The Root Cause Of Heart Disease & How To Tell If You're At Risk | Dr. Ronald Krauss

75% of people who were admitted to the hospital with a heart attack had normal cholesterol levels. Doctors are just laser focused on LDL and statins. It's really all driven by our typical cholesterol profile is probably not the most accurate in predicting heart disease and is not what we actually want to be measuring, which is sort of the opposite of what we thought. Cause we were all told to eat a low fat diet, cut out saturated fat, and then we all started eating, you know, tons of carbs, 6 to 11 servings of bread, rice, pasta day, according to the food pyramid in 1992. And then our weight blew up and our risks of diabetes is escalating. And now we see, you know, 93% of Americans in poor metabolic health, you know, and one and two have pre-diabetes or type two diabetes. So, you know, the pattern that you're talking about is the most prevalent lipid pattern today in America. And yet, it's, it's something that most people are not that tuned to because most of the drugs are really focused on lowering LDL, which is the Statin. And so we've kind of got this, this sort of LDL Centric hypothesis, and particularly just just general LDL numbers, not the subtypes. So it's kind of take us down the wrong path. I love to sort of hear how you first kind of came upon this theory that maybe our typical cholesterol analytes, you know, our total LDL, HDL cholesterol, weren't really giving us the full picture in the whole story.

Mark, the story does go way back, not quite as long as you had indicated. But when I, joined the laboratory in Berkeley, which is the laboratory that originally developed all the techniques for separating and identifying lipoproteins. In the 1940s, I inherited some interesting opportunities, and one of which was to see whether we might be able to examine LDL, low-density lipoproteins, in detail. to see whether there might be different forms. And sure enough, we discovered that there are several different forms of LDL in the blood, differing in size from larger to smaller. And we then showed that there was a relationship between the small form of LDL and low levels of HDL. And by that time, most people had come to accept that low HDL was a risk factor. But what we then began to test is the idea that it's really the small LDL that's the risk factor in that profile. And then we went on to develop tools to measure small LDL using more simplified methods, including what we're now currently using in the clinic. And as we got more and more data, we were able to confirm that idea and show that it really was an important predictor of heart disease itself. Although it was associated with low HDL, it's also associated with high levels of another blood fat called triglyceride. And so those three things together we discovered really represent a triad of risk that many people have because we now know that obesity, insulin resistance, type 2 diabetes, all of these things promote that triad, that lipid triad, which is part of something which we also have called the metabolic syndrome. So this is a whole collection of abnormalities, but the small LDL component of it, we and others have shown really is a a bad guy all by itself. This kind of challenges the orthodoxy, which.

Is that it's all about LDL cholesterol. And I think, you know, we're talking about it, and the belief was that saturated fat was bad, that it raises LDL cholesterol, and therefore it increases the risk of heart disease. But it's a much more nuanced story where it turns out that it's this, what we call atherogenic dyslipidemia, this collection of patterns of high triglycerides, low HDL, small LDL particles. that is actually the real risk factor. And that's not caused by so much saturated fat as it is by carbohydrates, basically refined sugars and starches. I wonder, Ron, if you could just, just break down a little bit. What is the difference between a cholesterol and a lipoprotein? And because this is what we're talking about, is it sort of language? And I don't think most people know.

What a, what the difference is. So help us sort of start with the basics, and then we'll get into what they all mean. Sure. Well, cholesterol is a waxy substance that is present in the blood attached to a particle. And so cholesterol is also called the lipid. So this is a fatty, waxy substance that is in all our tissues in the body. It's an important component of the structure of our cells. It has a lot of important functions. in our tissues, but in the blood when it's attached to lipoproteins, and depending on which lipoprotein it's attached to, it can either be associated with higher risk or lower risk. And so the lipoprotein is a particle. It's actually a little round tiny ball containing fat, including cholesterol, but other lipids as well. contain triglycerides, which we could talk about as well, in the package surrounded by some proteins. And so it's this lipid protein complex that gives it the name lipoprotein. That's where the name comes from. And cholesterol is an important part of it, but it's not the only part. And one thing I would just go back to from our earlier discussion, is that levels of blood cholesterol do not distinguish individual lipoprotein particles. We measure cholesterol in the blood. It's the sum of all of the cholesterol in all these individual particles. And even in the case of LDL, we talk about LDL cholesterol, it's the bad cholesterol. That's the amount of cholesterol on this little LDL particle, but even that doesn't necessarily reflect the amount of those particles in the blood. And in fact, individuals who have this very, very prevalent metabolic trait, this atherogenic dyslipidemia that you mentioned, very often have normal levels of cholesterol, normal levels of LDL. And that's because the particles, the lipoprotein particles that constitute that triad, surprisingly, we discovered, do not have a super large amount of cholesterol. They do have cholesterol as part of the structure of these particles. But there are other features of these small particles, the small LDL in particular, that render them more toxic to the arteries. There are several things that these particles have on them that cause them to bind to the artery wall more tightly, to be cleared less effectively and removed from the body so they tend to hang around longer. They're oxidized more rapidly than larger LDLs so they can become more toxic because oxidation of lipids can lead to inflammatory processes which are very important in heart disease. So all of these properties of small LDL are quite different and quite distinct from the cholesterol content. And that's why the cholesterol measurement, while it's a reasonable thing to include in the lipid panel, it does not provide necessarily meaningful information about these particular components. The real risk. Yeah, the components that really are much more prevalent in the population than even high cholesterol.

