, but it's really the APOB particles carrying the cholesterol. They go hand in hand together. So they're both causal. But what generates APOB concentrations above the safe threshold is dysfunctional or lack of of enough LDL receptors or also their cellular half life. The longer they live, the better. So LDL receptors are the reason that we all have high apob. We don't have enough LDL receptors. We can increase LDL receptors through lifestyle, nutrition or drugs. And that's how we lower apob. All right, so what is lp? Well, LP is a marriage of an LDL particle. An LDL particle is a collection of cholesterol ester, 80%, 20% triglycerides, an entire surface full of phospholipids, a semi soluble lipid and some unesterified or free cholesterol. That's what an LDL particle is. But it is soluble because it's wrapped by a gigantic protein. A protein that binds to lipids is called an apolipoprotein. So there is one basically apoprotein, which is called an apolipoprotein when it attaches to cholesterol, and that's apolipoprotein B. It's the biggest apoprotein that we have, over 500 kilodaltons in our. If you are measuring molecular weights, so that's an LDL particle. LDLs come in different sizes in different core compositions, but there are heterogeneous molecules mixture that has densities in a centrifuge within a certain range. So how do I change an LDL particle into what? Yuri just asked me about lipoprotein little A. I just attach to the apob, the structural protein and ectopic protein that shouldn't be there. And when I attach another protein to apob, I'm going to totally change the function of that LDO particle. Because all of a sudden it's not apob that's determining the function of the particle, it's this other protein. So apoprotein little A. That nomenclature comes from the professor who discovered it, I believe in 1963. Carrie Burr.

1963, yeah. Okay.

Long time ago he was experimenting with lipoproteins and trying to find out what the heck's on these lipoproteins. So he's looking, looking at a bunch of. He was exposing these particles to antigens and he was making the antigen, he was using rabbit sera and he would throw in antigens in. And if an Antigen stuck to something. He's identified something on a lipoprotein we didn't know existed before. And all of a sudden he's antigen is sticking to, or this antibody is sticking to an antigen that's on some of the particles but not on all of them. What the heck is it? So he had to name it and he says, well, wait a minute, it's an antigen on this particle that the antibody is sticking to. I'm going to call it antigen. A small case, not a capital A. So it was lipoproteins carrying a LP for lipoprotein, small A for an antigen. So that's where the initial terminology. Now, long story short, many years they find what the heck is this? A. It's a protein much smaller than apob, but a protein nonetheless that we now know has incredible atherogenic properties. And if you attach it to an ldl, an LDL is basically atherogenic once it crosses a concentration threshold. But now if it's carrying something that might worsen its atherogenesity, oh my God. So who's got, who has the ability to make this apoprotein aa? Anybody's liver. Who has inherited the gene that tells the liver endoplasmic reticulum, the protein making apparatus to make a protein called apoprotein. If you don't have the gene, your liver can't make apoprotein, so you can't have LP particles. Now how do we get our blood types mom and dad and we sort of combine our genes for that's called CO dominant inheritance and that's what LP is. So you get one LPA as the gene, capital L, capital P, capital A in italics. When you're talking about a gene, the protein it creates, capital L, capital P, capital A, not in italics. Genes and proteins italics proteins, non metallics. So if you inherit an APO little A gene from mom, you're gonna, your liver is going to produce too much LP if you acquire from dad. Your liver, if you acquire from both mom and dad, you're going to produce two types of apoprotein because each APO little A creates a slightly different isoform of the APO protection.

Is there a functional utility for apo?

We're starting to understand it. So now if your liver, you have the wrong genes, your liver is going to produce apoprotein little A your liver. Everybody has thought that LDL particles come from VLDL particles that lose their triglyceride. Well, that's where about 60% of your LDLs come from. 40% of your LDLs come from DE novo production in the liver. So your liver is shooting LDL particles all day long. 40% of your LDLs. So when the liver makes a primordial LDL particle, it's taking cholesterol, triglycerides, phospholipids, and it's wrapping them with APOB100. But if your liver is producing apoprotein little A, it has an affinity for a certain segment of the apob. So here comes apo little A. Bingo. It attaches to apob on the primordial LDL particle. Now your liver has produced an LP particle which the liver secretes. Now you have an LP particle floating in your plasma. So we know LDL particles are bad news if they invade your artery wall. But what if the LDL particles are carrying a passenger? What attributes of that passenger might do if they enter the artery wall? Well, for the longest time, because apoprotein has great homology, that means it's very similar to a coagulation protein called plasminogen, which is involved with our clotting system, what's called fibrinolysis, getting rid of clots. But if you inhibit fibrinolysis, you keep clots not good. So look, they thought was, oh my God, apo, it's like plasminogen. It's a defective plasminogen. It's a clotting factor. The last thing you'd want to send into an artery wall is a protein that has clotting attributes or inhibits fibrinopolysis. And there were other fact things in the coagulation system that it looked like APO had the ability to interfere with. So for the longest time, all of the pathology associated with LP was attributed to its thrombogenicity. We now know that it inhibits platelets, it affects tissue factor. So there is of a lot, a lot of the probably coagulation disturbance associated with it, but it's taken a backseat to something else apoprotein carries to make this easy. Apoprotein A is a protein of a certain length. It could be long or short. But the segments of apoprotein little A are made up of loops of proteins called kringles. And crinkles are just a bunch of amino acids, some that bind to each other. So. So it looks like a curlicue named after a Danish pretzel. You know, pretzels are curly looking things. So there is one kringle on the entire APO protein that has tremendous affinity to bind to what we call oxidized lipids, Most specifically oxidized phospholipids. Phospholipids are the lipids that live on the surface of every cell in our body and on the surface of every lipoprotein because they're partly water soluble. That's why they're on the surface of cells that interact with plasma or lipoproteins. But if you start giving a person abnormal phospholipids oxidize people. If you don't know what oxidation is, ask a fireman. It means something's on fire. If you don't have oxygen, you can't have a fire. Oxidant fuels fire. Oxygen attaching to certain lipid moieties causes oxidation of lipids. Oxidized lipid moieties are incredibly dangerous tissue destructive, associated with any number of diseases. So if all of a sudden you have a protein that is a magnet for oxidized phospholipids, when it enters the artery wall, it's basically bringing a particle, it's on fire. So whatever inflammation is already going on in the artery wall, thanks to the APOB invasion is now made 10 times worse. So it's a very pro inflammatory particle.

So I'm not hearing. Typically the way I think about things is when you hear a story like this, usually there's like a negative side and a positive side to having something. And so I'm only hearing downside to the apo. Yeah, lipoprotein little A. And it's an impact on apob and how this is a pro inflammatory plasminogen like particle. Is there actually a benefit to this at all? Is there only downside?

You have to be a teleologist to answer that question. Why did evolution give us an LPA gene? For God's sakes. At one time in our evolution, was it good to produce a lot of apoprotein? And the answer, the thought is now that yes, at one time in our existence it was was good to have a lot of clotting factors because trauma was so prevalent in the early human existence. Falling down, getting bit, scraping yourself, People were bleeding all day long. So those who had a propensity to rapid clotting had survival. Nobody was worrying about atherosclerosis 40 years later. So having a clotting factor was probably good at a certain point in our revolution, but at a certain point it became. Became deleterious. So all of a sudden there's been a loss of the LP gene. And so that's the core. Who really knows you know, now with the way we don't need a coagulation factor today in our blood.

Yeah. So with the way you described it, can you have. Is this possible? I'm just thinking here, having an elevated lp, but if your APOB is low, it won't have anything to attach on and so you mitigate some of that negative impact. Does it work like that or is that, do you, do you always have an elevated apob? If the LP is elevated in general, yes.

Because lp, the risk of lp, is related to its concentration in plasma. And we measure LP particles and basically you're measuring a tiny subsegment of apob LDL particles, so you can't separate it.

Okay. So it's not, not like it's not.

Impossible if you, you see, everything depends on what you consider a normal apob is. If we consider what for the average person is a good APOB might be 80, but it's carrying apo little A, that's probably a very deleterious APOB concentration and we might want to lower it in that patient. That's the novel thinking that's coming below. So whereas in General An APOB of 80 is going to hurt most people, if it's carrying APOL A it is. And if your APOB is in the stratosphere and it's carrying apol, Both, your LP is also in the stratosphere. So it is highly related to apob. The one last thing to figure where we now have dismissed a lot of the coagulation stuff or put it as a second reason LP is dangerous is because if it was such a bad clotting factor factor as one's LP goes up, why don't they get venous thrombosis and they don't. So that for years, once they started analyzing that and the Mendelian study started to show that there's no venous thrombosis in these people. Well, holy crow. So it's an arterial coagulation bad nose protein, but it's not a venous. Turns out it might be, but only for those who like in the 98th percentile of LP, they have so many that there might even be some degree of venous thrombosis in those people. Most people never get that extreme LP concentration. Thank God.

So. So those are the only three directly causal things for atheroscleric disease.

No, there are rather even that CETP I mentioned. Well, maybe I didn't mention that little tube that transfers cholesterol between an hydrogen HDL and in ldl, its name is cholesterol ester transfer protein. It really ought to be cholesterol ester triglyceride transfer protein because it's transferring lipids in two ways. But they shortened it. What's the abbreviation for cholesterol ester transfer protein? Cetp. So we know that people who have genetic loss of function of cetp, guess what they have. They cannot transfer cholesterol from their HDL to the LDLs. Their HDL cholesterol is in the stratosphere. 140, 150. And yet they that seems to be a longevity gene. They don't seem to get atherosclerosis. So there no doubt there are other genes that are causal. So I named one there apoc3 and you almost have to bring me back for another lecture to get into the complexities of that that is causal for whether you have gain of function or loss of function. Loss of function, longevity gain of function. You're going to be seeing a lipidologist early in your life. So there are other genes affecting lipids that are causal for atherosclerosis. But we can only discuss so much. Most people are not measuring Apoc3. Yeah.

I've not heard about Apo C3 before actually.

So it's a big longevity gene. It's one of Peter's favorite genes. But you want to have a loss of function.

Yeah.

Most people have data function.

So as far as like a lot of the other non causal associative factors like hscrp.

Yes.

Which some of the original statin homocysteine measure.

Yeah.

Fibrinogen, which is a clotting factor and so many things.

Any other inflammatory marker you may be measuring other than CRP, LP, PLA2, MPO.

All of those ADMA, as long as.

You see them, you worry. But ultimately at the end of the day you're going to lower apob. That's going to be the way to treat causality. And all of those markers are way more dangerous if the APOB is high, if not. So you're always going to circle back to apob. But let's say I have two patients with apartment APOB that I'm a little worried about. If one it's APOB and I can find nothing else. But in the others I find homocysteine, fibrinogen, you know, high absorption markers, APOE 4 strike 1, strike 2, strike 3, strike 4 on top of your APOB. So you don't dismiss those things. They're worth measuring. But at the end of the day you could the and there's studies with a lot of them that lowering it. Them things by themselves don't matter. You gotta lower apob. And in the process of lowering apob, I think you should use other therapies that probably do mediate at least homocysteine or some of the Omega 3s if you're out of whack. So there are many other things you might want to address on top of apob. It's not all APO B and you're done. There are these other factors including building muscle mass and you know, nutritional aspects.

Control your insulin level, getting your A1C down.

Yeah, that's a whole nother ball game. And look, the low HDL cholesterol, who do you really see that in? Who's going to get a heart attack? Insulin resistant people. And what do insulin resistant people have? If you knew how to measure it and respect it at a certain degree a triglyceride excursion at a certain plasma level of triglycerides. And it's way before 130 triglycerides start entering the HDL particle. And when a triglyceride goes into HDL it knocks out a cholesterol. So the real reason diabetics and insulin resistant people have low HDL cholesterol is it's a hypertriglyceridemic state that's depleted the HDL and its cholesterol and put a molecule that it. An HDL should never carry trigs. If an HDL is carrying trigs, it becomes a substrate for a couple of lipases. Hepatic lipase first and then endothelial lipase. They hydrolyze the trigs, which are now the major lipid component. The HDL shrinks down to such a small HDL it breaks apart APOA one goes to the kidney where it is catabolized into amino acids and gets peed away. And that's why diabetics have low HDL cholesterol. Low Apoa1 triglycerides has induced destruction of their HDL particles as well as induce some degree of inflammatory dysfunction to the HDLs too. So it all ties into trigs. But what is the goal of therapy when you treat trigs? Non HDL cholesterol. If you're not measuring apob, that's the guideline goal of therapy. It's not to lower trigs to this level, that level, that level, because there would be zero trial evidence supporting that. But in all the trials that lower trigs, they only reduce MACE if they've lowered APOB or non HDL cholesterol. So again, do whatever you got to lower trigs through lifestyle, blah blah blah, maybe drugs. But at the end of the day, APOB is what you're measuring to attest to the efficacy of your multitude of treatments.

So a lot of information. So we'll make a transition now to therapies which you've kind of alluded to and you mentioned there's four major therapies to get in this world. One of the things like in the functional medicine world, we focus on inflammation, the homocysteine, HSCRP, inflammatory markers, all that kind of stuff. So. So what I want to do is I want to focus on like the medication therapies that you kind of talked about to get these things down. So what are these four major class.

Is referred to so easy. It was so hard for most of my life because first we had an unusable drug called a stearamine. We had niacin which proved that we were probably hurting people. Vibrates very select.

Where's well called? You consider well call.

