March 31, 2020
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  • 2:53 pm Why You Should Try “Cook Once Eat Twice” Meal Prep | What We Ate Over a Weekend (Healthy Recipes)

[Rhonda]: Welcome to another episode of the
FoundMyFitness podcast. I’m sitting here with Dr. Ronald Krauss, who
is the director of the atherosclerosis center at Children’s Hospital Oakland Research Institute,
and he is an adjunct professor at the University of California, San Francisco. I personally think of Dr. Krauss as one of
the scientists that played a very important role in changing the way we think about cholesterol. And the way that he was able to do that was
developing an assay that is able to differentiate between the different sizes of lipoproteins
that carry cholesterol. Now, I’ll let Ron talk a little bit more about
that, but, you know, thanks for being here, Ron. [Ron]: Well, I’m delighted to have this conversation. [Rhonda]: So, for decades, we, meaning, you
know, most people, have this idea in our minds that there are two types of cholesterol. There’s the good cholesterol and the bad cholesterol. And the good cholesterol was thought to be
high-density lipoproteins or HDL, the bad cholesterol was thought to be low-density
or in low-density lipoproteins or LDL. But we know now, from your research and other
people’s research, that it’s much, much more complicated than that. There’s actually various sizes and densities
of these lipoproteins. Can you explain a little bit about what the
various sizes of these lipoproteins are and what they do in the body, what their normal
function is and what that means for heart disease risk? [Ron]: Yes. As you mentioned, cholesterol is part of the
LDL, but it’s not the whole story. When we measure LDL cholesterol, it’s really
the summation of cholesterol in a whole series of LDL particles that range from very small
and compact, or dense LDL, to large and more, people use the word “fluffy,” which is a term
that I’m not particularly fond of, but it’s buoyant and they tend to float more because
they actually have more cholesterol and they’re larger. So that spectrum of particles, we started
to break down with methodology that I was fortunate enough to have available to me and
helped develop to show that these different forms of LDL across this spectrum really have
very different metabolic and pathologic properties. And to keep it relatively simple, we initially
categorized those spectrum of particles into two major forms, those that are smaller and
more dense versus those that are larger and more buoyant. That somewhat oversimplifies the story, but
it does capture an important feature, which was what first attracted our attention to
this, and that is people with a higher heart disease risk and people who have evidence
of heart disease tend to have more of the particles that are smaller and more dense
particles. And those individuals that are more healthy
tended to have more of the larger, more buoyant LDL. That became somewhat counterintuitive because,
when we measure LDL cholesterol in the clinic as the summation of cholesterol and all of
these particles, we do know that that is with heart disease risk. LDL cholesterol is a reasonable measure of
heart disease risk. But what it turned out is that within these
particle profiles that we were studying, the highest risk was related to particles that
actually have less cholesterol in them. So it led to kind of a rethinking of the role
of cholesterol, not that cholesterol is not relevant to heart disease. In fact, it’s cholesterol that goes up in
the arteries. The question is, how does it get there? And it turns out that, even though these smaller
particles carry less cholesterol, they do have a greater tendency to wind up in the
artery wall. They can be bound more tightly to artery tissue. And once they get into the arteries, they
tend to stick, and they tend to be oxidized more rapidly. And all of these features we noticed helped
to characterize once we discovered this differentiation between larger and smaller LDL, and it helped
explain the associations that we saw, that is the particles that are smaller and more
dense do bring cholesterol into the arteries, but they have other properties that make them
more damaging to the arteries, as I’ve described, versus the larger LDL, that even though they
have more cholesterol, do not have the same pathologic features. And that differentiation, although it was
a somewhat oversimplification of what is in fact a much more complicated picture, does
carry into the clinic. And so we were able to develop a test that
had been used clinically in practice, I think, more and more over time, people are appreciating
the value of these measurements and thinking more about LDL particles rather than LDL cholesterol. [Rhonda]: I usually think of LDL cholesterol,
the larger, buoyant LDL cholesterol, as something that’s important for cells that need to repair
damage, to repair the cell membrane, those growing cells. What causes the formation of these smaller,
dense LDL particles? [Ron]: Well, it is true. We think about, you know, LDL as if it’s bad,
and cholesterol is bad. It, you know, gets in the arteries. But, of course, cholesterol itself is vital
for every aspect of human biology, ranging from cell membrane function, as you point
out, proliferation of cells, growth and the health of cells, are dependent on cholesterol. Most tissues, in fact, really, virtually all
tissues in the human body, under normal conditions, are capable of manufacturing their own cholesterol. That’s really an important system, which relates
to some of the other work we are doing when we start to manipulate cholesterol metabolism
with the use of drugs like statins and also with diet. But the fundamental role of cholesterol is