Yeah, interesting. I mean, I read a study once where I think 75% of people who were admitted to the hospital with a heart attack had normal cholesterol levels. And that's like, I'm shocking when you think about it. Now, I mean, is it because they're on a statin? I don't know. But I think it sort of speaks to the fact that you can have a horrible profile, but actually, you look okay. So, I remember a patient who had cholesterol was like 150, right? But their triglycerides were 300 and the HDL was 30. and they have this terrible profile with small particles, I'm much more worried about someone like that than someone with an LDL or a cholesterol of 300, but an HDL of 80 or 90 and triglycerides of 50, right? So, you kind of don't get the true story. And then doctors just see the LDL being higher, the total being high, and they go, you need statin instead of actually asking the real question, which is.

What'S causing the abnormal profile in the first place. Right. In terms of treatment, since you brought up statins, What I'll mention is that even though the small LDL trait is associated with high triglycerides and low HDL, there's really very little evidence, if any, that lowering triglyceride or raising HDL itself has a benefit. Whereas lowering of the LDL particles clearly is the central goal of our treatment algorithm. And we certainly use statins when these particles are elevated. They can work. They're not quite as effective in lowering the small LDL compared to the large LDL, but they can be effective. And so statins still represent something that's relevant if there are high levels of these small particles. And in terms of diet, as you mentioned briefly, We, one of our other eye openers was when they started to do dietary studies, I was very interested in nutritional effects and heart disease risk. And I inherited the old paradigm of low fat is good for you, right?

Yeah, yeah, yeah. We all did.

I chaired the American Heart Association Nutrition Committee for a few years, bearing that burden, that mantra. And at the same time, I was doing research in my lab, it showed that when we put people on this low fat, high carb diet, we started to induce levels of small LDL. We actually can raise them in about 25% of the population. The levels went up. And so that was, to me, a complete paradigm changer. And I started to try to talk about this. It was not exactly accepted with open arms by our colleagues and nutrition.

Putting it mildly, it was heresy.

And it took a while. It took, as you say, there's a lag time between discovery and implementation. It took quite a while for the nutrition community. the dietary guidelines to start recognizing it, although there still is an inordinate focus on carbohydrate can be okay, saturated fat is bad. And in terms of saturated fat, I think, as you also touched on, we did a number of studies that showed that when you put somebody on a high saturated fat diet, this is fat from dairy or and/or meat, you did raise the LDL cholesterol level. This has been well established for many years that the cholesterol level in LDL does go up when you put them on this high saturated fat diet. But we found that it was almost exclusively in the larger LDL particles, not small particles, which are much less related to risk. So there was kind of a mismatch between the cholesterol reading and the impact on the bad guys. Whereas, as you also mentioned, turning it around and putting people on a high carbohydrate diet raised the small LDL. And when we started studying therapies, we showed, fortunately, that if you take people who have a high level of small LDL, the LDL is very prevalent trait and put them on a low carbohydrate diet, and/or had them lose weight. Both of those things extremely effective in lowering small LDL. There is a genetic component to all of this, which unfortunately some people are struggling with and diet doesn't always work. Statins don't always do the job. We sometimes have to go to something more intensive treatments.

Yeah.

Well, it's interesting. The way I think about it may be very simplistic, but I think about you know, different, you know, when you get your cholesterol number, it's measuring the weight of the cholesterol, like milligrams per deciliter. When you're looking at particles, you're looking at the number of the particles and the size of the particles, which is more qual, a qualitative than a quantitative view. And, and so the way I think about it is that, you know, you could have a cholesterol like 200, but it could be made up of, you know, 2, 000 little BBs or, you know, a hundred little beach balls, you know, basically, and the beach balls are the big particles that bounce off your arteries. And the BBs are like the small LDL particles that go in and cause heart disease. And, and I think, you know, it's, it is, it is very surprising to think about, you know, the, the advice we've been getting for decades about cutting saturated fat, increasing carbohydrate. Even today, there's still a big, you know, group of professional societies and dietary recommendations that are, haven't kind of progressed. And, and I think, you know, I sort of want to kind of go back to what you said about saturated fat because you've published a lot of reviews and papers on the roles of saturated fat and lipids. And in a way, you're a bit of a kind of a black sheep in the cardiology Community because you're, you're saying, wait a minute, the saturated fat may not be as bad as we thought it was. I mean, combining with carbohydrates is bad, combining it with starches, sugars is bad. But when you, instead of butter on your bread may not be good, but butter on your broccoli may be okay. And so, you know, when you think about it that way, the question is, do we want to eat saturated fats to raise our size of our LDL or is it better just to kind of stick with more monounsaturated and just cut the carbohydrates? Like what's the current thinking about this? Because it's constantly changing. And I also think there's a lot of variation in the population I want to talk about. But for most people, you know, we see suffering from poor metabolic health, which is in part genetic predisposition, but not genetic predestiny. I mean, in other words, you might have a family history of diabetes, but it doesn't mean you're going to get it if you follow a healthy lifestyle.

Right, right. Yeah, let me just touch on that last point and then I'll go back to that question. We've done a number of studies in which we varied the carbohydrate content of diets and also achieve weight loss in various studies and various combinations. And what we showed when we published this is that even though there's this very high prevalence of this pathogenic small LDL trait, the triad, if you will, the prevalence of that could be reduced down to maybe 5% in the population. if you follow a low carb diet and lose weight. So it's 95% reversible with diet alone. Now, most people don't get that far. And sometimes, you know, we can talk about low carb diets. There's a whole discussion about that, but at least the notion is, as you were saying, that this is not destiny. It's highly manageable with lifestyle. Now regarding the saturated fat issue, yes, I have been sort of, how should I say, poking the bear, if you will, and have generated quite a bit.

Of.