You put that with bile acid sequestrant has the ability to bind to bile acids and you excrete them in the stool. You really can't reabsorb them. Your liver uses up cholesterol which induces LDL receptors. Bile acids equestrians can only bind to X number of bile acids. So well call was an engineered part of molecule that binds to way, way, way more bile acids than can a bile acid sequestrate. So it's called a bile acid polymer. So you will just excrete a lot more bile acids if you use well coal, which is a more usable usable than the old. I don't hope anybody's not using cholestyramine anymore. Well, cola it turns out through other actions can actually lower glucose improvements and sensitivity. So there are other reasons to consider well call and it's not absorbed, so it's great for a pregnant woman. A drug you can putz around with cholesterol if you need to. So that's where well call sits. So right now if I want to lower apob, my therapies have to make the liver produce more LDL receptors or whatever. LDL receptors exist, let them recycle, live longer. I told you. LDL receptors grab the apob particles, pulling them into the liver. What should happen is the LDL particle gets dissolved in the lysosome, but the LDL receptor is freed up to go back to the surface. So if that happens, LDL receptors can recycle many times over a few days. But if your lysosome decides to destroy the LDL receptor, it cannot recycle. So just keep that in mind. So it would be good if we could trick our lysosomes into recycle the LDL receptors, please, because we need them. But once the LDL receptor is at the surface of the liver, extending into plasma, you clear APOB particles a lot more. So the drugs that we now can write to lower apob and they're so typically an algorithm we go through because of cost. If we didn't, cost wasn't aside, we'd all be using maybe the most expensive one because it's the most potent way of lowering apob. But here's where we start. So how do I make your liver make more LDL receptors? What determines how many LDL receptors the liver makes? The pool of cholesterol in the liver. If the liver pool is full, it doesn't make any LDL receptors. You can't clear APOB particles. But if all of a sudden you can make the liver have a deficient cholesterol pool, the liver is going to, I got to get LDL cholesterol. I got to get cholesterol. It's going to manufacture and express LDL receptors. They make them at the endoplasmic reticulum, and they transmigrate to the surface of the liver. Grab the apob, pull it in. All right, so how would I deplete the amount of cholesterol in your liver? I got a couple of ways. The most commonly used one is, let me just tell the liver to stop synthesizing cholesterol. And that's where the statins came into play. And they discovered that in animals long before they knew, let's try it in humans. And it worked. And before they even knew it worked, somebody had to discover LDL receptors. And the two guys who did that, Goldstein and Brown, won the Nobel Prize for discovering LDL receptors. So if I prescribe a statin, you inhibit cholesterol synthesis in your liver. By the way, the liver, because of its size, is the king organ in the body at expressing LDL receptors. And the only one that, once it clears APOB particles, can digest them and get rid of them. You don't want other cells internalizing LDL particles. So fortunately, we inhibit most of the species synthesis of cholesterol is going to be in the liver. Less cholesterol, the liver makes more LDL receptors. You clear more LDL particles. APO B goes down, LDL cholesterol goes down. Usually, LDL cholesterol goes Down a little more than apob. That's why you should follow up with apob because you may normalize LDL receptor and not normalize apob. So it's wise to do the best blood test now that it's readily available. Any insurance company is not strengthened to tell you not to order people. All right, so is there another way I can deplete the cholesterol pool in your body? Well, what is a big source of cholesterol other than de novo synthesis? Our intestines absorb cholesterol and they put it in our biggest lipoprotein, a chylomicron. The intestine takes absorbed cholesterol, puts it on both the surface in the core of the chylomicron, secretes it into the lymphatics. It goes out through the thoracic duct it into the systemic circulation. Primary purpose is deliver all the fatty acids which are incorporated into triglycerides to your muscles. Hey, muscles, here's your energy for supper tonight. So the tissues that express the most triglyceride dissolving enzyme, lipoprotein lipase, are your muscular beds. So here's the chylomicron particle, attaches to lipoprotein lipase. Lot of free fatty acids. They just enter the muscle cell. The chylomicron shrinks down carrying very little triglycerides, mostly cholesterol. No cholesterol is given to the muscle cell. The muscle makes all its own cholesterol. It doesn't need a cholesterol in delivery. So the chylomicron then is cleared rapidly within minutes by the liver. And the liver recognizes something on a chylomicron that induces its clearance. The apob on a chylomicron is half the size of the APOB on all our other particles. APOB 100 on V alleles and alleles, APOB 48 coming out of the intestine. We have a receptor that binds to ApoB48, LDL receptor related protein LRP. But what is the major ligand for LRP? ApoE. Chylomicrons carry several copies of ApoA. Once the chylo shrinks, ApoE conforms to a ligand binding conformation. Your chylomicron is gone in minutes. The half life of a chylomicron is minutes. Plasma residence time a couple of hours. So absorbed cholesterol gets brought right to the liver. Thank you. The liver says, I got all the cholesterol I need now, but what if I block the absorption of cholesterol in the gut and herbs? A few ways of doing that. Nowadays the Most potent way is to prescribe a drug that inhibits cholesterol absorption. Ezetimibe, brand name Zetia. People who have loss of function of the transporter that pulls cholesterol into the gut have hypocholesterolemia, hypobatal lipoproteinemia. They get far less heart disease. So we know reducing cholesterol absorption reduces heart disease. Proven by Mendelian studies of the Neiman Pixi 1 like protein also now. So, okay, I can now deplete cholesterol synthesis in the liver. I can reduce absorption of cholesterol from the gut, depleting the cholesterol pool. We do have a backup way to inhibit cholesterol synthesis nowadays. It's called bempedoic acid. Nexclitol. It inhibits a different step in the cholesterol synthesis chain. Not quite as potent as the statins which inhibit the rate limiting enzyme. But nonetheless, I can further reduce cholesterol synthesis. If I combine bempedoic acid in the statin, I can really shut off cholesterol synthesis. But even by itself, bempedoic acid shuts off enough cholesterol synthesis that the liver will have to get cholesterol. Cholesterol elsewhere upregulate LDL receptors pulling in your particles. So ezetimibe statins and bempedoic acid all lower apob the statin. It's dependent on the dose you use. Ezetimibe, there's one dose, you can even use less of the one dose. Intermittent dosing and you pretty much get the same efficacy. Bempedoic acid, there's only one dose, you never have to titrate anything. So and by the way, the amount of LDL receptor upregulation you get with a statin, 80% of it occurs with the lowest baby dose of the statin. As you double, triple, quadruple the dose of the statin, you get 6 to 8% more. Far less efficacious I say all you get is side effects by doubling and tripling the dose of a statin. So we should all. Whatever your favorite statin is, you should be looking using the lowest dose. If you're a rosuvastatin fan like I am for a variety of reasons, 5 milligrams of rosuvastatin you get almost like a 38% lowering of APOB. That's as much as higher doses of other statins, for God's sakes. So of course, adding ezetimibe to a statin or bempedoic acid to a statin if need be. You can get a lot more APOB line by itself ezetimibe or we'll lower 15 if you're lucky, 20% of APOB bempedoic acid a little bit higher 20 to 23%. So now the howitzer that we can take out if needed is our last drug, which as you know, our PCSK9 inhibitors. And we have two types now one is monoclonal antibodies that bind to PCSK9. And the other is at small interfering RNA. Drug that goes into the nucleus interferes with RNA, so you can't translate the the RNA, the messenger RNA that comes out. Your liver stops making PCSK9. So then you obviously have less PCSK9 through that mechanism. So what the PCSK9 does is remember I told you LDL poly receptors recycle. The PCSK9 does not let the LDL receptor get by inhibiting PCSK9. The LDL receptor will not be catabolized as readily in that lysosome. PCSK9 tells the lysosome destroy the LDL receptor. So if we can inhibit PCSK9 the LDL receptor gets to recycle many times the more you recycle your LDL receptors. People be. Now think of this. What If I upregulated LDL receptors with the first three drugs I mentioned and then I draw a PCSK9 on top of them. Goodbye Apob. Remember, all of the PCSK9 studies have been done on top of at least statin or Ezetimibe monotherapy. There's small ones on top of bempedoic acid that didn't work. I haven't seen a triple therapy yet. Statin, ezetimibe and pcsk9. But I can tell you in practice I've seen it used many times for the apobe nightmares of the world. So that's it, doctors. And here's what I will tell you. When Ezetimibe is like next to zero side effects, you have to know one you should inform the patient you're affecting the makeup of sterols in your biliary tree. And gallstones are due to both bile acids and cholesterol in the bile. So there's this minuscule trivial evidence that has maybe been seen in the trials of Ezetimibe and suggested even in Mendelian studs gallstones. So you alert the person. We'll deal with that should they occur. A minuscule number of people might get mild transaminosemia. We don't even know if that means anything. Very rarely will you triple the transaminases, which is where guidelines tell you to back off any drug tripling aminases, even though nobody's proved that that's harmful even at that level. But most would stop it. So you're going to measure transaminase periodically after ezetimibe bempedoic acid. Look, there's a trivial chance that given to the wrong patient you could elevate uric acid. So you never give it to a patient who's had a lot of gout, or if they have had hyperuricemia, you've controlled it through other mechanisms, then it's probably safe. The uric acid excursion is small, but you wouldn't want to precipitate Galpa. If I had a gout propensity patient where for some reason I couldn't tolerate everything else and I had to use, I would warn them gouto swelling the knee, call me up and we'll deal with that if it occurs. I don't know of any other side effects of bempedoic acid. I can tell you a lot of maybe benefits that are going to come, including the elimination or de escalation of insulin resistance and diabetes. But that's again a lecture for another day. And then you have the PCSK9 inhibitors and I don't know of any side effects of them right now. Now you know we've got at least 5, 6 years worth of data on them. We don't have 30 years of data like we do on the statins, but so far very safe drugs. We have more data on the monoclonal antibodies than the sirnas. Sirnas? For those who don't know, they're much longer acting. So the monoclonal antibodies, alirocumab, evolucumab, pralant, repatha that people use every two weeks, it's a minor injection, whereas the SIRNA drugs, baseline injection, three month injection, then every six months thereafter because it really interferes with the RNA through a complex mechanism for a long time. It's very hepatoselective. By the way, bempedoic acid only works in the liver, can't affect any other cell in your body. So the last thing is the statins. If you're going to be a statin writer, there are things you have to know about. So yes, you can get apo beta control and you will drastically reduce mace. That is not even arguable that I really do reduce the number one killer cause of morbidity mortality in the world. But at what price so we will look at the aminases on statins again. An extreme minority. We'll have elevations of transaminase at a certain level that you might cut back or stop the statin two. We have this. Oh my God, you'll cause diabetes with a statin. Now at a molecular level, statins in some people, mostly those genetically prone to insulin resistant can. If you're measuring very complex markers of insulin resistance, you will see statins do aggravate insulin resistance in some people. And ultimately if you aggravate insulin resistance and type 2 diabetes is a loss of insulin sensitivity, you will get a glycemic excursion that might put you into the pre diabetes level. Glucose of 100 might cross the barrier of 126 where I can say you a type 2 diabetic. So certain people on statins have gone into oh my God, you're now a pre. They were mostly people who had a sugar of 96 or 94 as opposed to 76 for people who don't have who have great insulin sensitivity. And ultimately if you must continue to statin because that's the only way you get APO B to control they may actually cross the 126 threshold. It's almost always in obese insulin lost people who have already loss of insulin sensitivity who you probably are going to get that with a statin. So you watch for it. But we also know that even though I may cross some barrier that changes the definition of what is diabetes or not to me diabetes is a glucose of 8890 where I know you're on your way insulin most of the time. So I don't need a sugar of 126. And the bad all the microvascular complications of glucose can occur long before a glucose of 100 or 126. So but I'm still reducing mace in these diabetics, the leading killer of diabetics. So I can deal. And if I really do put you in a diabetic threshold, obviously easiest thing would be crack the lifestyle a little bit improve their insulin sensitivity. But God, the list of pharmacology. We can reduce insulin sensitivity if you feel you have to with a stand. Why are they not all on wegovy or zip down nowadays if that's what's causing their insulin resistance and they're not going to do lifestyle or it doesn't work in them. So we have solutions to that too. That's pharmacology in a nutshell. It's so easy and the statins are the only ones you almost have to maybe worry about.

So that's a lot of information, a lot of useful information. I almost want to transition to like a lightning round thing.

Go ahead.

And I'm actually the lightning round actually the first thing is going to have to do with the statins and the increase of lp. What are your thoughts about that?

I'm so glad you asked me that. Because atherosclerosis is a apob mediated disease. It's cholesterol in the artery wall. But if you got the genes that make apoprotein X percentage of your LDL population are going to be LP particles. So you should be measuring LP in molar concentration. That's nanomoles per liter. If it crosses 50 nanomoles per liter, you enter the world of LP mediated risk. At a level of 125 nanomoles per liter, you entered a world of wow, you're in big trouble with LP. That's 125 nanomoles of LP particles. If I took that same person now has an LP of 125 and I counted the number of LDL particles that don't have apolo little A attachment is an easy way of doing that. I would find it's 1800 to 2000. So, okay, so I don't want you to have an LP of 125 and I sure as hell don't want you to have a regular LDL particle count of 1200, 1500, 1800. So I'm going to give you a statin that may in X number of people increase the number of LP particles. We now know how it does it, but we can get to that if you want to. But if I give you a statin, probably a rare instance, I should actually repeat the LP to see are you one of the ones. So if you have an LP of 125I may increase it to 130 to 150. But your LDL particles without L apola attached, I've reduced from 1800 to 2000 to 1000, drastically lowered your cardiovascular risk. So the trivial increase in LP particles is abrogated by the drastic reduction of non apo carrying LDL particles. And that's why the few trials we have where they actually looked at LP and people on statins and that Jupiter is the biggest trial that looked at that. They looked at their people with abnormal LP and they all were on statins, rosuvastatin or placebo. And in the people with lp, the rosuvastatin reduced mace. It didn't reduce it as much as it did in the people who didn't have lp. So what we say is the statin reduced residual risk. Unfortunately not as bad as the people who weren't gifted with lp but it helped you. So the statins worked despite the fact in Jupiter it raised LP particle concentration. So if we're on the camera right now it increases LP that much and it drops normal LDL particles.

So it's an issue of just degree.

It's like the statins raising glucose at the end of the day they reduce heart attacks. But yeah, there's a little you wish you in raise glucose. I wish the statins didn't raise LP in most people. It's a trivial raise that is of zero concern. The Internet frauds use this as a way why you shouldn't use statins. It's ridiculous. Statins help people with lp. Any guideline that you pull out now says if you have an LP that's in the at risk concentration after you've done whatever lifestyle if your LDL C is still high like apob, prescribe a statin to lower LDL cholesterol. That's the first guideline suggested treatment for LP. And look to that you can add ezetimibe, you can add bempedoic acid but the little hey and you better be rich because your third party payer isn't going to pay for it because there's no FDA indication. The only drug we have nowadays that lowers LP by preventing the synthesis of LP particles in the liver is the PCSK9 inhibitors at 25% or so lowering. So should you take a PCSK9 inhibitor? Yes, if you need to get APO beta control but and if I had high LP personally I would be taking a PCSK9 inhibitor but maybe I can afford it whereas the running it's $6,000 a year that you're going to have to pay for it.

So. Well, I'll ask you actually an educational question about patient and we actually talked about this before we went on the video today the concept of hyper absorbers we kind of briefly ran over it and I'm thinking about an individual in my head who cholesterol if I remember correctly 283 hundreds reacted poorly with statins, reacted poorly with the zetia, couldn't tolerate alcohol so went through the list of things I've not gone down the PSK9 rabbit hole with her, did massive dietary changes. We actually did measure her phytosterol levels and that was I think it was Boston Heart Labs I think was yeah.

They'Re pretty Much the only one.

Yeah, it was a little bit of a hassle to get. She did herself, went to the website and all that kind of stuff. Yeah, it's a little different.

You're not affiliated with that lab. It's tougher to get.

Yeah, yeah. So because we're.

By the way, there is Empower dx, a company that uses direct to consumer. They will mail you a lancet and a minuscule tube that you have to put like four different drops of blood in. And they take that and they send it to Boston Heart and you'll get the exact same sterile pill.