one that promotes health. Where we get into trouble is when it exceeds
the ability of cells to take cholesterol out of the blood quickly through the liver, and
it builds up in the blood and gets into the arteries, is where it becomes pathologic. But where do these particles come from? That is something that we’re very interested
in. The origin of LDL particles is in the liver. The liver packages lipids, cholesterol, as
well as other lipids, triglycerides and phospholipids into this spherical particle that also has
proteins, and so it’s a combination of lipids and proteins, and that’s how we get the term
lipoproteins, lipids and proteins complex together, for the most part, in the form of
triglyceride-rich, not cholesterol-rich, particles. There are ways of unloading triglyceride from
the liver. Triglyceride is a fat that’s used also for
many positive features of our life, such as energy storage and metabolism. And in packaging these triglyceride-rich particles,
there’s some cholesterol that comes along with it, and there are specific proteins that
characterize these particles, as well. There’s different forms of these triglyceride-rich
particles that are called very-low-density lipoproteins or VLDL. And the different forms of VLDL give rise
to different forms of LDL. That’s one of the reasons that we have these
different forms of LDL is that they can originate from different precursors produced by the
liver. So cholesterol, in a sense, is a passenger
on a train that is mainly delivering triglyceride, but that triglyceride gets used by the body. It gets hydrolyzed, it gets broken down into
fatty acids, which are used for energy and for energy storage, and muscle and in adipose
tissue, very important metabolic players. And as that process occurs through a lipase
that breaks down the triglyceride, the particles get smaller and smaller. They lose their triglyceride, but they tend
to retain most of their cholesterol. So there’s a shrinkage, where there’s a big
buoyant triglyceride-rich VLDL particle to a smaller, more dense LDL particle, and to
the extent that that process can continue to occur during the excursion of lipoproteins
in the blood, they can get smaller and smaller. And that’s how you finally wind up with the
smaller LDL particles that we’ve been talking about. So the role of cholesterol in these particles
is not a crucial feature of their biological role. As I say, most tissues can…in fact, all
tissues, as I said, can make cholesterol. Tissues don’t make triglycerides. So the triglyceride transport is a main feature,
and most people don’t understand that. And the LDL is kind of a byproduct of that
metabolic conversion that we’ve just described. And LDL are used by tissues, you know, a gland
uses LDL cholesterol, the gonads use cholesterol to synthesize, for example, hormones that
are made by those tissues. So LDL does have a role, and the cholesterol
does have a biological role, but it’s not a crucial one. And so that’s one of the issues that we have
as humans versus almost all other species, we don’t have a very efficient way of removing
LDL from the blood. So our levels are much higher than almost
any other species, certainly most other mammals. You have to feed an enormous amount of cholesterol
in order to get anything like what we have in our blood. So it’s this inefficient removal of LDL that
leads to the potential for accumulation in the blood and ultimately arteries, and it’s
really the fundamental reason that we, as a species, are so susceptible to heart disease
risk. [Rhonda]: I usually think of the HDL as serving
that role of removing it from our arteries. Is that an accurate way to think about it? [Ron]: Yeah. So HDL, and again, it’s the same general principle
that I’ve just described for LDL, is that HDL is a particle, or HDL are particles, because
again, like LDL, in fact, even more so than LDL, HDL is very heterogeneous, and there’s
even more biological variability among the different forms of HDL particles than is the
case for LDL particles. But if you group them together and you measure
the cholesterol within the collective HDL particle distribution, that measurement is
strongly associated with lower heart disease risk. We know this from countless studies. In fact, most people don’t realize that. So why is that true? Well, certainly, one of the reasons that’s
true is thought to be the process you’ve just described, which is the ability of HDL, and
particular forms of HDL which are still being studied, to extract cholesterol from tissues. All tissues, as I say, make cholesterol, and
when there’s excess cholesterol in the cell, it can be toxic to the cell. So it’s an important role for HDL to scavenge
cholesterol or to extract it from these tissues that are making cholesterol. And one of those tissues is the artery, and
there are cells in the artery, macrophages, that are filling up with cholesterol that
could ultimately cause heart attacks, you know, through plaque formation. Those cells, when they convey too much cholesterol,
can unload it onto HDL particles. And so it’s one of the reasons we think higher
HDL is beneficial. However, HDL cholesterol as a marker for heart
disease is not saying the same thing as HDL cholesterol is a cause or the factor that
low HDL cholesterol actually causes heart disease, because low HDL cholesterol is also
associated with an increased level of these small LDL particles. And that fact, that was an observation that
I first made that led me to realize that these LDL particles that are small and dense may
be associated with heart disease because they were associated with low HDL. And that represented, really, the axis of
a larger complex of metabolic relationships that we’ve termed atherogenic dyslipidemia. So what does that mean? That means there’s a collection of interrelated