Backlash for some of the things that we published and reported. But there is a fair amount of science behind this, and this is the idea. First of all, saturated fat is nutrient. It's a chemical category consisting of many different types of fats. The other way of describing it, the saturated fatty acids, these are chemicals that have a certain chemical quality that makes.

Them.

Fit into this category of saturated fat. But there's 30 different types of saturated fatty acids. And so when we consume, we talk about saturated fat, it's already incorrect to kind of lump them all together. Number one. Number two is saturated fat is not consumed as a substance in itself. Like butter may be one of the closest things, but it still is not pure saturated fat.

Yeah.

Most of the saturated fat we consume is in, in fact, just about all of it is in the context of foods. And so I've been a strong Advocate for moving away from this kind of microbe precision focus on saturated fat to say, well, really what we should be thinking about is the overall effects of foods in the diet. And they may or may not contain saturated fat, but there are a whole lot of other things to consider when it comes to the nutritional and metabolic and health effects of foods. So there's two major, actually three major categories of foods that contain relatively high concentrations of saturated fat. There's red meat, white meat for that matter. There is dairy, whole fat dairy products, and there are tropical oils. Now these are all different foods and it's a mistake, I believe, and some of my, a number of, a growing number of my colleagues, I think, are beginning to believe that it's a mistake to focus on the saturated fat rather than on the food. Because, for example, there is a pretty good body of evidence now that whole fat dairy, I mean, not all whole fat dairy, but at least some whole fat dairy products such as yogurt, fermented foods, even cheese, can be associated with heart health benefits that have nothing to do with the saturated fat. there may be an increase in blood cholesterol, but as I said, it's these larger particles which we're less concerned about. And it's these other qualities which we're trying to understand that may have health benefits. So it's a mistake to throw out this particular baby with the saturated fat bath water because we're losing an important nutritional effect that may have significant health benefits. Meats are a bit more complicated. I'm not sure we can say the same thing about meats as having in themselves healthy effects other than the nutrients they contain, certain nutrients that are present in beef that are not present in plant foods.

Doesn't meat have more stearic acid, which doesn't have that great of an impact on blood cholesterol?

Yeah, but it can, yes, but there are other saturated fats that can raise, I mean, red meat can raise cholesterol, white meat can raise cholesterol, and it's the larger particles we published that.

But.

The other question that you raised that I just want to touch on is should we be trying to increase the size of LDL or make them larger? and I'd have to say that there's really no case to be made for that. The larger LdL particles are less dangerous than the smaller particles, but if you have a whole bunch of them, they can still add up. They're not completely harmless by any means. And so trying to increase the size of LdL, certainly by taking more, let's say red meat, for example, is not something that I would advocate.

So are you saying, are you saying that meat is a concern when it comes to.

Well, it's a more, no, not so much the lipid effects. There's just, there's a lot of controversy around this. And I, you know, we could spend a long time talking about the pluses and minuses that are out in the literature. Are there other adverse effects? Does it increase the risk of type 2 diabetes? Does it increase the risk of cancer? Are we talking about environmental effects that we should be concerned about? with the beef industry. I mean, there's all kinds of debate about this. And so it's not, there's, from a health standpoint, we're often unfortunately relying on what we call nutritional epidemiology, that is looking at populations and asking them what they eat and then finding out whether they get disease or not. That's a very difficult category of research because you have a lot of potential for error in making assumptions. But unfortunately, for most of our dietary recommendations, this approach represents the major source, major basis for making those recommendations. And in the case of red meat, there is a, you know, reasonable amount of evidence from these observational studies that raise some concerns. I'm not saying I that they're, I'm convinced they're true, but they're out there.

Yeah, I mean, it's like, you know, I always say, you know, like, you know, observational studies are like, you know, for example, saying, well, just women.

Over.

60 never get pregnant. And that, and, and women who have sex over 60 never get pregnant. So that means having sex doesn't cause pregnancy. It does, it's like, this is kind of essentially how we come up with these observational studies. there's a correlation, but it doesn't prove causation. So there's a lot of other factors. And with meat, it's like that, you know, a lot of people are eating meat. We're, we're in the studies, we're, we're during times where we thought meat was bad. And so everybody who was eating meat, you know, didn't take care of their health. And they actually had way worse confounding factors. They smoked more, they drank more, they ate more, they weighed more, they fruits and vegetables, they ate more sugar, processed food, didn't take their vitamins, didn't exercise. So, yeah, of course, they had more cancer, heart disease and everything else. And when you look at meat eaters and vegetarians who shopped at health food stores, meaning their overall diet quality was better. there was a reduction in risk of death by half in both the groups, whether they're eating meat or not. So I think it's complicated, you're right. I want to get back to this test because you developed this strategy to this test a long, long time ago. And I personally have been using it for 25 plus years. And now it's more available in Quest and LabCorp. There's different techniques that are used in each lab. Can you talk about this assay and actually what it's doing and how it works and why is it different than the typical cholesterol panel and why isn't that good enough?