Empower dx, I'm familiar with it actually. So they could, they'll do that.

They have a cholesterol panel that looks at the sterile markers. Okay.

Do you have any idea what the cost of that is?

99.

Oh, okay.

Yeah. So it's ways cheaper than the insurance. And look, if you had to pay cash for it at Boston Heart Labs, it's probably more than 99. Correct?

Correct. Yeah. I'm not gonna crip the numbers in my head because I'm not 100% convinced about it. But anyways, this individual got it to like 170, 180 with an incredibly restrictive diet. Like just crazy, crazy restrictive diet. So I'm kind of thinking, okay, we've tried a lot of other things. You know, she has not done a PSK9 right now. But one of the things is now this individual is almost malnourished. And so I'm at the plague where it's like, okay. And no, no diabetes, no blood pressure, no other risk factor. Risk treating numbers. And it's one of those things where it's like, is this individual by restricting their diet so greatly.

How old is facial?

She's in her 60s.

Okay. So at an age group where somebody could have atherosclerosis, especially if it's gonna.

Be like, it's gonna be 58 to 60. 58. 58.

Have you done a coronary calcium or any other imaging?

Yeah, we did CIMT as well and it was fine.

So zero cac?

Yes.

And even carotid? No carotid.

Yeah. We did a CMT in as well as ultrasound. The CMT showed her vascular age and her chronological age were within like one to two years.

So look to me right away that tells me in that 60 year old woman with a CAC of zero. And I put more weight on that than I do the imt, but mostly because there's more data on it, you've got at least 10 years to worry about an acute coronary syndrome. So you got time to play. So whatever I was doing nutritionally was making her malnourished. I back off of the nutritional advice I'm giving her. Maybe you're restricting saturated fat or something too damn low, even cholesterol in the diet. If she's not a hyper absorber, restricting cholesterol in the diet is a total waste of time. So I wouldn't use that. That might be even somebody. If she's not a hyper absorber, where giving a phytosterol or better yet, a phytosteronal supplement would help her. Lactobac bacilli, which reduce cholesterol absorption would not now nourish her, but at least could. And even in a normal absorber, if you've measured sterols and she didn't have hyper absorption. Reducing absorption will make the liver grow more LDL receptors. That might help you lower apob. If all of those drugs. You said she didn't respond. Now I want to know, is that because of side effects?

Side effects? Muscle aches, pains, fatigue.

Then I don't know what the hell to tell you. But if the patient comes back and says, I can't tolerate this drug or that drug, you pretty much have to believe them. You can't force a drug down there. They won't take it. So you're fooling yourself if you. So I, I don't know what you tell somebody like that, but I, I would back off on a diet to malnourish them, especially if I KNEW I had 10 years to play. If she had coronary plaque to that degree, I'd let her know. And what would you consider Life is in your hands.

And what would you consider like your Calcist scores are 0 to 100, 100 to 400.

Would you.

Would you say a score less than you know?

There was a nice study probably two years ago that came out, says you are in the same risk as somebody who's had an MI if your coronary calcium enters the 300 range. So that's the nightmare range. But as a preventive lipidologist and corona. I'm not a cardiologist, but we have the American Society of preventive Cardiology to which I belong. Even those type of cardiologists look for primordial prevention, which is what she would be ugly cholesterol metrics, apob metrics where we probably should lower it, but we have 10 years to lower it. But therefore any coronary calcium being positive would tell me I don't have 10 years, years. I don't know if I have eight years, five years, four years or two years. What I might do in that person is progress to a CTA with the clearly studies where they can see non calcified plaque. And regardless of whether you have calcified plaque or not, you can not only see non calcified plaque, but you get estimates on the vulnerability of that plaque. So it's a little bit more imaging costly. The third party payer isn't going to pay for it. So you're talking a few thousand thousand bucks, especially if you want the clearly or something regular rather than a regular cta. So there are more advanced imaging things you can go to if possible that might twist your arm. I got to get a drug in there.

I think locally, I guess we lost power here. I think locally insurance will pay for the CTA aspect and clearly evaluation is like 6 or $800, I think to get it. So you know that more than I do. Yeah, that's a good point. And I guess just for the audience because Clearly I think Dr. Tia mentions it in his stuff. I think it's part of his thing.

So I don't use it a lot. But we're actually experimenting a bit now to see what we are learning from it.

Why don't you tell us a little bit about that? That's something we have available here in the Richmond area that I've had a few patients ask me about.

It can give you other parameters of blood flow through the arm. Any fractional blood throw through either a true blockage or a dysfunctional blockage that is impeding blood blood flow. So if you have a little bit of a plaque and all, you know, X amount of blood should be flowing through that at a certain point where that fractional flow diminishes. And there are numbers that tell you, oh, that's no good, then you're into, you better do something about this. Now it doesn't mean you need a stent or anything if you're asymptomatic, but it does would call for more aggressive lipid management. So you would look at that. That's pretty much the main parameter of.

The reporting and my understanding as well also gives you a little bit of. They'll tell you about the wall thickness. So you might have an opening, it's clear, but then you might have a thickening until you've got some degree of.

Yeah, and you know the one problem with that in my mind too, and Peter Libby gets into this in all his inflammatory discussions and everything is yes, we have plaque and we have plaque erosion and plaque rupture. But there is something called the plaque erosion, which is a plaque that doesn't extrude into the lumen and may not even be associated with a lot of lipid abnormalities. But it's close to the endothelium and it causes erosion of the endothelium, which exposes the blood flow, mostly the coagulation system, to now the surface of that intracellular plaque. And it can induce a lot of hemodynamic changes, spasm and also so perhaps even clotting. And I don't know how you diagnose erosion, and I don't think it clearly tells you much about that. Now, that's a minority of plaques. Most of the plaques are the. You're going to see them and their dysfunction are going to rupture and cause.

So back to the coronary artery calcium. Like, because I get people and unfortunately sometimes. And it's which cardiologists do patients see? Right, so.

Oh yeah.

So like the patient's like 65. They have a calcium score of like, like 40 or 50. I'm kind of like, well, that's actually kind of low for your age. And then they see the cardiologist and they're like, oh my gosh, low for.

A 60 year old. But if that was a 35 year old, that's a 99th percentile, correct?

Well, it's all. That's devil's in the details, right? Totally, yeah. And so do you have a particular paradigm because you mentioned with this one individual, I'm thinking about score of zero. You're like, you got 10 years. So let's say you're in your 50, let's say 55 to 65 range. What calcium score would you think of? Like, okay, we've got eight years, you know, is it less than 40, 30? Is it going to be in the.

Real world that we have to make any decisions you make what. And it's age dependent. So rather than the absolute, you look at what percentile they fall and what Z score sort of is their particular parameter. And the higher the percentage, the more likely I'm gonna, I don't know if I got 10 years with you if. And I'm going to treat it.

So you're going, you're going totally off the report proper because it gives you those numbers on the report.

And then look, this comes down to what we've always called the practice in medicine. Sooner or later, as a doctor, you've got a lot of information, but you're going to have to make a darn decision, for God's sakes, based on your wisdom, your years of experience. It might just be an educated guess in some instances, but it's better you have an educated guest than their neighbor has an educated. Educated. Yes. So we have to do that sometimes. So we use numbers like that. If you're in a practice that is 100% devoted to longevity, and not only longevity, but when you reach old age you have health span. So you have none of the chronic diseases and you can enjoy longevity. You pretty much. I know Peter has said it on podcasts. If you listen to to some of his Instagram nightly 32nd, I don't know what they're called on his posts on Instagram. He gives some good stuff there. Peter looks at it like if you had somebody that had a bacterial infection, you eradicate that pathological bacteria. He thinks APOB is causal at a rather low concentration. The Mendelian study showed if you have hypo beta lipoprotein anemia, you don't get atherosclerosis. If you've already had it, you regress it and have a far decrease in mace. So he's of the belief you eradicate apob. So if longevity and health span is what is in your binoculars, you're treating APOB if it's a little bit high and that would be if you have LP above 60, maybe if you don't have LP or two terrific other risk markers of F, you can live with an APOB between 80 and 60, but it's likely to be a lot closer to 60 than 80. So that's what a longevity practice might do. A longevity practice that's written in New York Times bestseller book on how to achieve longevity. But for run of the world physicians where you do have limitations on what you can prescribe and course on what you can prescribe, maybe your apob you live with a little higher apob or you use different levels of apob, but if I have any calcium score, I want your APOB at least a bit lower than what it is and that's presuming you don't have lp because if you have lp, I don't care what your calcium score is. And there are studies showing that lp, although it's a terrible calcifier of your aortic valve, it it doesn't correlate that much with arterial wall calcification. So be careful not respecting LP despite a pretty good coronary calcium score.

So the lp, the primary risk is with aircraft valve calcification not coronary artery calcification.

Yes, you can get calcified arteries obviously, but you can also have non calcified arteries with high lp. So just, just be careful saying oh, your CAC score is zero. I'm not worried about your lp.

Okay, I got you in that context. Not in the context of overall cardiovascular disease, in the context of a zero calcium score. Okay, fair enough.

So look, I think you're going to live with certain amounts of calcium score. You're not throwing a kitchen sink of therapeutics at somebody, but you're going to watch it. The danger gets into repeating coronary calcium. I don't think think we know what that means especially if you're on a drug. We know statins can increase coronary calcification, but reduce me. So should you even be doing CACs again? And there are articles written that, yeah, but you don't mind a little bit of an escalation but if it's really going high and the worry is if you see calcified plaque, you're missing the vulnerable plaque that goes along with the calcified. So I wish we had definitive answers on any of these. We don't miss. This is why it comes down to the beauty of practicing medicine in an intelligent way and making decisions through other.

Information and looking at other labs and other stuff. It's not just simply treating numbers mentioned.

Part of my career was women's health and big time crack that gets even more complicated as a woman approaches perimenopause or post menopause. It even gets problematic nowadays if a woman decides I want to have children children, you better be doing serious metabolic and lipid evaluations before she decides to let's create a little embryo. You know, let's know what my cardiovascular where the embryo is going to live for nine months. It's better to live in a cardiovabetabolic healthy woman. So you want to check a lot of things ideally before pregnancy occurs. If not asat as soon as possible pregnancy occurs.

You look at a lot of stuff I can correct. We actually do that when patients come in for pre pregnancy preparation and we'll do a bunch of metabolic stuff and nutritional.

To be honest with you, when somebody becomes an adult now in a woman, of course they can conceive long before they turn 21. I think guys late teens, 20, 21 by then they need their initial lipid panel and an LP and that's a good start of course with a blood pressure measurement and a waist size measurement measurement. Then you're off to the races I.

Tend to like do those things to be honest with you, when I see kids before we go to college because my thing is like this from the.

Average high five in you with your.

Approach for the average American, unfortunately this is good as it gets you literally and your senior in high school. It's only going downhill from here, unfortunately. I tell them that. So let's check your cholesterol now and I'll see you in four years. Check your numbers, check your A1C, check your A bunch of things and we'll see how college did for you. I was the best health of my life at the end of college, which is not normal. And so it's.

And you know that we have done enough autopsy studies on young soldiers and even non military people who have croaked early and on autopsy. My God, look what's in their arteries. They weren't going to have a heart attack next week, but within the next 10 years. So that's where it takes decades to build up. But if you got the risk factors and you're 20, they've had two decades to screw up your arteries. So yeah, the sooner you look, the pediatric societies want a lipid panel by around the age 8 or 9 to rule out FH. I would say if you're doing a lipid panel doing LP though, you're not going to act on it in a pediatric range group but somewhere in your teenage years.

So this is a question I know someone in my community is going to ask me so I'm going to ask you this question like that. That recommendation only was in the last couple years when PSK9 came to market.

Say about 10 years. At what age you should start lipid screening. Now lipid treatment is going to just pretty much apply to homozygous FH or maybe severe heterozygous fh. And if God forbid your kid has that, you belong in a specialized lipid clinic that deals with children.

It's a different story.

We're talking very different therapeutics approach to that.

I don't personally think I've actually seen.

Yeah, most people in their lifetime would never see that. And in fact if you're doing good family histories, mom has, you know, heterozygous and dad has it. They should both be going to a lipidologist and a geneticist before they get pregnant to genotype them. What's. What are you going to pass on here? What are you not. Sometimes they only discover their own FHS when the kid gets a heart attack. They aging but it's rare.

It's a jog my memory. Like for homozygous and heterozygous. And this is, I realize it's a general question with the cholesterol numbers. If someone has a, you know, cholesterol of over 400, like what are the numbers? I have some gray stuff in my head where that you can think, oh my gosh, this person probably is homo versus heterozygous.

Again, it's a really poor marker because you really have to do more advanced testing. And look, if the LDL cholesterol is above 190, you at least might be familiar. Hypercholesterolemic. Step one is to rule out secondary hypercholesterolemia, severe hypothyroidism, kidney disease, certain liver diseases which should be obvious. Then the kidney disease, you'd be nephrotic with swelling. The liver disease, you'd probably be jaundice by that stage. But thyroidism, we don't usually see hypothyroidism to that degree. To drive they did in the old days. That's when they had myxedema and goiters that you could see from two miles away. We don't see that anymore that degree of hypothyroidism. But there are other causes. There are certain drugs that can send your cholesterol through the roof, sometimes mostly prescribed by either psychiatrists for some of the psychotic disorder dermatologists, some of the dermatologic drugs. But the most common cause nowadays are the ketogenic diets that in X number of people can give you what we call the FH phenotype. Your LDL cholesterol is from 240 to 400, which normally we're even thinking homozygous.

I've seen multiple patients do that and see the cholesterols go to 350s.

They're the people. My belief is they have to re examine the saturated fat in their diet. There is a little bit of evidence that if you love ketogenic diet, just do it without get ketogenic by not using saturated fat, using the monogenic monounsaturated fatty acids and the polyunsaturated fatty acids that can help you. Otherwise you want to eliminate the saturated fat and see if your LDL cholesterol apob disappear. If they do not, but you believe I got to go back to the saturated fat, then either you play Russian roulette and say it's not going to bother me or you take a lipid modulating drug. But I'm going to tell you if you're on One of those diets and your LDL C is 400, we could throw the kitchen sink at you and might not get your LDL cholesterol back to normal. When you make your LDL particles humongous. And anybody that has an LDL cholesterol above 200 has gigantic fluffy buffing LDL particles, don't assume they're innocent because they're killing FH patients right and left. When your APOB is at or your LDL particle is that big, the APOB that it's on the surface totally changes its conformation and it's no longer compliant with the LDL receptor. So LDL receptors is just as poor as clearing Fluffy Buffy LDLs as it is small LDLs. And that's why people with FA or diabetes have such high LDL particle counts. One it's too many fluffy buffies and the other ones it's too many smalls. So even that can't help you. So that's very high. But there are people out there who just say, I'm taking my chances. They do a coronary calcium. If it comes back zero, they say, oh, I got 10 years to play with almost all and you probably notice better than I. But even in the live experience I've had or other. Nobody stays on a ketogenic diet for 10 years. They can't. It's not the world's easiest diet.