traits that are related to heart disease risk, including, as I mentioned, small LDL, low
levels of HDL, particularly HDL cholesterol, and also high levels of these triglyceride-rich
lipoproteins and their remnants. These partially broken down VLDL particles
are called remnants. All of these things contribute to atherosclerosis
risk. So it’s a collective of this axis of interrelated
lipoprotein changes that is really the important measure of heart disease risk, probably the
single most important phenotype or trait related to lipids connected with heart disease in
the population. It’s not high LDL cholesterol that we most
commonly see, it’s this metabolic trait, atherogenic dyslipidemia, of which the small LDL is a
marker for and is almost certainly a causative feature of the disease associated with risk. But the HDL may be coming along, really, as
just a covariant. We don’t know that the HDL really has the
same important causal role as LDL. And the reason for saying that is there are
couple of lines of evidence, but the one that’s most compelling is that efforts to reduce
heart disease risk by treatments that raised HDL cholesterol have failed, whereas almost
every treatment that has been aimed at lowering LDL sufficiently has been successful. So as a causal factor, high LDL, and particularly
small LDL, is unquestionably a pathologic agent that is worthy of therapeutic lowering,
whereas the role of HDL is a bit more complicated. And the removal process is important, there’s
no question about that. The removal of cholesterol is important. But HDL is also a marker for this other syndrome,
and trying to raise HDL cholesterol is not necessarily guaranteed to reduce heart disease
risk the same way lowering LDL is. There’s also genetic arguments that have been
made. Genes associated with high LDL are associated
with heart disease risk. That’s a very important pathologic connection
because genes ultimately are the blueprint for our biology. And if the genes associated with high LDL
are also associated with heart disease risk, it says that the LDL is really the causal
agent. The genes associated with variation in HDL
cholesterol have, almost in every case, not been associated with heart disease risk, and
that is another argument that has sort of cast the HDL in a somewhat different light
than LDL, certainly as a target for therapeutic intervention. [Rhonda]: Yeah. You mentioned the generation of the small
LDL particles, the small, dense LDL particles, which, you know, through normal biology for
these LDL particles are donating triglycerides to cells and make them smaller and smaller. I’ve done a lot of reading directed from Mark
Shigenaga, he’d, you know, talked about some very interesting mechanisms and directed me
into the literature on the role of inflammation and inflammation in the production of VLDL. So, as inflammation goes up, VLDL production
is increased. And, at least in a couple of studies that
I’ve read in literature, it seems to be implied the reason for that is that inflammation increases
the release of endotoxin, which is a lipopolysaccharide from, you know, bacterial cell walls in the
gut that gets released, and it binds to lipoproteins, to all lipoproteins, and it’s sort of like
an adaptive response to make sure we don’t get sepsis or some sort of a toxic infection. And so I’ve done, you know, some reading on
a few studies that have shown that, you know, endotoxin does bind lipoproteins. And I’m wondering if you’ve looked into that
at all or what role the endotoxin in binding these lipoproteins seems to play in keeping
the smaller dense lipoproteins in the circulation longer or… [Ron]: Okay, all right. That’s a very interesting topic, and I’ll
just take a step back regarding the role of inflammation in lipoprotein metabolism because
that’s something that is not widely appreciated. We know that inflammation is an important
feature of many chronic diseases including heart disease. The artery wall inflammation really is the
major factor that converts a relatively benign cholesterol deposit into a much more nasty
and dangerous form that can cause blood clots and rupture and plaque formation that blocks
arteries. Inflammation is a key feature of that. So inflammation is really an important feature
of many aspects of the processes we’re talking about. But biologically, again, inflammation is not
designed to cause heart attacks, it’s designed to help us with host defense. So there’s a very interesting argument that
has been made that a part of the physiological driver for VLDL secretion by the liver, the
production of these triglyceride-rich particles, is really not a nutritional role, although
I think it does have an important nutritional role. But perhaps, even as importantly, it may serve
an important role in host defense. And so I’ll come to the LPS question at the
end of this little discussion because a really interesting sort of corollary of that is,
what role do lipoproteins have in the host defense mechanism? And what’s intriguing and it’s sort of like
a biological fact that we don’t want to make too much out of, but I think it’s very intriguing,
is that the liver constantly makes the major protein that forms the backbone of these VLDL
and multiple VLDL particles called ApoB, apoprotein B. It’s a very big protein that is biologically
ancient, it goes back to lobsters, and it’s a very important and complicated protein that
gives the integrity to lipoprotein particle. It helps keep all the fat contained and allows
the fat to be soluble in the bloodstream. That’s the secret of lipoprotein particles
is that there is a soluble protein that helps to keep the fat from forming droplets like
you see in chicken soup. It helps to dissolve the fat in a way. Anyway, the ApoB protein is constantly synthesized