Okay, so first of all, there are a couple of essays available and I'll discuss each of them. And as you mentioned a few minutes ago, these assays measure the number of particles in the blood, not just LDL, but all the different particles. There's HDL particles and very low density particles. So it's an entire spectrum of lipoprotein particles are measured and the units, as you said, are not in milligrams. They are in what we call nanomoles. They're actually a chemical way of defining the number of these particles. And both of these methods allow analysis of these particle concentrations as a function of their size. So the size of lipoproteins is an important feature of their overall effects, both metabolic and pathologic. And that spectrum goes from the smallest particles, which are the small HDL through LDL, the next largest particle, and then VLDL. And within each of those, it separates the different subspecies so we can measure small LDL as part of that spectrum. So that's the overall picture. Now, the two methods, I'll describe the one that I'm partial to because we invented it. And so that's a disclosure. And part of that disclosure is that the test was actually patented over 20 years ago and licensed to Quest Diagnostics. And so Quest offers it as part of what it calls the Cardio IQ panel. There's other tests that can include in that, but this is called Lipoprotein Fractionation. And the name of the test is Ion Mobility, I-O-N Mobility. So it's Lipoprotein Fractionation by Ion Mobility. the short name is cardioid Q. So that test actually I think it's still quite remarkable. It takes tiny amounts of blood and squirts it out through a little capillary. And the instrumentation winds up separating each of those particles one by one and spitting them out at the end. and then they're counted. So each individual particle is counted and the speed at which it goes through, the time it takes to go through, is a function of their size. So it goes from the smallest to the largest particles as you go through the system. So you get this readout, which is really quite detailed. There's more information there than we can actually interpret in the clinic, but there are some key clinical measures that we extract from that, and that is measures small LDL. We also measure something called medium LDL, which is associated with this. So those two categories together are the major LDL related risk factors. We measure large HDL particles. So there's information and sometimes I think one of the reasons we can talk about why it hasn't been taken up more widely is, In some sense, there might be too much information for people to try to digest. And I think trying to explain educate has been part of my mission for all these years.

I mean, listen, doctors are smart. That's their job.

But for completeness, I'll just mention the other method, which uses a completely different technique called nuclear magnetic resonance spectroscopy or NMR. And that test was developed by a company that is now part of LabCorp. And this offers a similar type of readout, although it measures these particles in a very different way. It doesn't actually separate and count them. It creates a signal that is then analyzed and within that signal, each of these components is identified. and that's also a widely used test now. Well, neither of them are actually widely used, but they're both been taken up, I think, by an increasing number of physicians who are beginning to understand, but it's still a very small minority.

So your typical cholesterol test is like a total cholesterol, your LDL, your triglycerides and HDL. That's pretty much it. and we'll talk about some other things that doctors may measure like Apo B and A1, but the test you're talking about measures that, but it also measures whether you have small, medium, or large LDL. It measures the size of the HDL, because that also matters. It's not just the size of the LDL, right? It measures the size of the triglycerides as well.

Yeah, yeah, those have less direct impact. on heart disease risk again. This goes back to the idea that there are three traits that tend to cluster as part of this atherogenic dyslipidemia that we talked about. One is high levels of small LDL, the other is high levels of VLDL, large VLDL particles which are measured by this technique.

And that's correlated with triglycerides, right?

That's right, you're right, that's where triglyceride is transported. primarily. And then there are low levels of the larger HDL particles, which we call HDL2 or HDL2B more technically. And that is a readout of this test as well. So it can sometimes help to show all three components of that. But the money, if you will, in terms of clinical payoff is mostly related to the small LDL particle.

And it measures two things, whether you have small and how many there are and how many total particles you have, which also matters, right?

Right.

It's both a total number and also the size that matters.

Right.

Can you explain that?

A little bit, yeah. Let's stack up and talk about the test you just mentioned, the ApoB test, ApoB capital B. That's a protein that is present in LDL and it's also present in VLDL. And there's one molecule of ApoB in each of these particles. So it turns out conveniently that if one measures ApoB in the lab, and this is not, this is an easy test to do, it's not expensive, it's widely available.

You get- Not widely done, but widely available.

It's widely available, right. It's well standardized despite some claims to the contrary. it measures the total number of those particles, the LDL and the LDL and also some particles in between called intermediate density lipoproteins. And so all of that together.

Is.

A pretty good measure of heart disease risk problems if that test is elevated, because it's usually associated with high levels of small LDL. That's often the major reason that one has high levels of apolipoprotein be. And as I say, there are other particles that may be concerning, even in a large LDL, there may be some that are not so good in the LDL also, they're not so good. So the total ApoB measuring turns out to be a pretty powerful tool for assessing risk, but it doesn't zone in on where that elevation is coming from, as you just mentioned. So from my standpoint, from the the standpoint of both evaluation and then treatment, I think it helps me a great deal. I do this in my practice pretty routinely is measuring these subfractions, including the small, the others. So I know what we're dealing with in a more specific way that we can then target and monitor and see if we can lower because there are people that show up in my clinic who have high levels of ApoB, but they have high levels of large LDL that are counting for that. And I do their profiles and I look at their overall risk, there's nothing else wrong. So treating the ApoB, I feel in those patients, this does not necessarily have the rationale that I would use to treat the small LDL, because these patients do not seem to carry that same degree of risk, even though the ApoB level is high.

There's some debate about this.

There's some people that feel ApoB really is the transcendent measurement and these subfractions are less important. But I think at least from the standpoint of management, I'd like to know what I'm treating. Well, yeah, you want to know as.

Much as you can. Why just like pick one, right? I mean, you want a full picture. And heart disease is very complex. I mean, it's not just reducible down to elevated LDL levels. It's inflammation, it's oxidative stress, it's metabolic health, it's ApoB, it's lipoprotein A, it's a lot of things that are, are being looked at holistically.

So this is the slice of the pie. Yeah, it's a big slice of the pie, but it's not the whole pie. Yeah.

Interesting. So, so basically right now we have commercially available tests that really, I think, engendered and created because of your pioneering research. So people need to understand, this is the guy who knows the deal on this. He kind of invented it and, and essentially It's not being used. So what are the statistics on, you know, what a percentage of physicians use this versus the total, like the regular cholesterol profile that people are getting?