I mean a lot of the literature and data on longevity is actually with three to five day water fasts. And so yes, everything else is trying.

To intermittent little fast.

So we're trying to replicate.

I'm a guy who lost 70 pounds with an intermittent fasting five days a month and the rest of the month sort of a hypocaloric diet, low carbs. And I lost 70, 70 pounds like that. And it turns out it was probably just the hypocaloric. For a guy like me who was eating tons of calories, I don't know, the intermittent fasting did that contributed. I. I mean the debate is still on in that, you know, so I don't know. But I do know this. I was religious with that for four years. But even me, who knew the consequences after four years you just start slipping and slipping and before you know it you're on that road to where you were again. So that's the problem with that type of diet. Nobody wants to stay ketotic. And if you're truly ketotic, you're sticking your finger all the time to prove you're ketotic.

Yeah, I kind of did some. There's a breath device you can use and the other things and you kind of get the feel for it. But personally, it takes me like 18 hours before I start creating ketones.

Yeah.

And so it's like day one.

Yes.

Yeah. And so you really need to be at least doing a 24 hour.

So I don't know that that's the answer. But I, as a lipidologist, I worry APOB is proven to be causal. I don't know. Obviously there are some people, as with almost any other risk factor for any disease, go through life and somehow escape the dangers of high APOB through whatever other protective genes they may have. But I don't think you know that till you're 90 years old. And you make it.

You make it.

So that's why I say, well, that's sort of Russian roulette.

Last thing I want to ask you and this, because I know some people that I'll see in the next couple months will ask me, why didn't you ask this question? Apoe 4. So obviously people who get their gene stuff done, they see that and all of a sudden they're like, oh my gosh, it's the end of the world. Right? Kind of thing. What are some brief thoughts about the not APOE 3 or I'll call them E3 or E3 like APOE 4. E4.

You know, I'm a believer. Just like everybody ought to have an LP once in her life in the future may need it more if we ever get successful therapies to attest the efficacy. But that's in the future. Right now you need one lp, so.

You wouldn't necessarily recommend repeating it and doing things and repeating the A two times.

Now we're repeated. If you're one of these statin worried people, you want to see does your LP go up? Fine, repeat it. But also make sure you're repeating APOB and I'll tell you how to calculate non APO little A APOB and very easy. You have to know one number to convert APOB to molar concentrations. So then I think people who go on PCSK9 inhibitors like to know you're telling me it lowers LP, so fine, we'll repeat it. If you're on a PCSK9 inhibitor, but I know of no other reason to repeat it. People are now saying, hey, as you go into menopause, apolita can go up. Estrogen is a factor that can keep apolitical A reduced. So it can go up as you lose estrogen. Usually it's a 5mg per deciliter variant. So it's in irrelevant. There is some variability in how it changes. Also some people go up a little higher. But I will tell you this, it almost never takes somebody who's in a low risk LP zone and puts them in the higher. You may go into the lower parts of the intermediate LP zone for which there's nothing we're doing about it now but lowering APOB anyway. And if you're a nightmare LP and you go on estrogen and it goes up a little bit, you're still a nightmare lp. So you haven't worsened anything. So there's that little thing, Never ever check LP why a patient is sick. Apolita is. Is produced in excess in acute situations. So in a really inflammatory disease or I got a sore throat, don't be checking helping little A, you know, have.

You seen gone up with people post Covid or with COVID or is that something.

I don't have that much experience. There's a lot of literature on that which I have not taken the time to read. So there are interactions there in the autoimmune system. A lot of interest into the research on LP in that situation.

So briefly, like the APOE 4, like.

What is that E4. So I believe everybody ought to genotype themselves for E4. And there's two reasons. One, whether you have one or two E4s, you are at increased risk for cognitive impairment and not only Alzheimer's disease, but Lewy Body dementia, frontotemporal dementia, believe it or not. E4, if you're a kid who's going to play football, if you're going into the military and you get concussed more than once, way more neurologic impairment down the road. We're almost at the point where if you carry an E4 gene, your kid should not play ice hockey or football or some other rugby or even soccer where the ball is hitting, go into some other sport, take up golf or something. So there's information emerging on this that if you have a stroke and you're at E4, the recovery can be a lot worse than if you're not E4. So there are good reasons to know that. So now you're not going to absolutely get dementia even if you have E4, E4, about 80% of them will be going down, but some won't. And just because you have E3, E3 doesn't mean you can't get cognitive impairment. You're at less rest for it, for sure. E2 seems to be protective against, against the standard types of Alzheimer's disease. But there is a type of dementia, even E2, it's rarely associated with such angioate deposits in the wall of your artery. Kind of rare angioid arteriopathy, it's called. So, but most people are not going.

To have that because I've had a patient with the beta amyloid. They actually had a vascular beta amyloid. And they actually.

Yeah, that's what it is, beta amyloid.

Okay. Yeah, Actually I've had one patient with that.

Yeah. Yeah. So that's something you have to watch for. E2 might be a little more. So if you have the preventive neurologist I work with, if you have E2, they're going to scan your MRI looking for certain deposits that would tell them, oh my God, you're getting that type of amyloid angiopathy. So be rare. But if you're a preventive neurologist, it's the type of stuff you watch for very carefully when you're counseling people on the results. Now listen, E4 also puts you at high risk for hypercholesterolemia, hyperbataliproteinemia. So they're at increased risk for heart disease. And one of the reasons is, and I'm the lead author of the article that brought this to light, while at HDL Labs, we had 600,000 sterile specimens that we could look at absorption of sterols in the blood and everything. And we showed that. But the major causes of hyperabsorption of cholesterol that you can predict ahead of time is carrying an E4 gene or being a menopausal women. So again, loss of estrogen is involved with going from a normal absorptive state to a hyper absorptive absorption of cholesterol. I'm not talking fatty acids or other lipids, specifically steroids. So kind of interesting. So APOE gives you a lot of stuff. Now the people say, oh my God, you don't want to know you're going to dementia because there's nothing you can do about it. That was true about 15, 20 years ago. But I can tell you there have been Alzheimer's disease clinics that for 20 years have been measuring the APOE 4 genotype because they believe there's a lot of stuff you can do if you get the E4s earlier in life with lifestyle and even certain supplemental, even prescription medicine nowadays, that would prevent the development of Alzheimer's disease. One of the things thought to be causal for Alzheimer's too is apob. So preventive neurologists treat apob with an aggressive passion in their E4 carriers or so there's other machinations you have to watch there, but you do so if you knew you had an E4 if you either should really assume they're a hyperabsorber of cholesterol and maybe just start with zeti if you need a drug to lower apob. In the past we were all told well E4s don't respond to statins. Of course not, because there's so many are hyper absorbers of cholesterol which identifies a group of statin hyporesponders. So if you know ahead of time you're a hyporesponder, the statin should not be your first APOB lowering drug ezetimibe.

Should be so maybe an E4 with high cholesterol.

Let me tell you E4 and high HDL cholesterol, just start Ezetimibe if you need a drug to lower HDL 4.

Because HDL and LDL absorb together like you said previously, they're probably hyper site.

When it hyper absorbs cholesterol it has to get rid of it. So it's three options. The intestine overloader would absorb cholesterol, can stick it in a color micron, ship it out, lipidate an HDL particle, take it out of here HDL or re secrete it to the gut via ABC G5 G8 transporter. But you have to have functional G5 G8. Most hyper absorbers that escape mechanism is broken genetically. So once cholesterol gets in they can't get rid of it. And that's why there's hyper absorption of cholesterol to begin with. If you were doing genetic analysis on people, if you're doing it day one and you see a loss of function of ABC G5 or G8 those are the sterile exporter membrane transporters. You know you're going to be a hyper it's by the way, if you have just heterozygous FH and you now have hyper absorption, you check G5 G8, you've identified another gene. You're a compound heterozygous. You got two genes driving your LDL cholesterol and one of the third therapies better be ezetimibe in such a patient. So there are interesting. That's why I believe sterile testing for everybody can really help you. Especially a practice like yourselves where you're looking at things to do precision medicine. Day 1 Knowing HyperSynthesizer Hyperabsorber if you get to the point that I need pharmacological treatment, you know, really smartly. Ezetimibe or statin bempedoic acid. And another interesting caveat to all of that, if I went with a statin monotherapy in everybody, God forbid, a hyper absorber. Statins can worsen the absorption of cholesterol because by inhibiting synthesis the body genes say oh my God, we're not synthesizing cholesterol, they turn on the absorption genes more. So that kind of information can tell. In such a case, if you're going to especially use a potent statin, you might day one go with baby statin and ezetimibe and you'll get way more apob lowering and many lipidologists. Now granted, most lipidologists people are walking into their office with scary apobs. They don't start monotherapy anymore. It's almost all statinized by day one. And I'll tell you, even most lipidologists are not measuring the sterile markers because of the complexity of being associated with Boston Heart. Most of them don't know about even a direct to consumer. Your patient has to do that mail. It takes a month to get there for them to do that and you get the results back, you know.

Understood.

Yeah, Roadblocks. So but you can see as you get into even better understanding absorption, you might make a little better therapeutic decisions. Hyper absorbers, that's where you should avoid the phytosterol supplements like they're the plague. Because not only will you absorb cholesterol, you'll start absorbing campestrel cytosterol and above a certain threshold in the plasma, they are toxic to your tissues, you know. So that's why I think even post therapy measuring of sterols provides information, but only if you understand that information. And luckily all you have to do is read my two chapters in therapeutic lipidology which totally deal with the intestine.

There you go. Sounds great. So, So I really appreciate your time dropping out here. We had a great conversation. If people want to know more about you. What are you doing? What are you, you know, I know you said you're like in the, you know, in a great situation, you're not really retired. Like where can people find more about you? Another question is what are you doing? Like what's your next thing? Are you like, like just in cruise mode, you know?

No, there's never a cruise mode methodology because I have to keep relearning what I used to think because it keeps changing and we're lots of I had to rethink the whole HDL hypothesis. We got into a little bit of that today. So I had to rethink the whole reverse cholesterol transport process. I didn't know anything about cholesterol absorption until ezetimibe came around and I was introduced to the world experts who were studying that because I was in on the ground floor with that too. So there's always much to learn and relearn. But for people who the best way to see what I'm thinking and keep on top of what I'm reading reading is. Follow me on Twitter rlippet It's not at Tom dayspring. Maybe you could put in a search thing. What's Tom Day Spring's Twitter, whatever they call them. And you'd find at DrLippid. If you're a healthcare professional, that doesn't necessarily mean MD or DO, but it could be you're a PhD researching lipids, you're a nurse practitioner, an RN, an LPN, a nutritionist, a lipid scientist, or I, you know, you know, you can ask to connect with me through LinkedIn. I try and keep it to healthcare professionals then because I think there's a little better understanding I can get a little deeper. And LinkedIn allows me to use a lot more words than Twitter does. Twitter, it's all graphics. Which is why people really love me. Because even if you you read the long paragraphs, seeing a picture sometimes makes it a little lot more of this. So now look on Twitter, my tweets. You can comment on my tweets and if it's a positive tweet, I'm either going to like it or I may even answer what you say to Hey, I want you to think a little bit. You can direct message me at Twitter, but it better be good. Better be a serious question. Don't message me and tell me I'm an idiot. That'll get you nowhere blocks, right? You won't be getting much more Day Spring stuff, don't worry. And of course LinkedIn, any professional who messages me there, I will absolutely answer. If not call. So that's a good way. And look, I don't give out my email address. If you message me, I might. There are patients who are detectives and they somehow find out my email somewhere on the dark Internet. It's out there. And they even only a few of them, thank God have found my cell phone number. Normally my cell phone, if I don't recognize it, I don't answer it. You would then have to leave a voicemail and if it's intelligent, then I might respond. But if I don't see it's Aaron Hartman calling me because he's in my list now, I'm probably not going to answer the cell phone, but they get it. And if they leave an intelligent voicemail and too often it's somebody who. It's a lipid nightmare. Who I know needs desperate help. I know this is help they can't get from their local doctor. Maybe they've even tried. I may interface a little bit. I'm not going to become their doctor. I don't practice any. But I can point them in the right direction. So that's the best way. You know, I still publish the oddball article but if I did it would be tweeted it. I actually get around through podcasts nowadays. This is why I jumped at this opportunity. And really so because it was an in person, which is way more fun than a zoom call where you still see me but it's sort of dark or it's a phone thing where you only have to listen to me. And God forbid, even Peter. In the initial eight podcasts we did slide notes with a lot of graphics, so that helps. So this has been great fun. So that's the way in. And even if you google me or want any of the search engines, I've done so many podcasts now, some are a lot better than others. I think this is going to be a real good one. There have been others. I just did with Simon Hill. It was two hours alone on lp. So that's like an ATEA podcast. Down and dirty. The last thing. Where am I going? Apart from still trying to help any doctor I can better understand, run of the mill or even rare lipid disorders. Peter 2 years ago did a podcast with one of lipidology's superb world experts on everything but especially high density lipoproteins, Dan Rader. I've known Dan for 30 years, for God's sakes. One of my first mentors, he was Philly. I was North Jersey. We weren't that far. We met at a lot of meetings and stuff. So Peter finishes PODCAST by Dan where are you going? And lipids. What's left? I mean we pretty much therapeutically have what we need for the vast majority of non genetic nightmares nowadays. So where else are we going? And Dan was very perceptive, as he always is. He goes, it's the brain. With this emerging incidence of cognitive and degenerative brain diseases, virtually every one of them has lipids. And part of the etiology of of them. So we better start discovering how lipids are manufactured and transported in the brain. And if there are lipoproteins in the brain, what are they? What do they do in the brain? Do lipoproteins have anything to do with amyloid or tau? And the more we understand, if we understood that, we might understand pharmacological approaches to correcting pathological brain alterations in lipoproteins.

That would be interesting.