by the liver. It’s under a tonic stimulation. It’s not much regulated, it’s just continually
being produced and degraded, which seems like a very inefficient process. But one of the thoughts that has intrigued
me and others is that the regulation of ApoB and the particles that are formed on ApoB,
the VLDL particles, is really to get these particles out in a hurry when they’re needed,
because VLDL, it’s a huge particle relatively speaking to most other biological proteins. Its molecular weight can be in tens of millions
as opposed to, you know, 50,000. So it takes a lot of work for the liver to
make one of these VLDL particles. And what the liver doesn’t want to do is spend
hours making a VLDL particle if it needs to come out in a hurry. But why would it need to come out in a hurry? Well, one of the arguments is it may be because
it contains components, which it does, that help promote inflammation in the circulatory
system. Why would that be important? Well, because when you have an organism, that’d
be the parasite or another infectious agent in the vascular system, malaria or parasites,
trypanosomas, whatever you care to mention, viruses, one way the body has of eliminating
them is by setting up an inflammatory response and an immune response related to that. And VLDL carry pro-inflammatory proteins,
they carry also pro-thrombotic proteins. They actually are a very efficient delivery
system, sort of like a fire truck that carries a lot of things that we can use to fight a
lot of infection. Now, biologically, in our current era of antibiotics
and antisepsis, that function has sort of faded, but the rapidity of this response and
the fact that it’s regulated, not by production of ApoB, but by degradation, suggests that
this is designed to come out in a hurry. And so degradation of ApoB is inhibited when
there’s lipid to be released. So the ability of the liver to secrete ApoB
and the lipids associated with VLDL is increased when there is this additional lipid production
that occurs, and that lipid production is stimulated by cytokines. So it comes back to the body having a foreign
agent in it, that foreign agent, these days, is more likely to be a plaque in the artery
rather than a bacterial agent, but the response is the same. So as we got cytokines, we got inflammation,
those come to the liver. And one of the early studies that got me interested
in this aspect of things is that we showed, in collaboration with people at UCSF, that
cytokines, such as TNF-alpha in particular, but interferon, as well, stimulate the production
of VLDL secretion by the liver. And so, again, infectious agent, inflammatory
signals, cytokines are produced, increasing lipid synthesis, reducing the degradation
of ApoB, allowing the rapid export of these VLDL particles, all of that occurs in minutes. And so that’s the sort of thing you want the
fire engine to get out of that fire station in a hurry. And so it’s an intriguing argument that is
consistent with the notion that inflammation is a key regulator of lipoprotein metabolism
in a positive way, historically, evolutionary-wise, but in an adverse way in our current environment. So where does LPS come in? Well, these particles that are secreted, as
I mentioned, will get smaller and smaller. LPS produced through this infectious inflammatory
signal does bind to these particles. Their binding to VLDL and LDL is partly, I
think, a protective mechanism to sequester the LPS. Again, this is somewhat hypothetical, but
it’s a plausible scenario, which requires a lot more study to really get the molecular
basis of this interaction understood. But from a physiological standpoint, there
is evidence that if you increase the clearance of LDL from the blood through drugs like statins,
which lower LDL by… We can talk about this perhaps later, the
role of LDL receptors in the liver is crucial to regulating LDL in the blood, because LDL
receptors, particularly in the liver, remove LDL from the blood. So it has been shown that if you increase
LDL receptor activity and increase LDL uptake from the blood, you can lower LPS levels. So it’s consistent with the idea that one
of the protective mechanisms, in addition to the secretion of these inflammatory molecules
that can kill bugs, one of the other ways that we are protected from the effects of
sepsis by lipoprotein metabolism is probably through the transport and ultimate removal
of LPS by these particles. HDL does that to some extent, as well. As I mentioned, all lipoproteins are capable
of binding LPS. Where that comes from, what’s the molecular
basis for this, and what regulates that binding, I think is an important question that we really
need to have more work on. [Rhonda]: I agree. And also, whether or not, you know, the binding
of these LPS to these lipoproteins stimulates more of an inflammatory response. [Ron]: Right, right. And the other thing you mentioned, which I’ll
come back to, is that the smaller particles, and, in fact, this is an important feature
of these smaller particles that I didn’t mention earlier, but may actually be one of the more
important reasons that they’re associated with heart disease risk, is they have less
affinity for the LDL receptor. That’s been shown by us and by others, that
as the particle shrinks to a smaller size, the region of the particle that is recognized
by the LDL receptor, which is actually a region of the ApoB protein, that is the receptor
recognition site for the whole particle, gets to be obscured, it gets to be less exposed. And that’s one reason we think that these
particles are less capable of being removed from the blood by the liver. There are other features of these particles
that contribute to that, including changes in other proteins that may inhibit receptor-mediated
uptake of the smaller LDL. So they hang around longer, and that may be