You know, I wish I can answer that. I've been told by my friends at Quest, for example, that they are not, they do not provide information on their test volume. So I've been quite curious about this.

But they won't tell you.

No, no, no, it's, it's a, it's apparently something they feel should not be widely advertised. I can't explain why, but. So I don't, I don't know the answer to that, other than it's, you know, it's probably, you know, I would just have to say it's a small minority of the testing, for example.

You.

Know, I think there's. you know, 100 plus million lipid panels that are run in these major clinical apps. Just based on the, on the amount of instrumentation that's available for the test, the quest test, at least, I can't imagine that it's more than one percent of that. I just think it's a tiny percent.

Yeah, I would, I would probably agree with you. I mean, I, I don't know the stats. I'd be interesting to find out, but I, I, as as a clinician, seeing patients on a regular basis from all over who bring their data from other doctors and from, you know, top executive physical programs from, you know, leading physicians. And I can say, I mean, maybe there's been a couple, but I don't remember ever seeing a lipoprotein fractionation on a regular, like it's just, it's just sort of amazing to me. And again, I've been doing this for almost three decades of using your test. It's just, I don't know how we would treat patients without it because you can't really you can't really interpret what's really going on unless you actually have the right information. And you might be mistakenly treating someone for something that maybe they don't have a risk for.

It seems obvious to me and to you, fortunately, and I just hope that eventually maybe programs like this, one reason I'm happy to have these discussions is maybe help people understand the rationale here. I think just to touch on one other test, I don't think we should leave out. It's not part of the fractionation analysis, but it's another important risk factor that's often overlooked. And that's like a protein small a.

Yeah, I mentioned it.

Or LP small a, which is an important independent research for heart disease. It, it looks like an LDL, but it has an additional feature that makes it even more toxic. So it's a, it's another bad guy that can be tested. using a different technique that's part of the overall lipid risk assessment. That's very important and very common to have high elevations even though they're genetic and very hard to treat. It's important, I think, to recognize the people who are at high risk.

Yeah.

Yeah.

Again, I mean, it seems like the, you know, the typical panel is not what people should be getting. They should be getting the lipoprotein fractionation. They should be measuring Apo B and A1. They should look at lipoprotein little A. they should be measuring inflammation levels with CRP. These are things that are not, you know, fringe ideas. These are mainstream ideas that are research and evidence-based but are not really in clinical practice much. And so often I think, you know, doctors are just laser focused on LDL and statins and that's what the pharma industry has been pushing. But, you know, the truth is, you know, there isn't like a magic pill for fixing pathogenic dyslipidemia, right? It's mostly diet related.

Yeah, diet, yeah, and of course, you know, medication plays into it as well.

I mean, the PC-KS9 inhibitors seem to be better at correcting some of the lipid abnormalities in the particle size that I've seen, but I don't know, it's a small sample size I have.

Yeah, it's probably just a result of the magnitude of the LDL reduction, 'cause with PCSK9 inhibitors, particularly on top of statins, you can get these very low levels of LDL and by that time there's just not enough to go around. There's small LDL or can be reduced, but it's not a selective effect. It's just sort of a hammering the whole thing down. Eventually, I guess, it's all LDL down. And that's due for high doses for statins as well. If you get the LDL low enough, a small LDL, concentration, even though people still may have a tilt towards smaller algal size, the amount of those particles is low enough that there's much less concern about risk. I just mentioned one thing going back to the testing. I'm not sure we need to advocate, at least I don't, routine fractionation in the entire population as a routine test. There's a even though the tests these days are not that expensive. I think.

No, it's like forty dollars.

I think.

Yeah. Yeah.

Regular cholesterol is maybe twenty dollars.

I don't know. I must say, my opinion about that has evolved as the price went down because it's the price. If the test costs a nickel, everybody should have it, right?

Yeah.

I mean, it used to be like 300 and now it's like, that's right.

Yeah. Yeah. So that, that. So that actually does. present the reason that I'm a little bit more open to more white spit testing now. But if someone starts off with a younger person with a low level of cholesterol, the standard test, triglycerides, HDL, normal, they're healthy, I think that might be sufficient, at least at that stage in life. Maybe later in life, as somebody starts to develop belly, you start screening for it. But, I'm not sure everybody absolutely needs to have this test, but I think unfortunately it's a large percentage of the population that really should have this kind of evaluation.

I mean, I mean, you just said something that I think I don't want to skip over, which is if you have a belly, because, you know, the, the key kind of indicator, you can see it from across the room to look, and I, I do this trick. It's like a party trick. I can look at someone and kind of guess their cholesterol levels. It's not like a party trick. And I can guess guess their triglyceride levels, and I can guess their HDL levels. I've seen so many thousands of patients, and I'm like, oh, you're gonna have high triglycerides, low HDL, small particles. And, you know, and it's like, as their belly grows, the worse it gets. And it's because of insulin resistance, which is really driving this whole phenomena. So it's really all driven by, like, pre-diabetes diabetes. And that's why people with diabetes have such a high risk of heart disease, because they have this particular profile. But now it's like one in two Americans have either pre- type 2 diabetes. And that's like a lot of us. And so, you know, when you think about the prevalence of it, it's, it's such an a critical, it's such a critical biomarker that often is being missed and, and really guides therapy because, you know, can you talk about, you know, the therapeutic implications? Because, you know, when you, when you just say, okay, take a statin, you're fine. You still may take, and I've seen this. People take statins and they're fine, but their triglycerides are still high. Their HDL is low. They have these small particles. it doesn't always work for that. And so how would you approach someone with this triad, this atherogenic dyslipidemia where the characteristics are these small particles, the low HDL, high triglycerides?