So that's where I'm going now. I'm fortunate enough to work with a world class preventive neurologist in the practice I am who was trained at the Cornell Cognitive Impairment center where now I understand takes three years to get an appointment to trained under Richard Isaacson, the forefather of preventive neurology who now has left Cornell, runs his own Alzheimer's clinic and Florida Google him. CNN did a couple of nice interviews with him over the last few weeks and she trained under him. I've known Richard Isaacson. Peter introduced me to him, I would say at least 10 years ago. And we started discovering lipidology in the brain together on a lot of things. So some of the things I now believe about the brain and Kellyanne are prevent neotis or preventive neurologists. And he recognizes there are markers you can actually measure in the blood nowadays that give you some insight to the brain. And they sure as hell want to know if you have APOE 4 because they want to know when you're 20 years old. And believe me, if you see the interview he did with Dr. Gupta on CNN, you will see some of their therapeutic approaches. And even when they take people with Alzheimer's nowadays disease, they actually improve it a little bit without using the big new drugs that you can prescribe that people like him will use here and there. But there are simpler things you can use. I will tell you Apob lowering is one of those. And we'll wrap this up and invite me back another time. When you prescribe a statin, statins not only inhibit cholesterol synthesis in the liver, but also in the the brain. Cholesterol. The brain has one supply of cholesterol. It makes it, it cannot get it from the plasma. That's why you can have an HDL cholesterol of 5 or an LDL cholesterol of 10 in your plasma and have no brain manifestations of that because no brain lipoprotein enters the blood. Brain barrier shares cholesterol with the brain. So the brain has to de novo synthesize all its core cholesterol would that be the reason?

Would that be the reason why certain like the water soluble versus the fat soluble statins, while certain ones might have more of a cognitive effect thought at.

One time now known to be irrelevant. We now know if you're going to prescribe a statin once it's in steady state, all statins get into the brain and have the ability to inhibit cholesterol synthesis. Now for Alzheimer's disease, some degree of lowering cholesterol synthesis is very desirable. What is not probably desirable is over suppression of cholesterol synthesis in the brain. So at a certain point, if you're suppressing cholesterol synthesis with a statin and look, even if you look at the statin data, they're neutral on cognition, they never worsen it. And a few people, they might even improve it. But it's not randomized controlled trials where we have this, that data. But you can't hurt anybody with a statin. But we think maybe there's a minority of patients you can. How about the few people who get brain fog when you do prescribe a statin? They certainly. Statin is a brain with significant.

Yeah.

Could they be the ones that day one you're over suppressing cholesterol synthesis. To show you how much cholesterol synthesis is desired and preserved in the brain cholesterol molecule half life in the plasma is three to five days gone. Either become a bile acid or out through fecal cholesterol. In the brain the half life is five years. That means some cholesterol molecules last 35 years. Rule of sevens with half lives. So that means once a brain synthesizes cholesterol molecule, it reuses it. Reuses it, reuses it. It doesn't excrete it and get rid of it like we do in the periphery and what the liver and intestine can do. So that's why it doesn't need cholesterol from the plasma because it makes its own but now artificially there's probably a certain point at which you don't want to stop synthesis. No other lipid drug affects lipid synthesis in the brain. So you don't have that worry with any other class.

Do you know if you were to suppress the lipid synthesis for like 10 years and then you stop the medication, does that like.

No, we don't know. All we know now is there have been people who have studied biomarkers of cholesterol synthesis and the primary one is desmostral. There are two pathways that cells synthesize cholesterol. One goes through desmosterol one goes through lithosterone. If you're doing the Boston Heart you get the concentrations of both of those. Lithosterone pretty much tells you about synthesis in the peripheral cells. There's mastrol as brain or steroidogenic tissue. They use the desmostral path. The nice study that you can measure desmosterol in the cerebral spinal fluid. It correlates extremely well with plasma desmosterol. Ergo measuring plasma desmostral tells you what's going on in the brain because where does the CSF get desmostero from the brain interstitial tissue. So desmosterol when it's low in the cerebral spinal fluid or the plasma associated with people who developed cognitive impairment and Alzheimer's disease. So that is pretty serious provocative hypothesis generating information that maybe we ought to look at desmostral and people were prescribing statins to and if we suppress it too much maybe that's where you back off the standard and lower apob with drugs that do nothing in the brain which is every other lipid modulation.

That's actually intriguing. That could almost be another conversation.

It is and I told you we just did a two hour conversation on the Proof with Simon Hill in August. He is so zoom. He's going to interview me and Kellyanne Otis. The world's second best. Maybe as good as Richard Isaacs in Preventive Neurologist. Who knows. And me and we're going to discuss lipids in the brain and degenerative brain. And there will be a lot of dismal.

That's in August.

There's one other sterile metabolite that if the brain has to get rid of cholesterol because extra cholesterol in the brain is associated with Alzheimer's disease. So you might want to know is there over synthesis of cholesterol in the brain? Now if you if neurons over synthesize cholesterol they have to get rid of it otherwise the cholesterol will crystallize and kill the neurons. Not advisable to kill neurons. So the neuron is the only brain cell that carries an enzyme that the liver carries the only two tissues that carry an enzyme that converts cholesterol into a hydrophilic oxysterol. Now what are the oxysterols that the liver produces? Bile acids which go right through the bile duct and you get rid of them. So changing cholesterol to a bile acid really a hydroxy sterol. It's excreted. The brain can convert cholesterol which is a kind of hydrophobic molecule that cannot pass through the blood brain barrier and escape to to a hydrophilic lipid called 24S hydroxycholesterol. It's a bile acid that the brain produces. And the brain only changes cholesterol to that bile acid when it wants to get rid of it. Because it has a hydroxy group on both ends. It's sort of. It can pass right through the blood brain barrier, right into plasma, where it jumps on the first lipoprotein, be it in HDL or in or a vlel. It comes by, they return it to the liver, which converts it to a bile acid and you get rid of it. So that is mother nature's way of brain getting rid of cholesterol. Change it to an oxysterol, which will make its way back to the liver. So if we could measure 24s hydroxycholesterol and it's up in the plasma, you know, there's too much cholesterol in my brain and that might suggest a therapy. If it's down, you don't find it in the blood. And by the way, almost all 24S hydroxycholesterol in the plasma has a brain origin. Then you might say, wow, if I'm not finding it, is there hyposynthesis of cholesterol in the brain? And by the way, when you do autopsy brains in Alzheimer's diseases, there is the low cholesterol.

Interesting.

Well, thanks. There's so much.

Yeah, thanks. That's super cool. Cool. Again, thanks for coming out to our office today. Thanks for your time. Really super appreciate it. Rlippid Twitter, you sound like you're super approachable. That's actually how I got. Actually I got introduced to you from a local colleague, but I actually got a hold of you through just reaching out via LinkedIn. So again, thank you for your time. Thank you for your wisdom and your insight. It's been really super helpful.

I've had so much fun chatting and maybe we can do it again on one of these subsegments.

Yeah, I know, it's like, it's almost like. Because we're always starting another conversation, which I think will take us another two, two or three hours.

Oh, yeah, no, you look. I should get way more into the HDLs. Gotten rid the brain, you want to get into the triglyceride pathology. So.

Fair enough. So a lot of information. So I'll make a transition now to therapies, which you've kind of alluded to. And you mentioned there's four major therapies to get in this world, one of the things like in the functional medicine world we focus on inflammation, the homocysteine, hscrp, inflammatory markers, all that kind of stuff. So, so what I want to do is I want to focus on like the medication therapies that you kind of talked about to get these things down. So what are these four major classes.

Referred to so easy. It was so hard for most of my life because first we had an unusable drug called a steering. We had niacin, which proved that we were probably hurting people. Vibrates very select where's well called.

You consider well call.

You put that with biology. Question. Has the ability to bond to bile acids and you excrete them in the stool. Urelium can't reabsorb them. Your liver uses up cholesterol, which induces LDL receptors. Bile acids equestrians can only bind to X number of bile acids. So Wellcol was an engineered part molecule that binds to way, way, way more bile acids than can the bile acid sequestrate. So it's called a bile acid power in there. So you will just excrete a lot more bile acids if you use well, coal, which is a more usable than the old. I don't hope anybody's not using cholestaramine anymore. Well, coal, it turns out through other actions can actually lower glucose, improve insulin sensitivity. So there are other reasons to consider welcome. And it's not absorbed, so it's a great for a pregnant woman, a drug you can putz around with cholesterol if you need to. So that's where well sits. So right now if I want to mower apob, my therapies have to make the liver produce more LDL receptors or whatever LDL receptors exist, let them recycle, live longer. I told you, LDL receptors grab the apob particles, pulling them into the liver. What should happen is the LDL particle gets dissolved in the lysosomes, but the LDL receptor is freed up to go back to the surface. So if that happens, LDL receptors can recycle many times over a few days. But if your lysosome decides to destroy the LDL receptor, it cannot recycle. So just keep that in mind. So it would be good if we could trick our lysosomes into recycle the LDL receptors, please, because we need them. But once the LDL receptor is at the surface of the liver, extending into plasma, you clear apob particles a lot more. So the drugs that we now can write to lower apob and there's typically an algorithm we go through. Because, of course, if we didn't cost wasn't aside, we'd all be using maybe the most expensive one because it's the most potent way of lowering apob. But here's where we start. So how do I make your liver make more LDL receptors? What determines how many LDL receptors the liver makes? The pool of cholesterol in the liver. If the liver pool is full, it doesn't make any LDL receptors. You can't clear APOB particles. But if all of a sudden you can make the liver have a deficient cholesterol pool, the liver is going to. I gotta get LDL cholesterol. I gotta get cholesterol. It's gonna manufacture and express LDL receptors. They make them at the endoplasmic reticulum and they transmigrate to the surface of the liver. Liver, grab the apobate, pull it in. All right. So how would I deplete the amount of cholesterol in your liver? I got a couple of ways. The most commonly used one is, let me just tell the liver to stop synthesizing cholesterol. And that's where the statins came into play. And they discovered that in animals long before they knew, let's try it in humans. And it worked. And before they even knew it worked, somebody had to discover LDL receptors. And two guys who did that, Goldstein and Brown, won the Nobel Prize for discovering LDO receptors. So if I prescribe a statin, you inhibit cholesterol synthesis in your liver. By the way, the liver, because of its size, is the king organ in the body in expressing LDL receptors. And the only one that, once it clears APOB particles, can digest them and get rid of them. You don't want other cells internalizing LDL particles. So fortunately, we inhibit most of the synthesis of cholesterol is going to be in the liver. Less cholesterol, the liver makes more LDL receptors. You clear more LDL particles. APOB goes down. LDL cholesterol goes down. Usually, LDL cholesterol goes down a little more at apob. That's why you should follow up with apob. Cause you may normalize LDL receptors and not normalize apob. So it's wise to do the best blood test now that it's readily available. Any insurance company is not strangling you to tell you not to order apo. All right, so is there another way I can deplete the cholesterol pool in your body? Well, what is a big source of cholesterol? Other Than de novo synthesis. Our intestines absorb cholesterol and they put it in our biggest lipoprotein, the chylomicron. The intestine takes absorbed cholesterol, puts it on both the surface and the core of the condomicron, secretes it into the lymphatics. It goes out through the thoracic duct into the systemic circulation. Primary purpose is deliver all the fatty acids which are incorporated into triglycerides to your muscles. Hey muscles, here's your energy for supper tonight. So the tissues that express the most triglyceride dissolving enzymes, lipoprotein lipase are your muscular beds. So here's the chylomicron particle attaches to lipoprotein lipase. Not a free fatty acids, they just enter the muscle cell. The chylomicron shrinks down carrying very little triglycerides, mostly cholesterol. No cholesterol is given to the muscle cell. The muscle makes all its own cholesterol, doesn't mean a cholesterol delivery. So the chylomicron then is cleared rapidly within minutes by the liver. And the liver recognizes something on a chylomicron that induces its clearance. The APOB on a chylomicron is half the size of the apob on all our other particles. APOB 100 on V alleles and alleles APOB 48. Coming out of each acid we have a receptor that binds to APOB48, LDL receptor related protein LRP. But what is the major line game for LRP? APOE? Chylomicrons carry several copies of APOE. Once the chylo shrinks, APOE conforms to a ligand binding confirmation. Your chylomicron is gone in minutes. The half life of a chylomicron is in minutes. Plasma residence time a couple of hours. So absorbed cholesterol gets brought right to the liver. Thank you. The liver says I got all the cholesterol I need now. But what if I block the absorption of cholesterol in the gut? And there are a few ways of doing that. Nowadays the most potent way is to prescribe a drug that inhibits cholesterol absorption. Ezetimibe, brand name Zetia. People who have loss of function of the transporter that pulls cholesterol into the gut have hypocholesterolemia, hypo beta lipoproteinemia. They get far less heart disease. So we know reducing cholesterol absorption reduces heart disease. Proven by Mendelian studies of the NEEM and PIXI one like protein also now. So okay, I can now deplete cholesterol synthesis in the liver. I can reduce absorption of cholesterol from the gut, depleting the cholesterol pool. We do have a backup way to inhibit cholesterol synthesis nowadays. It's called bempedoic acid. Nexletol. It inhibits a different step in the cholesterol synthesis chain. Not quite as potent as the statins, which inhibit the rate limiting enzyme, but nonetheless, I can further reduce cholesterol synthesis. If I combine bempedoic acid and the statin, I can really shut off cholesterol synthesis. But even by itself, bempedoic acid shuts off enough cholesterol synthesis that the liver will have to get cholesterol elsewhere. Upregulate LDL receptors. There's pulling in your particles. So ezetimibe statins and bempedoic acid all lower apob the statin, it's dependent on the dose you use. Ezetimibe, there's one dose, you can even use less of the one dose. Intermittent dosing and you pretty much get the same efficacy. Bempedoic acid, there's only one dose. You never have to titrate anything. So. And by the way, the amount of LDL receptor upregulation you get with a statistic statin, 80% of it, occurs with the lowest baby dose of the statin. As you double, triple, quadruple the dose of the statin, you get 6 to 8% more. Far less efficacious. I say all you get is side effects by doubling and tripling the dose of a statin. So we should all, whatever your favorite statin is, you should be lower using the lowest dose. If you're a satin fan like I am for a variety of reasons, 5 milligrams of rosuvastatin, you get almost like a 38% lowering of APOB. That's as much as higher doses of other statins, for God's sakes. So of course, adding ezetimibe to statin or nemadoic acid to a statin if need be, you can get a lot more APOB one by itself. Ezetimibe will lower 15 if you're lucky, 20% of APOB. Bempedylic acid a little bit higher, 20 to 23%. So now the howitzer that we can take out if needed is our last drug, which, as you know, our PCSK9 inhibitors. And we have two types now, one is monoclonal antibodies that bind to PCSK9 and the other is a small interfering RNA drug that goes into the nucleus interferes with RNA. You can't translate the. The RNA. The messenger RNA that comes out of your liver stops making PCSK9. So then you obviously have less PCSK9 through that mechanism. So what the PCSK9 does is remember I told you LDL receptors recycle. The PCSK9 does not let the LDL receptor get by inhibiting PCSK9. The LDL receptor will not be catabolized as readily in that lysosome. PCSK9 tells the lysosome destroy the LDL receptor. So if we can inhibit PCSK9, the LDL receptor gets to recycle many times the more you recycle your LDL receptors. People be. Now think of this. What If I upregulated LDL receptors with the first three drugs I mentioned and then I draw PCSK9 on top of them? Goodbye, Apob. Remember, all of the PCSK9 studies have been done on top of at least statin or ezetimibe monotherapy. There's small ones on top of bempedoic acid that didn't work. I haven't seen a triple therapy yet, statin, ezetimibe and pcsk9. But I can tell you in practice, I've seen it used many times for the APOB Nightmares of the world. So that's it, doctors. And here's what I will tell you. When Ezetimibe is like next to zero side effects, you have to know 1. You should inform the patient you're affecting the makeup of sterols in your biliary tree. And gallstones are due to both bile acids and cholesterol in the bile. So there's this minuscule, trivial evidence that has maybe been seen in the trials of ezetimod type and suggested even in Mendelian studs gallstones. So you'll learn. We'll deal with that should they occur. A minuscule number of people might get mild transient eminecemia. We don't even know if that means anything. Very rarely will you triple the transaminases, which is where guidelines tell you to back off any drug tripling aminases, even though nobody's proved that that's harmful even at that level. But. But most would stop it. So you're going to measure transaminase periodically after ezetimide. Benpedoic acid. Look, there's a trivial chance that given to the wrong patient you could elevate uric acid. So you never give it to a patient who's had a lot of gout or if they have had hyperuricemia, you've controlled it through other mechanisms, then it's probably safe. The uric acid excursion is small, but you wouldn't want to precipitate gout. But if I had a gout propensity patient where I, for some reason I couldn't tolerate everything else and had to use, I would warn them gout, delto, swelling, the knee, Call me up and we'll deal with that if it occurs. I don't know of any other side effects of bempedoic acid. I can tell you a lot of maybe benefits that are gonna come, including the elimination or de escalation of insulin resistance and diabetes. But that's again a lecture for, for another day. And then you have the PCSK9 inhibitors and I don't know of any side effects of them right now. Now you know we've got at least 5, 6 years worth of data. Now we don't have 30 years of data like we do on the statins, but so far very safe drug. We have more data on the monoclonal antibodies than the sirnas. Sirnas, for those who don't know, they're much longer acting. So the monoclonal antibodies, Alirocumab, Pralent, repatha that people use, every two weeks it's a minor injection, whereas the SIRNA drugs, baseline injection, three month injection, then every six months thereafter because it really interferes with the RNA drug complex mechanism for a long time, just very hepatoselective. By the way, bempedoic acid, it only works in the liver, can't affect any other cell in your body. So the last thing is the statins. If you're going to be a statin writer, there are things you have to know about. So yes, you can get apob control and you will drastically reduce mace. That is not even arguable that I really do will reduce the number one killer cause of morbidity mortality in the world. But at what price? So we will look at the aminases on statins again. An extreme minority will have elevations of transaminase at a certain level that you might cut back or stop the statin. Two, we have this. Oh my God, you'll cause diabetes with a statin. Now at a molecular level, statins in some people, mostly those genetically prone to insulin resistance, can, if you're measuring very complex markers of insulin resistance, you will see statins do aggravate in some resistance resistance in some people. And ultimately if you aggravate insulin resistance and type 2 diabetes is a loss of insulin sensitivity. You will get a glycemic excursion. It might put you into the pre diabetes level of glucose of 100 might cross the barrier of 126 where I can say you're a type 2 diabetic. So certain people on statins have gone into oh my God, you're now a pretty they were mostly people who had a sugar of 96 or 94 as opposed to 76 for people who don't have who have great insulin sensitivity. And ultimately if you must continue to statin because you that's the only way you get apob to control they may actually cross the 126 threshold. It's almost always in obese insulin lost people who have already loss of insulin sensitivity who you probably are going to get that with a statin. So you watch for it. But we also know that even though I may cross some barrier that changes the definition of what is diabetes or not to me diabetes is a glucose of 8890 where I know you're on your way to insulin most of the time. So I don't need a sugar of 126. And the bad all the microvascular complications of glucose can occur long before a glucose of 100 or 126. So but I'm still reducing mace in these diabetics the leading killer of diabetics. So I can deal. And if I really do put you in a diabetic threshold obviously easiest thing would be crack the lifestyle a little bit improve their insulin sensitivity. But got a list of pharmacology we can reduce in some sensitivity if you feel you have to with why are they not all coping or zip down nowadays if that's what's causing their insulin resistance and they're not going to do lifestyle or it doesn't work in them. So we have solutions to that too. That's pharmacology in a nutshell. It's so easy and the statins are the only ones you almost have to maybe worry about.