one of the more important reasons that they’re bad, is not because, partly because of the
binding to the artery wall, the oxidation, all of that is important, but the fact that
they’re circulating so much longer gives them much more opportunity to interact with the
arteries and undergo transformations that can be pro-inflammatory themselves. And the ability of LPS to stick to the VLDL
means that some of that LPS remains on the particle as it gets smaller and smaller. And if that particle isn’t being cleared rapidly,
the LPS will be circulating even longer, and it may be part of the whole process by which
this contributes to atherosclerosis. [Rhonda]: And I think that makes perfect sense,
and that’s a really elegant way of explaining it. But the inflammation brings me to another
topic, and that is diet. So I think you mentioned earlier that we produce
cholesterol in our cells, we’re making cholesterol ourselves. And I think that most people think about cholesterol
in their body as originating from the food they eat. They think, for example, if they eat an egg,
a yolk, which is high in cholesterol, if they eat six of those eggs, then their blood cholesterol
is going to go up, but that’s not necessarily true. Can you explain? [Ron]: So one of my multiple lives has been
in the world of nutrition, and, early on, I’ve been interested in nutrition virtually
all my life and really came into lipoprotein research because I had felt that diet had
a very important role in heart disease, and the lipoprotein effects of diet, I thought,
were really important. And I’ve been studying that now for a long
time. And so I became involved, not just on the
research side of things, but also more on the public health side through my work with
the American Heart Association, I became chairman of the nutrition committee quite a few years
ago now. And I remember that committee, which has now
morphed into a larger organization that I helped to establish within the AHA, so I’ve
been an important part of the American Heart Association’s messaging to the public. [Rhonda]: You’re involved in the dietary guidelines,
right? [Ron]: Yeah, from the American Heart Association,
I’ve actually did that twice. And so I was forced to sort of deal with translating
the science, such as it is, about diet and heart disease risk into something that could
be actionable. And that’s tough because the data linking
diet to heart disease risk through any mechanism, lipids or otherwise, really doesn’t necessarily
establish a causal role because there’s so many features in diet. You can’t just easily pick one thing or another. But cholesterol was on the radar screen. So, when I became chairman of the nutrition
committee on my first cycle, there was a lot of media. I spent a lot of my time dealing with the
media, and I was just astonished by the questions I would get about dietary cholesterol, blood
cholesterol, and, as we say, people just conflated those two terms. And I’ve spent a considerable portion of my
time trying to educate, like, the so-called science…well, the science writers who are
often not trained in science at all, actually, I’m sorry if I offended anyone. But they are trying to understand this and
they just simplify this right to the point where it becomes totally meaningless. The body makes cholesterol. It regulates the absorption of cholesterol
from foods. And the contribution of dietary cholesterol
on blood cholesterol, I was actually forced to address this in a very rigorous way through
a committee that I was on for the Institute of Medicine of the National Academy of Sciences,
which established dietary recommendations for macronutrients, which it was the first
time that anybody really did that seriously. So we produced this enormous volume. We had a committee looking at every aspect
of macronutrients and health. And my topic, which I had to take on, was
cholesterol, dietary cholesterol. And when I went through the literature, I
was just astonished that how small the effect is, and it’s very difficult to even imagine
how an effect of excess dietary cholesterol couldn’t influence heart disease risk unless
when you either had a mutation that caused the cholesterol to build up, or when receiving
an enormous amount of dietary cholesterol. But for the most part, the effect was so small
that it was almost unmeasurable. So we wrote that report and I’d sort of made
that point. And then 15 years later, the current dietary
guidelines come out saying, “After all these years of recommending keeping cholesterol
less than 300 milligrams per day, we realized that we no had data to support that.” And so it took a long time for the U.S. dietary
guidelines to catch up, and I was really in a bind because there was this historical precedent
of limiting dietary cholesterol because of its potential role in blood cholesterol levels. And it’s really not even worth talking about. [Rhonda]: But the idea is still out there,
and physicians still even recommend not eating eggs. [Ron]: I know. Yeah. So eggs is in a whole, another story. And so, again, when it moves from dietary
components to the food that those components are contained in, which was really one of
the messages that I’ve tried to emphasize in all the work that we’ve done, trying to
reach the public, which is, again, a nice opportunity here for me to do this with you,
is that we should be thinking about the overall context in which those nutrients are adjusted,
foods and dietary patterns. And finally, the U.S. dietary guidelines are
beginning to think about dietary patterns rather than just individual nutrients. However, they still have not abandoned focus
on measuring this or that fatty-acid. We should be thinking more about the overall
food context. And the important regulators of heart disease