Yeah.

Well, first of all, I would rely on statins as the first line and trying to use the maximum amount of statins the patient can tolerate sometimes patients tolerate the statin, but to try to get as much reduction of those particles as I can, the statin alone. And that would follow the general guidelines out there for LDL lowering, because again, they can eventually hit the small particles. Adding a second category of drug, which I might mention it, it's called ezetimibe or zetia is CETIA that acts by a different mechanism than statins that can further lower cholesterol. We sometimes consider PCSK9 inhibitors if that's the LDL side. So the initial attack is really on the cholesterol side of things because those drugs that lower cholesterol sufficiently will eventually have some benefit. But if there still is a small LDL trait, and the kind of patient you mentioned, I see a lot of I actually turned to an even older medication called nicotinic acid or niacin vitamin. And we spent a lot of time talking about niacin. It had a very good reputation for a number of years, particularly when it was the only lipid lowering drug that was out there, quite effective in lowering cholesterol, but it was supplanted by the statins. statins and newer drugs in this category. And there's been a lot of backlash on using niacin. First of all, it can be difficult to use. Some patients can develop some adverse reactions. Many people get flushing and get uncomfortable. So it's not necessarily an easy drug to use. But despite some of the studies that have failed to show a benefit of niacin, It's been usually in patients whose LDL is already very low. And those patients niacin isn't going to do much. It can raise HDL. That's one of the reasons it's been advocated. But turns out raising HDL doesn't do the job. It's not effective in that regard. But it can lower those small LDL particles. We published that. And so I do use niacin. It takes high doses. It's not something you go to the drugstore and buy.

1500 milligrams a day, yeah.

You've got to use up to 2000 milligrams a day. That has to be done under medical supervision because there can be adverse effects that need to be monitored. But when the risk is high enough and the trade is there and we're not getting what we want from the standard cholesterol-lowering drugs, niacin can be extremely effective and should not be thrown out. as many people are advocating for that reason.

And what you're saying is the reason is that it may actually work on the small LDL particles.

Yes, it does. It can lower the small LDL particles. And that's in effect on top of statins. I would still consider the standard approach starting with statins to begin with, but this in combination with statins can be quite effective. And there's been some studies to support that. It's been hugely controversial because of the recent trials, as I mentioned, that there weren't patients who had really low cholesterol. But most patients, unfortunately, that we're talking about, they may have normal cholesterol. They don't tend to have very low cholesterol. And so those patients are not the kind that have been studied. Yeah.

Yeah, interesting. I think, you know, you know, one of the things also I wanted to talk to you about was the sort of heterogeneity in the population in response to diet and also even, you know, medication. And, and, you know, I just have a couple of patients that I always sort of think back to. One, one was a woman who was overweight, struggled to lose weight, very insulin resistant. Her triglycerides were like 300, her total was cholesterol was 300, or HDL was like 30 something, which is a terrible profile. She had a lot of small particles. She had very high total particle number. And I said, listen, I, I, let's do an experiment. We've tried a lot of stuff. Why don't you go on a ketogenic diet and eat butter and coconut oil, basically? And she did. And she came back and she lost 20 pounds, which she'd not been able to do before. Her triglycerides dropped 200 points. down to 100. Her total dropped 100 points. Her small particles went way down. Her total particles went way down. And she was so happy. And I was like, wow, this is amazing. And then I had another guy, and this is basically the opposite of what we're told to do, right? Don't feed people saturated fat, butter and coconut, which is saturated fat. But for her, it worked. There was another guy who was about 50 something who was thin, kind of like me. It was thin, older athlete, mid-50s biked like 50 miles a day, super athletic. He's like, I want to trade a ketogenic diet. I'm like, okay, but like, let's make sure we track your lipids and see what's going on. And he did it. And the exact opposite happened. He got his total cholesterol went up, his particle number went up, his small particles went way up. I'm like, you got to stop this. It's not good for you. So, can you explain that? And, and this whole concept of this lean mass hyper-responder versus the poor metabolic health and how we sort of maybe segment populations to figure out which group should have which therapy and which diet?

Well, I'll respond to that, but I'll tell you right at the beginning, the answer is going to be we don't know. I'll tell you a little bit about what we've been thinking.

That's like Einstein saying, I don't know. I don't have trouble with math, you know, I think you know.

Because we've looked at this a little bit, and it's mostly my clinical experience rather than any published studies. But patients who start off with this wastes, this lipemic problem, or pre-diabetes in particular, they're the ones who show the benefit on the lipid profile. They can lower their triglycerides, they lower the small LDL, as you mentioned. It's partly related to weight loss, it's partly related to low carb diet. The LDL cholesterol can sometimes rise, but it's the larger particle. So that's the kind of thing that in the end gives an overall benefit despite not lowering the standard LDL cholesterol test. And so that's a good thing in many of those patients. Weight loss is a big part of it, low carb is a big part of it. Now the subgroup of people you describe, I see those as well. They come to me exactly the kind of person you describe. A lot of people who are just health conscious and fit, embarrassed because they're fitter than I am. I think my goodness, here I am trying to tell them what to do, they're already doing it. But they've gone in this diet and their LDL has gone to really scarily high levels. I mean, not just elevated, but through the roof. And I have to say, first of all, in those patients from a clinical standpoint, and I've written on this, I actually wrote an editorial about this to one of the lipid journals stating that people should not assume that just because these individuals are healthy and their metabolic state appears to be normal, when they have an LDL in the ranges we're talking about, it's in the same range as we see in patients who get heart attacks in their 30s and 40s because they have genetic defects. They need to be treated and they should either go off the diet or if they consistent saying on the diet that should be on the drug to lower the LTL. So that I think that's an important clinical message. Why that happens is really an interesting question. And we're launching a study. I'll tell you right now that we're trying to raise money for this study because it's not the sort of thing that the standard funding agencies tend to be interested in. So we've got a program in collaboration with some colleagues in other institutions where we're gathering these so-called lean mass hyper responders across the board.