So that's a lot of information, a lot of useful information. I almost want to transition to like a lightning round thing and I'm actually the lightning round actually the first thing is going to have to do with the statins and the increase of lp. What are your thoughts about that?

I'm so glad you asked me that because atherosclerosis is an apob mediated disease. It's cholesterol in the artery wall. But if you got the genes that make apoprotein little a X percentage of your LDL population are going to be LP particles. So you, you should be measuring LP in molar concentration. It's nanomoles per liter. If it crosses 50 nanomoles per liter, you enter the world of LP mediated risk. At a level of 125 nanomoles per liter, you enter the world of wow, you're in big trouble with LP. That's 125 nanomoles at LP or particles. If I took that same person now has an LP of 125 and I counted the number of LDL particles that don't have apolitaction. There's an easy way of doing that. I would find it's 1800 to 2000. So, okay, so I don't want you to have an LP of 125 and I sure as hell don't want you to have a regular LP allele particle count of 1200, 1500, 1800. So I'm going to give you a statin that may in X number of people increase the number of LP particles. We now know how it does it, but we can get to that if you want to. But if I give you a statin, probably a rare instance, I should actually repeat the LP to see are you one of the ones. So if you have an LP of 1 12, 25, I may increase it to 130 to 150. But your LDL particles without L ankle little A attached, I've reduced from 1800 to 2000 to 1000. Drastically lowered your cardiovascular risk. So the trivial increase in LP particles is abrogated by the drastic reduction of non on apo little A carrying LDL particles. And that's why the few trials we have where they actually looked at LP and people on statins and Jupiter is the biggest trial that looked at that. They looked at their people with abnormal LP and they all were on statins, rosuvastatin or placebo. And in the people with lp, the rosuvastatin reduced. It didn't reduce it as much as it did in the people who didn't have lp. So what we say is that statin reduced residual risk. Unfortunately not as bad as the people who were weren't gifted with, but it helped you. So they statins worked despite the fact that Jupiter it raised LP particle concentration. So if we're on the camera right now, it increases LP that much and it drops normal LDL particles.

It's an issue of just degree.

It's like the statins raising glucose. At the end of the day they reduce heart attacks but yeah there's a little you wish you didn't raise glucose. I wish the statins didn't raise LP in most people. It's a trivial race that is of zero concern. The Internet frauds use this as a way why you should shouldn't use statins. It's ridiculous. Statins help people with it. Any guideline that you pull out now says if you have an LP that's in the at risk concentration after you've done whatever lifestyle if your LDL C is still high apob prescribe a statin to lower LDL cholesterol. That's the first guideline suggested treatment for LP and look to that you can add as ezetimibe you can add bempedoic acid but the little hey and you better be rich because your third party payer isn't going to pay for it because there's no FDA indication. The only drug we have nowadays that lowers LP by preventing the synthesis of LP particles in the liver is the PCSK9 inhibitors at 25% or so lowering so should you take a PCSK9 inhibitor? Inhibitor yes if you need to get APO beta control but and if I had high LP personally I would be taking a PCSK9 inhibitor but maybe I can afford it whereas the running it's $6,000 a year that you're going to have to pay for it.

So I'm going to ask you actually about educational question about patient and we actually talked about this before on the video today the concept of hyper absorbers we kind of briefly ran over it not thinking about an individual in my head who cholesterol if I remember correctly 283 hundreds reacted poorly with statins reacted poorly with the zetia couldn't tolerate alcohol so went through the list of things have not gone down the PSK9 rabbit hole with her did massive dietary changes. We actually did measure her phytosterol levels and that was I think it was Boston Heart Labs I think was yeah they're pretty much yelling yeah it was a little bit of hassle to get she did herself went to the website and all kind of stuff. Yeah it's a little different.

You're not affiliated with that lab. It's.

Yeah yeah.

So because there is Empower DX a company that uses direct to consumer you can they will mail you a lancet and a minuscule tube that you have to put like four drops of blood in and they take that and they send it to Boston Heart and you'll get the exact same same Sterile panel, Empower dx.

I'm familiar with it actually. So they, they'll do that.

They have a cholesterol panel that looks at the sterile markers.

Okay. Do you have any idea what the cost of that is?

$99.

Oh, okay.

Yeah. So it's ways cheaper than the. And look, if you had to pay cash for the Boston Heart Labs, it's probably more than $99, correct?

Yeah, yeah. I'm not, I'm not going to quit the numbers in my head because I'm not 100% convinced about it. But anyways, this individual got it to look like 170, 180 with an incredibly restrictive diet. Like just crazy, crazy restrictive diet. So I'm kind of thinking, okay, we've tried a lot of other things. She has not done a PSK9 right now. But one of the things is now this individual is almost malnourished. And so I'm at the plague where it's like, okay, and no, no diabetes, no blood pressure, no other risk factor, restricting numbers. And it's one of those things where it's like, is this individual by restricting their diet so greatly, is that how old this patient? She's in her 60s.

Okay. So at an age group where somebody could have atherosclerosis, especially if it's gonna.

Be like, it's gonna be 58 to 60. 58, 58.

Have you done a coronary calcium or any other imaging?

Yeah, we did CIMT as well. It was fine.

So zero cac?

Yes.

And even carotid? No carotid.

Yeah, we did, we, we did that. We did a CMT and as well as ultrasound, the CMT showed her vascular age and her, her chronological age were within like one to two years.

So look to me right away that tells me and that 60 year old woman with a CAC of zero. And I put more weight on that than I do the imt, but mostly because there's more data on it. You probably, you've got at least 10 years to worry about an acute coronary syndrome. So you got time to play. So what if whatever I was doing nutritionally was making her malnourished? I'd back off of the nutritional advice I'm giving her. Maybe you're restricting saturated fat or something to damn low even cholesterol in the diet. If she's not a hyper absorber, restricting cholesterol in the diet is a total waste of time. So I wouldn't use that. That might be in somebody if she's not a hyper absorber. Where giving a phytosterol or better yet a phytostanol supplement would help her. Lactobacillin, which reduces reduce cholesterol would not malnourish her, but at least could. And even in a normal absorber, if you've measured sterols and she didn't have hyper absorption reducing absorption will make the liver grow more LDL receptors. That might help you lower apob. If all of those drugs you said she didn't respond. Now I want to know is that because of side effects?

Side effects, Muscle, legs, pains, fatigue, then.

I don't know what the hell to tell you. But if a patient comes back and says I can't tolerate this drug or natural, you pretty much have to leave them. You can't force a drug down there, they won't take it. So you fool yourself if you so I don't know what you tell somebody like that, but I would back off on a diet to malnourish them, especially if I KNEW I had 10 years to play. If she had coronary plaque to that degree, I'd let her know.

And what would you Life is in your hands. And what would you consider like your composite scores are 0 to 100, 100 to 400. Would you. Would you say a score less than.

There was a nice study probably two years ago that came out says you are in the same risk as somebody who's had an MI if your coronary calcium enters the 300 range. So that's the nightmare range. But as a preventive lipidologist, and I'm not a cardiologist, but we have the American Society of Preventive Cardiology to which I belong. I do even those type of cardiologists look for primordial prevention, which is what she would be ugly cholesterol metrics, APOB metrics where we probably should lower it, but we have 10 years to lower it. But therefore any coronary calcium being positive would tell me I don't have 10 years. I don't know if I have eight years, five years, four years or two years. What I might do in that person is progress to a CTA with the clearly studies where they can see non calcified plaque. And regardless of whether you have calcified plaque or not, you can not only see non calcified plaque, but you get estimates on the vulnerability of that plaque. So it's a little bit more imaging costly. Your third party path isn't going to pay for it. So you're talking a few thousand bucks. Especially if you want the clearly or something regular rather than a regular cta. So there are more advanced imaging things you can go to, if possible, that might twist your arm. I got to get a drug in there.

I think locally insurance will pay for the CTA aspect. And clearly evaluation is like 6 or $800, I think, to get it. So you know that more than I do. That's a good point. And I guess just. Just for the audience, because clearly, I think. I think Dr. T mentions it in his stuff. I think it's part of his thing.

So we use it a lot. But we're actually experimenting a bit now to see what we are learning from it.

Why don't you tell us a little bit about that? That's something we have available here in the Richmond area that I've had a few patients ask me about.

Can give you other parameters of blood flow through the arm. Any fractional blood flow through either a true blockage or a dysfunctional blockage that is impeding blood flow. So if you have a little bit of a plaque and all X amount of blood should be flowing through that at a certain point where that fractional flow diminishes. And there are numbers that tell you, oh, that's no good, then you're into, you better do something about this. Now, it doesn't mean you need a stent or anything if you're asymptomatic, but it does would call for more aggressive lipid management. So you would look at this. That's pretty much the main parameter of the reporting.

And my understanding as well, also gives you a little bit of. They'll tell you about the wall thickness, so you might have an opening, it's clear, but then you might have a thickening until you've got some degree of.

Yeah. And the one problem with that, in my mind too, and Peter Libby gets into this in all his inflammatory discussions and everything is, yes, we have plaque, and we have plaque erosion and plaque rupture, or plaque rupture. But there is something called the plaque plaque erosion, which is a plaque that doesn't extrude into the lumen. And that may not even be associated with a lot of lipid abnormalities. But it's close to the endothelium, and it causes erosion of the endothelium, which exposes the blood flow, mostly the coagulation system, to now the surface of that intracellular plaque. And it can induce a lot of hemodynamic changes, changes, spasm, and also perhaps even clotting. And I don't know how you diagnose erosion And I don't think it clearly tells you much about that. Now, that's a minority of plaques. Most of the plaques are the, you're going to see them and their dysfunction are going to rupture and cause.

So back to the, the coronary artery calcium. Like, because I get people and unfortunately sometimes. And it's which cardiologist do your patients see? Right. So time. Yeah. So like the, the patient's like 65. They have a calcium score of like 40 or 50. I'm kind of like, well, that's actually kind of low for your age. And then they see the cardiologist and they're like, oh my gosh, low for.

A 60 year old. But if that was a 35 year old, that's a 99th percent correct.

Well, it's all. That's. That's devil's in the details, right? Totally. Yeah. And so do you have a particular paradigm because you mentioned with this one individual, I'm thinking about score of zero. You're like, you got 10 years. So let's say you're in your, your 50, let's say 55 to 65 range. What calcium score would you think of? Like, okay, we've got eight years. Is it less than 40, 30? Is it going to be in the.