risk from a dietary standpoint go way beyond the effects on blood cholesterol. And we have to think of a lot more complexity
in the role of diet, not that cholesterol and lipoprotein effects aren’t important. In here, we can point to saturated fatty acids,
for example, we can have a discussion about that if you wish, raising blood LDL levels. Does that translate into higher heart disease
risk? Well, it’s very hard to show that. In fact, there’s almost no evidence to support
that relationship. And parenthetically and maybe importantly,
we’ve shown that the form of LDL that increases with saturated fat is not the small LDL, but
the large LDL. And in fact, that led me to question whether
or not saturated fat was really an important factor in heart disease risk because our studies
did not show that it was increasing small LDL in the majority of the population. Maybe there are individuals who are hyper-responders
who probably ought to stay away from saturated fat, but for the general population, I began
to suspect that this relationship was not as strong as people thought because it was
the less dangerous form of LDL that was increased by saturated fat. In fact, that’s what we showed. And I have gotten involved now in a lot of… I’ve taken a lot of heat for that. But as time has gone on, we first published
this with Dr. Siri-Tarino, in my group, about five years ago now, and we were really hit
hard when we published that first paper questioning the relationship between saturated fat to
heart disease risk. I’m glad to say that, over the last year or
two, there have been a number of reports that have supported that absence of the strong
relationship. And the LDL part of the story, I think, may
be part of the reason for that, but there may be other factors, as well. Again, it may not be the saturated fat itself
that should be incriminated here, it should be the foods in which that is consumed. And there may be, for example, in fact, there
is evidence from epidemiology that red meat, particularly processed red meat, which contains
saturated fat, may have adverse effects on heart disease as well as life itself, life
expectancy, and other diseases, and it may not be the saturated fat that’s the most important
factor there. We don’t know. [Rhonda]: What about carbohydrates, processed,
refined carbohydrates and their effect on small, dense LDL particles? You’re talking about context with the food. [Ron]: Right, that’s right. So that takes me back to the nutrition committee
again. So, I started… I said I’d been involved in lipoprotein research
for a long time, and dietary effects on lipoproteins is part of our program. And I got into the American Heart Association
nutrition activity, really, as a result of that interest. And in addition to inheriting this confusion
between dietary cholesterol and blood cholesterol in the general public, I also inherited from
my colleagues and predecessors in the field the mantra that we should be going for low-fat
diets. There was a very strong campaign to keep the
message simple and stay away from fat, and there were a lot of forces in society as well
as in the academic and industrial worlds that had an interest in pushing that message as
a way to keep the public focused on what they felt was the most important thing they should
be doing, which is restricting fat and saturated fat in particular. But what nobody really thought about seriously
was the unintended consequence that that message, which the food industry responded to in a
very responsible way, they said, “Well, experts in the field are telling us to use low-fat
products, so we’re going to make low-fat foods. We’re going to make low-fat cookies. We’re going to make low-fat Snackwell’s brownies.” [Rhonda]: And butter and cooking oil. [Ron]: And so there was this tremendous response,
which led to a reduction in fat intake and saturated fat levels did go down in the diet. But the tradeoff was an increase in carbohydrates. So, getting back to your question, we became
very interested in studying the effects of a low-fat diet on lipoprotein metabolism. And so the very first study I did when I came
here to Berkeley and started to do some dietary work was to test the effects of a low-fat
diet, the traditional low-fat diet. This is, again, when I was trying to get involved
with the Heart Association. I was still in that mode. I was thinking, “Well, low-fat diets are good. This is what my predecessors had said, and
so, maybe that’s what we should be studying.” And the hypothesis was that people with small
LDL would have a good response, that we’d put them on a low-fat diet, their heart disease
risk should go down. Well, it turned out that it was actually the
opposite. We had a completely contrary result. We found that people who started off with
large LDL, when they’re put on a low-fat diet, actually made their LDL smaller. So it went exactly the opposite direction. And that was, like, an eye-opener to me, and
I think it’s still sort of somewhere percolating through the nutritional world. Not everybody has really understood the implications
of this. But what we’ve found shortly thereafter is
it wasn’t so much of the low-fat aspect of the diet that was causing this to happen,
it was the fact that we were substituting carbohydrates. High-carbohydrate diets can promote the production
of these VLDL particles from the liver that makes small LDL. So high carbohydrates clearly push the lipoprotein
metabolism in the direction of atherogenic dyslipidemia, all the features, high triglycerides,
small LDL, and to some extents, a lower HDL. And so we’ve tried to sort of break down the
dietary response into a more specific role of particular carbohydrates. As you know, carbohydrates cover a wide range
of food substances, ranging from simple sugars, like fructose and glucose, to complex starches