I'm one of them, by the way. I'm definitely one of them.

Oh, are you? Well, maybe we'll get your butt. So we're taking blood samples. Because what we think is that the subset of people, because we haven't found the genes yet, but we think there's some genetic underpinning to this. And so we're looking to see if we can identify this metabolically from looking at their blood cells. So that's the, as I said, The end of it is you don't know yet, but we're working on it. It's really an important question to answer because it's such an enormous change in our perspective on what regulates LDL levels. So this kind of a response can raise the LDL that high. We need to learn why. And so we really are focused on trying to find that.

Yeah, I mean, I actually, you know, I had a family history of heart disease in my family, and I was very curious about this. And I actually, you know, you know, Michael Davidson from University of Chicago, I'm sure he's a great lipidologist and he recommended a series of genetic tests specifically looking at lipid genetics and, you know, was able to identify patterns that I wasn't aware I had that were really interesting that kind of predisposed me to higher absorption or higher LDL production and, you know, more susceptibility to sort of changes. So I think, you know, people should not be guessing. You know, I actually co-founded a company, and I'm the chief medical officer of a company called Function Health. And, it's really about empowering people with this information. If 1% of your doctors are ordering this test, you're not getting what you really need. And, you're not looking at the lipoprotein fractionation. You're not actually even maybe looking at the other things that matter that we talked about, like lipoprotein(a) or ApoB, which are also part of the story. So, you're not even measuring insulin or blood sugar. So, we actually provide all these at very low price for people to be able to get, you know, for $500, a whole panel of 106 biomarkers and includes a lot of these things that we're talking about today that are often missed and it allows you to give a much more personalized view. And then you can track yourself over time. I mean, if you change your diet, you don't just want to do that and not look, right? You gotta see what happens, right? I started to change my diet and ate more saturated fat. I'm like, oh, well, this is not good for me. I can't do that. But it's great for, you know, my patient Sally or her Jenny who's very overweight and has really poor metabolic health.

Yep.

Really interesting. It's really interesting. And I think the question is.

Should.

This test be done every year? How often should it be done? And what do you think should be the sort of perfect, like if you're seeing your cardiology patients, you're looking at their limits. What does your panel look like? What are the things that you want to have to see for you?

That's interesting.

Well.

I order a limited number of tests. I'm not necessarily one of these guys that orders, you know, dozens of tests to start with. Because when I see a patient, it's usually because of a lipid problem to start with a lipid question. and so it is focused on that axis. So I order a standard chemistry profile, looking at things like fasting blood sugar, liver function tests. I should mention just briefly that the kind of doughy fat patient you were talking about also tends to have fat in the liver. And that fatty liver is becoming an increasing problem in the population, leading to cirrhosis in many patients, and that's part of the syndrome as well.

Yeah, it's connected to the poor metabolic health, right? So it's all one problem.

Right. And the highest, the people with that kind of liver disease, they tend to have heart disease because it's part of the whole syndrome. Anyway, I just wanted to throw that in because liver is a big part of it. And so we measure liver tests. Sometimes the treatments that we use, the medication can raise liver function tests. So I get that as a baseline. And then, of course, I measure the lipoprotein. profile I do our iron mobility test. I do that routinely. We measure Lp(a), we measure hemoglobin A1c, which I feel is a good screen for the insulin resistance, at least to start with. I don't necessarily insist on people having a more extensive glucose testing, but hemoglobin A1c works for me. And then every so often, if there are other concerns, particularly somebody who's already had some evidence of vascular disease, that's a big inflection point. If somebody comes in healthy, I usually stop there. If they have any previous history of heart disease, I would often order inflammatory tests, CRP as you mentioned. And that's actually about it. That to me is sort of a core set of tests captures really most of what I feel.

You check lipo protein A or Apo B?

I do measure Apo B. I don't routinely measure Apo B, not because it's not a useful test, but because the particle counts that we do essentially replace that. All the particles together make a nApel B, so I don't usually learn anything. Sometimes I do it to just sort of double check to corroborate the the results. But I do sometimes make sure that as well.

Yeah, amazing.

And.

In terms of the treatment, you mentioned statin, you mentioned the niacin, you mentioned maybe the PCSK9 inhibitors. In terms of dietary approaches, what are you telling your patients?

As we discussed, I've done a lot of work over the years with variance carbohydrate intake. And my focus has been sort of moderate. I have not been an advocate of the extremely low carbohydrate intake that characterizes the ketogenic diet, except perhaps in patients with diabetes, where we've been involved with some studies that have shown considerable benefit in reversing diabetes with this diet.

But for the ounce of prevention, pound of cure thing, right?

Right. So.

The majority of the people that.

I.

Give advice to on diet is based on the benefit of going to about half of what they're usually eating. So the average carbohydrate intake in the population is about 50-ish percent of total calories or higher. Or more. And so we studied down to 24-25%. So just taking half the carbs away can have a very dramatic benefit on the small LDL profile. That's the kind of diet I mentioned earlier that we tended to study the most. And that's considered pretty low. It's not super low, but it's well below the current population recommendations. And so it makes it a little less acceptable to our colleagues in the world of dietetics and nutrition, but it's not difficult to achieve that by certainly taking as much added sugar as you can, if not all added sugars out of the diet. That's the first place to start.