Real world that we have to make any decisions? You make what. And it's age dependent. So rather than the absolute, you look at what percentile they fall and what Z score sort of is their particular parameter. And the higher the percentage, the more likely I'm going to, I don't know if I got 10 years with you in it. I'm going to treat it.

So you go and you go until you're off the report proper because it gives you those numbers on the report.

And look, this comes down to what we've always called the practice in medicine. Sooner or later, as a doctor, you've got a lot of information, but you're going to have to make a darn decision, for God's sakes, based on your wisdom, your years of experience. It might just be an educated guess in some instances, but it's better. You have an educated guest and their neighbor has an educated guess. We have to do that sometimes. So we use numbers like that. If you're in a practice that is 100% devoted to longevity, and not only longevity, but when you reach old age, you have health span, so you have none of the chronic diseases and you can enjoy longevity. You pretty much. I know Peter has said it on public podcasts. If you listen to some of his Instagram nightly 32nd what I don't know what they're called on his posts on Instagram. He gives some good stuff there. Peter looks at it like if you had somebody that had a bacterial infection, you eradicate that pathological bacteria. He thinks APOB is causal at a rather low concentration. The Mendelian study showed if you have hypo beta lipoproteinemia you don't get atherosclerosis. If you already had it, you regress it and have a far decreasing mace. So he's of the belief you eradicate apob. So if longevity and health span is what is in your binoculars, you're treating apob if it's a little bit high. And that would be if you have LP above 60, maybe if you don't have LP or terrific other risk markers of F, you can live with an APOB between 80 and 60, but it's likely to be a lot closer to 60 than 80. So that's what a longevity practice might do. Longevity practice that's written in New York Times bestseller book on how to achieve longevity. But for running the world metaphysicians where you do have limitations of what you can prescribe and course on what you can prescribe, maybe your apob you live with a little higher apob or do you use different levels of apob? But if I have any calcium score I want your APOB at least a bit lower than what it is. And that's presuming you don't have lp, because if you have lp, I don't care what your calcium score is. And there are studies showing that lp, although it's a terrible calcifier of your aortic valve, it doesn't correlate that much with arterial wall calcification. So be careful not respecting LP despite a pretty good coronary calcium score.

So the LP the primary risk is with aortic valve calcification, not coronary artery calcification.

Yes, you can get calcified arteries obviously, but you can also have non calcific calcified arteries with high lp. So just be careful saying oh, your tag score is zero. I'm not worried about your lp.

Okay, I got you in that context, not in the context of overall cardiovascular disease, in the context of a nor of a zero calcium score. Okay, fair enough.

So look, I think you're going to live with certain amounts of calcium score. You're not throwing a kitchen sink of therapeutics at somebody, but you're to going to watch it. The danger gets into repeating coronary calcium. I don't think we know what that means, especially if you're on a drug. We know statins can increase coronary calcification, but reduce mesa. Should you even be doing cats again? And there are articles written that yeah, but you don't mind a little bit of an escalation. But if it's really going high and the worry is if you see calcified plaque, you're missing the vulnerable plaque that goes along with the council. So I wish we had definitive answers on any of these. We don't. This is why it comes down to the beauty of practicing medicine in an intelligent way and making decisions through other.

Information and looking at other labs and other stuff. It's not just simply treating numbers.

You mentioned part of my career was women's health big time. That gets even more complicated as a woman approaches perimeter menopause or post menopause. It even gets problematic nowadays if a woman decides I want to have children, you better be doing serious metabolic and lipid evaluations before she decides to let's create a little embryo. Let's know what my cardiovascular where the embryo is going to live for nine months. It's better to live in a cardiovascular metabolic healthy woman. So you want to check a lot of things ideally before pregnancy occurs, if not asap. As soon as pregnancy occurs, you look.

At a lot of stuff I can correct. We actually do that when patients come in for pre pregnancy preparation and we'll do a bunch of metabolic stuff and nutritional.

To be honest with you, when somebody becomes an adult now in a woman, of course they can conceive long before they turn 21. I think guys late teens, 20, 21 by then they need their initial lipid panel and an lp. And that's a good start of course with a blood pressure measurement and a waist size measurement. Then you're off to the races.

I tend to like do those things to be honest with you, when I see kids before you go to college because my thing is like this from.

The average five and you went with.

Your approach for the average American. Unfortunately this is good as it gets you literally and your senior in high school. It's only going downhill from here, unfortunately. I tell them that. So let's check your cholesterol now and I'll see you in four years. Check your numbers, check your A1C, check your A bunch of things and we'll see how college did for you. I was the best health of my life at the end of college, which is not normal. And so it's and you know that.

We have done enough autopsy studies on young soldiers and even non military people who've croaked early and on autopsy mind. God, look what's in their arteries. They weren't going to have a heart attack next week, but within the next 10 years. So that's what it takes decades to build up. But if you got the risk factors and you're 20, they've had two decades to screw up your arteries. So yeah, the sooner you look, the pediatric societies want a lipid panel by around the age 8 or 9 to rule out your FA. I would say if you're doing Olympic panel, doing an lp, you're not going to act on it in a pediatric range group, but somewhere in your teenage years.

So this is a question I know someone in my community is going to ask me, so I'm going to ask you this question like that. That recommendation only was in the last couple years when PSK9s came to market.

Say about 10 years. What age? You should start lipid screening. Now, lipid treatment is going to just pretty much apply to homozygous FH or maybe severe heterozygous. And if, God forbid, your kid has that, you belong in a specialized lipid clinic that deals with children.

Different story.

We're talking very different therapeutic approach to that.

I don't personally think I've actually seen.

Yeah, most people in their lifetime would never see that. And in fact, if you're doing good family histories, mom has fh, you know, heterozygous, and dad has it. They should both be going to a lymphedologist and a geneticist before they get pregnant to genotype them. What are you going to pass on here? What are you not? Sometimes they only discover their own FHS when the kid gets a heart attack at age 8, but it's rare.

It's a jog my memory like for homozygous and heterozygous. And this is real as the general question with the cholesterol numbers, if someone has a cholesterol of over 400, like what are the numbers? Guys have some gray stuff in my head where that you can think, oh my gosh, this person probably is homo versus heterozygous.

Again, it's a really poor marker because you really have to do more advanced testing. And look, if the LDL cholesterol is above 190, you at least might be familiar with hypercholesterolemic. Step one is to rule out secondary hypercholesterolemia, severe hypothyroidism, kidney disease, certain Liver disease diseases which should be obvious. Then the kidney disease, you'd be nephrotic with swelling. The liver disease, you'd probably be jaundice by that stage. But hypothyroidism, we don't usually see hypothyroidism to that degree to dry building they did in the old days. That's when they had myxedema and quarters that you could see from two miles away. We don't see that anymore, that degree of hypothyroidism. But there are other causes that are certain drugs that can send your cholesterol through the roof. Sometimes mostly prescribed by either psychiatrists for some of the psychotic disorder dermatologists, some of the dermatologic drugs. But the most common cause nowadays are these ketogenic diets that in X number of people can give you what we call the FH phenotype. Your LDL cholesterol is from 240, 40 to 400, which normally we're even thinking homozygous.

I've seen multiple patients do that and see their cholesterols go to 350s.

They're the people. My belief is they have to re examine the saturated fat in their diet. There is a little bit of evidence that if you love ketogenic diet, just do it without get ketogenic by not using saturated fat, using the monogenic monounsaturated fat fatty acids and the polyunsaturated fatty acids that can help you. Otherwise you want to eliminate the saturated fat and see if your LDL cholesterol b disappear. If they do not but you believe I got to go back to the saturated fat, then either you play Russian roulette and say it's not going to bother me or you take a lipid modulating drug. But I'm going to tell you, if you're on one of those diets and your LDL LC is 400, oh, we could throw the kitchen sink at you and might not get your LDL cholesterol back to normal. When you make your LDL particles humongous and anybody that has an LDL cholesterol above 200 has gigantic fluffy Buffy LDL particles, don't assume they're innocent because they're killing FH patients right and left. When your apob is at or your LDL particles radical is that big, the apob that it's on the surface totally changes its confirmation and it's no longer compliant with the LDL receptor. So LDL receptors is just as poor as clearing fluffy Buffy LDLs as it is small LDLs. And that's why people with FH or diabetes have such high LDL particle counts. One it's too many fluffy buffies and the other ones it's too many smalls. So even that can't help you. So that's very high. But there are people out there who just say, I'm taking my chances. They do a coronary calcium. If it comes back zero, they say, oh, I got 10 years to play with almost all. And you probably notice better than I. But even on the live experience I've had or other. Nobody stays on a ketogenic diet for 10 years. They can't. It's not the world's best, easiest diet.

I mean a lot of the literature and data on longevity is actually with three to five day water fasts. And so yes. So everything else is trying to intermittent little fast. So we're trying to replicate.

I'm a guy who lost 70 pounds with an intermittent fasting five days a month and the rest of the month sort of a hypocaloric diet, low carbs, and I lost 70 pounds and it turns out it was probably just the hypochondrial work. For a guy like me who is eating tons of calories, I don't know. The intermittent fasting, did that contribute? I, I mean the debate is still on in that. So I don't know. But I do know this. I was religious with that for four years, but even me, who knew the consequences after four years you just start slipping and slipping and before you know it, you're on that road to where you were again. So that's the problem with that type of D. Nobody wants to stay ketotic. And if you're truly ketotic, you're sticking your finger all the time to prove you're ketotic.

Yeah, I kind of did some. There's a breath device you can use and other things and you kind of get the feel for it. But personally it takes me like 18 hours before I start creating ketones. And so it's like day one.

Yes.

Yeah. And so you really need to be at least doing a 24 hour.

So I don't know that that's the answer, but I, as a liquidity lipidologist, I worry. Yeah, apob is proven to be causal. I don't know there. Obviously there are some people, as with almost any other risk factor for any disease, go through life and somehow escape the dangers of high apob through whatever other protective genes they may have. But I don't think, you know, that till you're 90 years old and you've.

Made it, you make it.

So that's why I say, well that's.

Sort of Russian last thing I want to ask you. And this I know some people that I'll see in the next couple months will ask me, why didn't you ask this question? APOE 4. So I've seen people who get, get, get their gene stuff done. They see that and all of a sudden they're like, oh my gosh, it's the end of the world, right? Kind of thing. Like what do you, what are some brief thought thoughts about the. Not APOE 3 or I'm com E3 3 or E3 like APOE 44.

You know, I'm a believer just like everybody going to have an ill people a one months in your life in the future you may need it more if we ever get successful therapies to attest the efficacy. But that's in the future. Right now you need one lp.

So you wouldn't, you wouldn't necessarily recommend repeating it and doing things repeating the.

Two times now where we repeat it. If you're one of these statin worried people you want to see does your LP little A go up? I'm fine, repeat it but also make sure you're repeating APOB and I'll tell you how to calculate non apolitical apob. And it's very easy. You have to know one number to convert APOB to molar concentrations. So then I think people who go on PCSK9 inhibitors like to know you're telling me it lowers LP. So fine, we'll repeat it. If you're on a PCSK9 inhibitor, but I know of no other reason to repeat it. People are now saying, hey, as you go into menopause, apolylate can go up. Estrogen is a factor that can keep apolitical a reduced. So it can go up as you lose estrogen. Usually it's a 5mg per deciliter variant, so it's in irrelevant. There is some variability in how it changes. Also some people go up a little higher. But I will tell you this, it almost never takes somebody who's in a low risk LP a zone and puts them in the high. You may go into the lower parts of the intermediate LP zone for which there's nothing we're doing about now but lowering APOB anyway. And if you're a nightmare LP and you go on estrogen and it goes up a little bit, you're still a nightmare lp. So you haven't worsened anything. So there's that little thing. Never ever check lp. Why a patient is sick. Apolita is produced in excess in acute situations. So in a really inflammatory disease or any. I got a sore throat. Don't be checking lp.

Yeah. Have you. Have you seen. Gone up with people post Covid or with COVID or is that something.

I don't have that much experience. There's a lot of letters on that which I have not taken the time to read. So there are interactions there and what a lot of interest into the research on LP in that situation. So.

So briefly, like the APOE 4, like.

So I believe everybody ought to genotype themselves for E4. And there's two reasons. One, whether you have one or two E4s, you are at increased risk for cognitive impairment and not only Alzheimer's disease, but Lewy Body dementia, frontotemporal dementia, believe it or not. E4, if you're the kid who's going to play football, if you're going into the military and you get concussed more than once, way more neurologic impairment down the road. We're almost at the point where if you carry an E4 gene, your kid should not play ice hockey or football or some other rugby or even soccer, where the ball is hitting, go into some other sport, take up golf or something. So there's information emerging on that. If you have a stroke and you're at E4, the recovery can be a lot worse than if you're not E4. So there are good reasons to know that. So now you're not going to absolutely get dementia even if you have E4. E4, about 80% of them will be going down, but some won't. And just because you have E3, E3 doesn't mean you can't get cognitive impairment. You're at less rest for if they're short. E2 seems to be protective against the standard types of Alzheimer's disease, but there is a type of dementia. Even E2 is rarely associated with such angioid deposits in the wall of your artery. Kind of rare angioid arterioptom. But most people are not going to.

Have that because I'm a patient with the beta amyloid. They actually had a vascular optic beta amyloid and they actually.

Yeah, that's where is. Okay, yeah.

Actually, I've had one patient with that. Yeah.

Yeah. So that's something you have to watch for. E2 might be a little more. So if you have the preventive neurologist I work with, if you have E2, they're going to scan your MRI looking for certain deposits that we tell them, oh my God, you're getting that type of amyloid angiopathy. So it can be rare. But you, if you're a preventive neurologist, it's the type of stuff you want to watch for very carefully when you're counseling people on the results. Now listen, E4 also puts you at high risk for hypercholesterolemia, hyperbata, lipoproteinemia. So they're at increased risk for heart disease. And one of the reasons is, and I'm the lead author of the article that brought this to light, while at HDL Labs we had 600,000 sterile specimens that we could look at absorption of sterols in the blood and everything. And we showed that the major causes of hyper absorption of cholesterol that you can predict ahead of time is carrying an E4 gene or being a menopausal women. So again, loss of estrogen is involved with going from a normal absorptive state to a hyper absorptive absorption of cholesterol. I'm not talking fatty acids or other lipids, specifically steroids. So kind of interesting. So APOE gives you a lot of stuff. Now the people say, oh my God, you don't want to know you're going to dementia because there's nothing you can do about it. That was true about 15, 20 years ago. But I can tell you there have been Alzheimer's disease clinics that for 20 years have been measuring the APOE 4 genotype because they believe there's a lot of stuff you can do if you get the E4 earlier in life with lifestyle and even certain supplemental, even prescription medicine nowadays that would prevent the development of Alzheimer's disease. One of the things thought to be causal for Alzheimer's too is APOB. So preventive neurologists treat APOB with an aggressive passion in their E4 carriers. Or so there's other machinations you have to watch there, but you do. So if you knew you had an E4, if you either should really assume they're a hyper absorber of cholesterol and maybe just start with Zeti if you need a drug to lower APOB. In the past we were all told, well, E4s don't respond to statins, of course not, because there's so many are hyper absorbers of cholesterol, which identifies a group of statin hyporesponders. So if you know ahead of time you're a hyper responder, the statin should not be your first APOB lowering drug. Ezetimibe should be.