and fiber that are less easily metabolized and do not raise blood sugar levels the way
processed starches do. So we had been very interested in narrowing
that down, and we and others have pretty much come to the conclusion that probably the chief
culprits in the production of this atherogenic dyslipidemic trait, low-fat, high-carbohydrate
diets, are probably the simple sugars, and fructose in particular among them, which is,
of course, a component of table sugar and added sugars, half of that is fructose, the
other half is glucose. So we think all carbohydrates have this potential
for pushing lipid metabolism in that direction, but sugars, and particularly fructose, we
think are the most potent, and this has flown in with a huge popular attention. Now, people really do understand, I think
for the most part, that dietary added sugars have adverse effects, not just on lipids or
heart disease risk, but on many aspects of health and obesity, for example, being perhaps
the biggest public health issue that has been associated with added sugars, particularly
from liquids. [Rhonda]: But when you’re saying fructose,
what about fructose found in fruits or…? Is that as much of a problem? [Ron]: Well, fructose is, of course, a fruit
sugar, that’s how it gets its name. But when it’s, again, in the context of a
food, like a, let’s say, even an orange or an apple, you are not getting either the dose
of fructose or the packaging of fructose that you get when you add sugar to a Coke and then
drinking it in a concentrated form that’s absorbed more rapidly, and there’s much more
of it. You have to eat an awful lot of fruit to get
the amount of fructose that you get from a single can of Coke, for example. But also importantly, it’s the fiber and it’s
the overall packaging of the sugar that can sort of buffer its metabolic effects in fruits
that, I think, make it much less of a problem, from a dietary standpoint. [Rhonda]: So just that people understand,
you know, your research and others have shown that it’s more of the foods that have a high
glycemic index maybe. Foods that are more refined, had added sugars,
added fructose? [Ron]: Well, I kinda carefully avoid that
issue because I think there’s still a lot of uncertainty on that score. I think that the effects of fructose, the
metabolic effects of fructose are unquestionable. I don’t think there’s any doubt that this
fructose makes fat, makes the liver, when it encounters fructose, makes fat, and that
starts this whole process in motion. Starches, again, coming in various packages,
ranging from more easily processed and more rapidly broken down starches that makes glucose,
because that’s a big-time product of starch, they are considered high glycemic index, ranging
in starches that are less processed and consumed in the context of high fiber, which are less
rapidly broken down, have lower glycemic index. That’s all, no question about the differences
in those characteristics of those starches. However, it’s been difficult to show that
glycemic index itself is an important influence on lipoprotein metabolism or, for that matter,
heart disease risk. We sort of vilify processed foods, which I
think there’s a good reason to do, and that spills over into vilifying processed starches,
and I don’t have any reason to recommend to… I know, I see patients, I certainly tell them
to stay away from that stuff because it just adds calories and doesn’t have all the nutrients
that are contained in a fiber-rich whole grain form. But whether the glycemic index itself or the
glycemic load, which is the total amount of those carbohydrates that are consumed that
raise blood sugar levels, whether those are really harmful or not, I’ve tried to stay
out of that argument because I don’t think there’s really been a compelling amount of
evidence either way. In fact, a study was just reported by a colleague
of mine from Harvard in which they failed to show a relationship between glycemic index
and LDL levels or lipid levels. So I’d say that’s an open question. I think focusing on sugars and added sugars
is a way that we can all come together. People who would have been focused on fat
as a culprit, for the most part, are also acknowledging that added sugars is a big problem. So we’ve come together on this issue. Beyond that, I think we still have a lot to
learn. [Rhonda]: And the combination between the
added sugars and the saturated fat, is that perhaps the worst combo? [Ron]: That would be…that’s the one study
that I would like to see somebody fund. I’ve been trying to do nutrition research
in a controlled way for a number of years. And we sort of worked our way to that question. Could there be some combinatorial effect that
could explain what I would, you know, call sort of the Big Mac effect by having your
red meat, your bacon, and your cheese on a white bun with a milkshake? [Rhonda]: Right, with your Coke. [Ron]: Right, right. So I think that might be true, but it really
hasn’t been studied, and it’s something I really would… It’s very hard to find sponsorship. These studies are hard to do. They’re expensive to do. And we haven’t yet found anyone interested
in that question enough to seriously consider funding it. Because it involves doing a…when you get
into combinatorial nutrition, it gets really expensive, because you have to have an arm
where there’s a high saturated fat with lower carb, high saturated fat with high carb, low
saturated fat, you know, etc. You get into a very big production in order
to do that study properly, plus, which we think there’s heterogeneity in the population
that there are some people that are more sensitive to these adverse effects. So you have to have a large enough study population,
you know, 40, 80, 100 people minimum, to be able to sort out these effects. I’m somewhat, how should I say, frustrated