And refined starches too, right?

And refined starches. And that you can do an awful lot of good in replacing white starches with brown starches, replacing white rice with ground rice replacing, kind of standard breads with whole kernel grain breads, dark wheat breads.

German rye bread or something, right?

Yeah, exactly. Using high fiber cereal with no sugar. These are the kinds of things I tell my patients to do. And it's not difficult for most of them to follow their kind of diet. and they lose weight. Yeah, it's true.

Because, you know, it's, it's, you know, what the hidden dark side of this abnormal lipid profile is it's, it's kind of a indirect measure of your metabolic Health, right? It's in the measure of insulin resistance and your pre-diabetes and so when you have that, your insulin levels typically are high and that makes it very hard to lose weight. And so insulin is a fat storage hormone, makes you store fat and, and actually blocks this process called lipolysis, which is the breaking down of fat. so you can't actually burn fat. You store fat. It's like a one-way turnstile on the subway. You can get through, but you can't get out. And so, you know, you know, this is really the, the problem. So if you, if you look down and you see right now you have a little bit of belly fat, you're at risk. And it's important to check that. And even if you're not, it's important to check. You know, I think it's surprising this.

Whole category of healthy athletes who, you know, are kind of walking around with things that they, they have as an issue. We used to say, we used to say, pinch an inch. that's about. Yeah, there's some skin in there. Yeah.

And I think, you know, it's also this highlights this sort of, you know, the reality that we're still learning, you know, we're still learning about heart disease, even though it's the number one killer. And, you know, I had a patient the other day that just kind of, kind of totally was, was a outlier. He, he was, you know, a 63 year old guy. who exercise all the time, no body fat, you know, eats super low starch sugar diet, lots of good fats, some saturated fat, but not, like, overabundance. And, you know, but his lipid particle number was really high. And his, his small idea was really high, even though his HDL and triglycerides were perfect. His CRP was perfect. His blood sugar, metabolic health was perfect. So I'm like, wow, we need to do a test to see, like, do you have any heart? disease. And so we did a newer type of coronary angiogram that uses CT technology, but with the AI interpretation that allows you to look at soft plaque. And I was sort of shocked. I thought he was going to have like a heart disease filled, you know, arteries filled with plaque. And they were basically clean, even though his lipids were terrible. And I was like, well, this guy would go to a normal heart doctor or cardiologist, and he would be immediately put on statins. How do you think about somebody like that?

Well, I do exactly the same thing you just described. When I see patients who seem to be overall healthy and we're trying to decide because of the lipids, should they be on a statin, a coronary calcium test, one of the calcium-related imaging tests is extremely useful. In a patient like yours, and I see these patients as well, I think there's a perfectly legitimate argument, and I present this usually to the patient to help us decide. Should they just take kind of hedge their bets on potentially in the future developing some vascular disease, because we may not be seeing it now, but by the time if we do another test to see if it's progressed, it may be too late. And so are we going to just play the odds and treat anyway? But there is a perfectly legitimate, alternate approach, and that is to consider this person somebody that might be protected for reasons that we would like to understand from these bad effects of these lipids in their blood. I'd like to know about their family history, if they happen to have relatives who developed heart disease, I'd be a little more concerned. If not, it's not necessarily doesn't rule out a problem, but I'd be less concerned. I'd be willing and offer this as an option for those patients. Let's check you again in a couple of years. Maybe you're one of those people that are genetically free. On the other hand.

Is.

It that bad to just take a statin? I call it like a dietary supplement.

You just sort of, yeah, I'm not sure about that. I'm not sure about that.

I don't know. I mean, they're dietary supplements. Well, I know you're. I know you're dietary supplement, but there's some.

I should say there's some supplements that may be more harmful. That's fair. That's fair. But, you know, I think that concerns me about the status is that. Is that, you know, it has mitochondrial effects and it's such an important part of healthy aging.

Yeah.

And I worry about that. You know, I think. I don't know. I saw a paper once where they did muscle biopsies on everybody taking statins, and basically, universally, everybody had.

Even if they had no muscle pain.

Or elevated CBKs, which are muscle enzymes, they would have some mitochondrial damage from the statin. And I worry about that.

Yeah, I'm concerned about as well. Let me just mention one thing in relation to that, that even though we've been talking mostly clinical experience, I spend 95% of my time running a research lab. That's what I mostly do. And one of the projects that we're currently doing book, which we've just written up and actually, it's actually been published, is a study showing some of these mitochondrial effects of statin. It's actually in the literature. You can find it. Oh, yeah.

We'll put those in the show notes for anybody listening. Maybe, Ron, you can share that with us. But I'd like to put those in.

Because I share that concern. And I am concerned about somebody taking statin for 40 years and eventually developing muscle wasting that is worsened because of statin. I'm perfectly, I'm very concerned about that. However, if the risk is there, I tend to have that, you know, kind of be the overriding issue.

Yeah, for sure.

And if patients are asymptomatic and staying physically active, I mean, I have many patients taking statins in their 70s and 80s still, in fact, we keep asking you still need to take statins at that age who are just exercising and So again, it's a very individual as we talked about in terms of the LDL response to diet. I mean, people vary a lot in that. And so a lot of it is just based on careful clinical monitoring and judicious use of statins when they're needed. Yeah.

This is where medicine is an art and not always a science. If you love that last video, you're gonna love the next one. Check it out here.

If you are a male and your waist is 40 inches or greater, the chances are you have visceral and/or liver fat. And that probably means you have insulin resistance and you have mitochondrial dysfunction. If you.