So maybe an E4 with high the high cholesterol.

Let me tell you E4 and high HDL cholesterol, just start adenom if you need a drug to lower hdl because.

HDL and LDL absorb together like you said previously, they're probably enterocyte.

When it hyper absorbs cholesterol, it has to get rid of it. So it's two, three options. The intestine overloader. When absorbed cholesterol can stick it in a column micron, ship it out, lipidate an HDL particle, take it out of here HDL or re secreted to the gut via ABC G5GA transporter. But you have to have functional G5G. Most hyper absorbers that escape mechanism is broken genetically. So once cholesterol gets in, they can't get rid of it. And that's why there's hyper absorption of cholesterol to begin with. If you were doing genetic analysis on people, if you're doing it day one and you see a loss of function of ABC G5 or G8 those are the sterile exporter membrane transporters. You know you're going to be a hybrid. It's by the way if you have just heterozygous FH and you now now have hyper absorption, you check G5 G8, you've identified another gene, you're a compound heterozygote. You got two genes driving your LDL cholesterol and one of the therapies better be ezetimibe in such a patient. So there are interesting. That's why I believe sterile testing for everybody can really help you. Especially a practice like yourselves where you're looking at things to do precision medicine, they unknowing hypersynthesizer, hyper absorber. If you get to the point that I need pharmacological treatment, you know, really smartly. Ezetimibe or statin benoic acid. And another interesting caveat to all of that, if I went with a statin monotherapy in everybody, God forbid a hyper absorber. Statins can worsen the absorption of cholesterol because by inhibiting synthesis the body genes say oh my God, we're not synthesizing cholesterol. They turn on the absorption genes more. So that kind of information can tell. In such a case, if you're going to especially use a potent statin, you might day one go with baby statin and ezetimibe and you'll get way more apob Lowering so and many lipidologists now granted most lipidologists people walking into their office with science scary apobs they don't start myotherapy anymore. It's almost all statinized by day one And I'll tell you even most lipidologists are not measuring the sterile markers because of the complexity of being associated with Boston Heartland. Most of them don't know about even a direct to consumer your patient has to do that now it takes a month to get there for them to do that and you get the results.

Back, you know so understood.

Yeah roadmaps so but you can see as you get into even better understanding absorption you might make a little better therapeutic decisions. Hyper absorbers, that's where you should avoid the phytosterol supplements like they're the plague because not only will you absorb cholesterol, you'll start absorbing campestrel cytosterol and above a certain threshold in the plasma they are toxic to your tissues. You know. So that's why I think even post therapy of measuring of sterols provides information but only if you understand that information. And luckily all you have to do is read my two chapters in therapeutic lipidology just totally deal with the intestine.

There you go. Sounds great. So. So I really appreciate your time dropping out here. We had a great conversation. If people want to know more about you. What are you doing? What are your. I know you said you're like in the in a great situation. You're not really retired like where can people find more about you? Another question is what are you doing? What's your next thing? Are you like like just in cruise mode, you know?

No, there's never a cruise mode methodology because I have to keep relearning what I used to think because it keeps changing and we're lots of. I had to rethink the whole HDL hypothesis. We got into a little bit of that today so I had to re rethink the whole reverse cholesterol transport process. I didn't know anything about cholesterol absorption until ezetimibe came around and I was introduced to the world experts who were studying there because I was in on the ground floor with that too. So there's always much to learn and relearn. But for people who the best way to see what I'm thinking and keep on top of what I'm reading is. Follow me on Twitter Lipid it's not at Tom Day Spring maybe you could put in a search thing. What's Tom Day Springs Whatever they call them, you'd find out Dr. Lippy. If you're a healthcare professional, that doesn't necessarily mean MD or DO, but it could be you're a PhD researching lipids, you're a nurse practitioner, an RN, an LPN, a nutritionist, a lipid scientist, or I, you know, you can ask to connect with me through LinkedIn. I try and keep it to healthcare professionals then because I think there's a of lot little better understanding. I can get a little deeper. And LinkedIn allows me to use a lot more words than Twitter does.

This is true.

Twitter is little graphics which is why people really love me. Because even if you you read the long paragraph, seeing a picture sometimes makes it a lot more than this. So now look on Twitter, my tweets, you can comment on my tweets and if it's a positive tweet, I'm either going to like it or I may even answer y the same say hey, I want you to think a little bit. You can direct message me at Twitter, but it better be good, better be a serious question. Don't message me and tell me I'm an idiot. That'll get you nowhere blocked, right? You won't be getting much more data strings, don't worry. And of course LinkedIn, anybody, any professional who messages me there, I will absolutely answer your question. If not cool. So that's a good way. And look, I don't give out my email address. If you message me, I might. There are patients who are detectives and they somehow find out my email somewhere on the dark Internet it's out there. And they even only a few of them, they got it. Found my cell phone number. Normally my cell phone, if I don't recognize it, I don't answer. Answer it. You would then have to leave a voicemail and if it's intelligent then I might respond. But if I don't see it's Aaron Hartman calling me because he's in my list now, I'm probably not going to answer the cell phone, but they get it. And if they leave an intelligent voicemail and too often it's somebody who it's a lipid nightmare who I know needs desperate help. I know they this is help they can't get from their local doctor. Maybe they've even tried I may interface a little bit. I'm not going to become their doctor. I don't practice any, but I can point them in that direction. So that's the best way. You know, I still publish the oddball article, but if I did it would be tweeted. I actually get around through podcasts nowadays. This is why I jumped at this opportunity. And really so because it was an in person which is way more fun than a zoom call where you still see me but it's sort of dark.

And dark.

Or it's a phone thing where you only have to listen to me and God forbid, even Peter. In the initial eight podcasts we did slide notes with a lot of graphics so that helps. So this has been great fun. So that's the way. And even if you google me or one of any of the search engines you I've done so many podcasts now, some are a lot better than others. I think this is going to be a real good one. There have been others. I just did with Simon Hill. It was two hours alone on LP Middle A. So that's like an ATEA podcast down in dirty. The last thing. Where am I going apart from still trying to help any doctor I can better understand run of the mill or in rare lipid disorders. Peter, two years ago did a podcast with one of lipidology's superb world experts on everything but especially high density lipoproteins, Dan Raider. I've known Dan for 30 years for God's sakes. One of my first mentors, he was Philly, I was North Jersey. We weren't that far before we met at a lot of meetings and stuff. So Peter finishes podcast by day. Dan, where are you going in lipids? What's left? I mean we pretty much therapeutically have what we need for the vast majority of non genetic nightmares nowadays. So where else are we going? And Dan was very perceptive, as he always is. He goes it's the brain. With this emerging incidence of cognitive and degenerative brain diseases, virtually every one of them has lipid and part of the etiology of them. So we better start discovering how lipids are manufactured and transported in the brain. And if there are lipoproteins in the brain, what are they? What do they do in the brain? Do lipoproteins have anything to do with amyloid or tau? And the more we understand, if we understood that, we might understand pharmacological approaches to correcting pathological brain alterations in lipoproteins.

That would be interesting.

So that's where I'm going now. I'm fortunate enough to work with a world class preventive neurologist in the practice I am who was trained at the Cornell Cognitive Impairment center where now I understand takes three years to get an appointment to trained under Richard Isaacson, the forefather of providing inventive neurology who now has left Cornell, runs his own Alzheimer's clinic down in Florida. Google him. CNN did a couple of nice interviews with him over the last few weeks and she trained under him. I've known Richard Isaacson. Peter introduced me to him I would say at least 10 years ago. And we started discovering lipidology in the brain together on a lot of things. So some of the things I now believe about the brand Kellyanne or prevent neotis or preventive neurologist and he recognizes there are markers you can actually measure in the blood nowadays that give you some insight to the brain. And they sure as hell want to know if you have APOE 4. Yeah because they want to know when you're 20 years old. And believe me, if you see the interview he did with the Dr. Gupta on CNN, you will see some of their therapeutic approaches. And even when they take people with Alzheimer's now disease, they actually improve it a little bit without using the big new drugs that you can prescribe that people like him will use here and there. But there are simpler things you can use. Bilateral APO beam lowering is one of those. And we'll wrap this up and invite me back another time. When you prescribe a statin, statins not only inhibit cholesterol synthesis in the liver but also in the brain. Cholesterol. The brain has one supply of cholesterol, it makes it, it cannot get it from the plasma. That's why you can have an HDL cholesterol of 5 or an LDL cholesterol of 10 in your plasma and have no brain manifestation. Because no brain lipoprotein enters the blood brain barrier shares cholesterol with the brain. So the brain has to de novo synthesize all its cholesterol.

Would that be the reason? Would that be the reason why certain like the water soluble versus the fat soluble statins, while certain ones might have more of a cognitive effect thought at.

One time now known to be irrelevant. We now know if you're going to prescribe a statin once in steady state or all statins get into the brain and have the ability to inhibit cholesterol synthesis. Now for Alzheimer's disease some degree of lowering cholesterol synthesis is very desirable. What is not probably desirable is over suppression of cholesterol synthesis in the brain. So at a certain point if you're suppressing cholesterol synthesis with a statin and look if, even if you look at the statin data, they're neutral on cognition they never worsen it. And a few people, they might even improve it. But it's not randomized controlled trials where we have that data. But you can't hurt anybody with a statin. But we think maybe there's a minority of patients you can. How about the few people who get brain fog when you do prescribe the statin? They certainly would. They be the ones that day one, you're oversupplied. Suppressing cholesterol synthesis to show you how much cholesterol synthesis is desired and preserved in the brain. Cholesterol molecule half life in the plasma is three to five days gone. Either become a bile acid or out through fecal cholesterol in the brain, the half life is five years. That means that sub cholesterol molecules last 35 years. Rule of sevens with half lives. So that means once a brain synthesizes cholesterol molecule, it reuses it. Reuses it, reuses it. It doesn't excrete it and get rid of it like we do in the periphery what the liver and intestine can do. So that's why it doesn't need cholesterol from the plasma, because it makes its own. But now artificially, there's probably a certain point at which you don't want to stop synthesis. No other lipid drug, drug affects lipid synthesis in the brain. So you don't have that worry with any other classes.

Do you know if you were to suppress the lipid synthesis for like 10 years and then you stop the medication, does that like.

No, we don't know. All we know now is there have been people who have studied biomarkers of cholesterol synthesis and the primary one is desmostral.

Okay.

There are two pathways that cells synthesize cholesterol, cholesterol. One goes through desmostral, one goes through lithosterone. If you're doing the Boston Heart, you get the concentrations of both of those lithosterol pretty much tells you about synthesis in the peripheral cells. Desmosterol is brain or steroidogenic tissue. They use the desmostral path. The nice study that you can measure desmostral in the cerebral spinal fluid, it correlates extremely, extremely well with plasma desmosterol. Ergo, measuring plasma desmostral tells you what's going on in the brain, because where does the CSF get desmostral from the brain interstitial tissue. So desmostral when it's low in the cerebral spinal fluid or the plasma associated with people who developed cognitive impairment and Alzheimer's disease. So that is Pretty serious provocative hypothesis generating information that maybe we ought to look at Desmostral and people were prescribing statins to and if we suppress it too much maybe that's where you back up the statin a little lower. Apob with drugs that do nothing in the brain which is every other lipid.

Modulation that's actually intriguing. That could almost be another conversation And.

I told you we just did a two hour conversation on the Proof with Simon Hill in August. He is so zoom he's going to interview me and Kelly Andiotis the world's second best maybe as good as Richard Isaacson preventive neurologist who know and me and we're going to discuss lipids in the brain and degenerative brain and there will be a lot of and Desmostral that's in August. There's one other sterile metabolite that if the brain has to get rid of cholesterol because extra cholesterol in the brain is associated with Alzheimer's disease. So you might want to know is there over synthesis of cholesterol in the brain? Now if neurons over synthesize cholesterol they have to get rid of it otherwise the cholesterol cholesterol will crystallize and kill the neurons. Not advisable to kill neurons. So the neuron is the only brain cell that carries an enzyme that the liver carries. The only two tissues that carry an enzyme that converts cholesterol into a hydrophilic oxysterol. Now what are the oxysteroles that the liver produces? Bile acids which go right to the body bile duct and you get rid of them. So changing cholesterol to a bile acid really a hydroxy sterol gets excreted. The brain can convert cholesterol which is a kind of hydrophobic molecule that cannot pass through the blood brain barrier and escape to a hydrophilic lipid called 24S hydroxycholesterol. It's a biological bile acid that the brain produces. And the brain only changes cholesterol to that bile acid when it wants to get rid of it because it has a hydroxy group on both ends. It's sort of it can pass right through the blood brain barrier right into plasma where it jumps on the first light bulb protein, be it an HDL or an LDL or a vle it comes by, they return it to the liver which converts it to a bilas acid and you get rid of it. So that is mother nature's way of brain getting rid of cholesterol, change it to an oxysterol which will make its way back to the liver. So if we could measure 24s hydroxycholesterol and it's up in the plasma. There's too much cholesterol in my brain and that might suggest a therapy. If it's down, you don't find it in the blood. And by the way, almost all 24 S H cholesterol in the plasma has a brain origin. Then you might say, wow, if I'm not finding it, is there hyposynthesis of cholesterol in the brain? And by the way, when you do autopsy brains in Alzheimer's diseases, there is the low cholesterol.

Interesting.

Well, thank you so much.

Thanks for answer. That's super cool. Again, thanks for coming out to our office today. Thanks for your time. Really super appreciate it. At drlipid Twitter. Twitter, you sound like you're super approachable. That's actually how I got it. Actually. I got introduced to you from a local colleague, but I actually got a hold of you through just reaching out via LinkedIn. So again, thank you for your time. Thank you for your wisdom and your insights. Been really super helpful.

I've had so much fun chatting and maybe we can do it again on one of these subsections.

Yeah, I know, it's like, it's almost like because we we're starting another conversation which I think is gonna take us another two, two to three hours.

Oh yeah, no, he's looking. If you get way more into the HDLs got rid the brain, you want to get into the triglyceride pathology.

So another great. Well, thanks a lot for John. Really super appreciated.