that that question may go unanswered. [Rhonda]: It’s a very important question that
we’re talking about. You mentioned that you think the role that
nutrition plays in cardiovascular health is very, very important. So people need to know what to eat. [Ron]: Well, you know, I’ll just say this
as an editorial comment. It’s a fact that NIH, which has been the major
funder of, which is the major funder biomedical research in the world, has basically pulled
the plug on clinical research support in general as a general area of emphasis. The infrastructure for doing good, and nutritional
studies in particular has relied on a mechanism that is now being withdrawn due to funding
constraints, and it’s affecting our ability to do good nutritional research. So we have to rely on other sources. And when we rely on industry, I’ve done a
lot of work that’s sponsored by the National Dairy Council, I’ll say that, you know, and
acknowledge as a disclosure, but they haven’t told me what to find, they didn’t tell me
that my first study was going to come up with a completely opposite result from what I expected. And nothing I have done since then has been
dictated by their industry, but they have been very good about funding the work because
we’ve been able to show that saturated fat is not maybe the evil agent of doom that it’s
been made out to be. And others have shown that when saturated
fat is packaged in a dairy product, particularly a fermented dairy product, there may actually
be some metabolic benefits. So we’ve been on a sort of a parallel course,
not because they’ve told me what to do, but because we’ve been very interested in pursuing
work that really, I think, justifies a somewhat more relaxed approach to consuming dairy fats
than has been generally recommended. Having said that, you know, I think that the
sponsorship for research of this scale has to come from other sources. And so I’m, you know, very glad that I’m involved
in an advisory role to such work that’s going on, funded through philanthropy. And I think that’s one of the best ways to
do research of the type we’re talking about, is through philanthropic support. But we still, I personally have not yet gotten
to the point where I see the potential for doing these large studies with the kind of
support we need. And as we say, I think it’s really important
that we figure out ways of getting that support. [Rhonda]: Well, you’ve certainly pioneered
much of the research that has changed the way the public thinks about, you know, cholesterol
and LDL cholesterol in particular, and also the foods we eat and how the foods we eat
affect cholesterol. It’s becoming more and more popular now that
saturated fats aren’t the culprit to heart disease [crosstalk 00:49:53]. [Ron]: As such, right. [Rhonda]: But here’s my next question for
you. So we spend, as a country, you know, tens
of billions of dollars every year on this drug that you mentioned, LDL-lowering drugs
like statins, and this, as far as I understand, is on the premise mostly that when someone
goes to get their lipid panel measured from their doctor, from their primary care physician,
it’s based on their total LDL cholesterol, because most physicians do not measure all
the different particle sizes of LDL cholesterol. [Ron]: Yeah. I mean, it’s not always… I’ll just say, it’s not something that has
to be done across the entire population. But certainly, when one is considering treatment,
there, I think, it does have a role. [Rhonda]: Yes. And so what are the effects of statins on
the small, dense LDL particles and in health, in general? [Ron]: So you’ve hit on another one of my
lives, because more than half of my research program, and in fact, the majority of my research
program now that’s NIH-funded is through a grant to study statin effects and the basis
for response to statins and the basis particularly for differential response across a population. So, as we’ve gotten deeply involved in studying
statins effects, we certainly have had an interest in determining how that relates to
the lipoprotein profile. And if you think back to what I described
about the role of the LDL receptor in clearing LDL particles, and the fact that the small
LDL particles are less efficiently removed by the LDL receptor, and one accepts the well-established
fact that a major mechanism by which statins lower LDL is by increasing LDL receptor activity
to take all that information and put it together, you come out with a conclusion, or the hypothesis,
perhaps, to start with, that statins would have a lesser effect on smaller VLDL particles
because they are more dependent on receptor-mediated uptake. And in fact, we’ve shown that. So we’ve done… Now, we’ve studied almost every statin and
shown that the effects on smaller LDL particles, particularly the very smallest LDL particles,
are blunted compared with the larger LDL. It’s not as if there’s no effect at all, but
they are less efficiently cleared. So statins tend to work primarily on the larger
cholesterol-rich LDL particles and the lowering of LDL cholesterol by statins is more strongly
related to that effect than the effect on smaller LDL, which are cholesterol-depleted. Now, having said that, there is absolutely
no doubt that the LDL-lowering effect of statins contributes to reduced heart disease risk. I think that’s unquestionable. There are other mechanisms involved, I’m sure,
that we’ve been studying that can be influenced by statins, including adverse effects, which
is a very important part of our current research. But the benefits are absolutely well-established. One of the most effective treatments we have
for any medical condition, other than maybe antibiotics for infections, are statins for
lowering LDL, 30%, 40% reduction of risk, big time. And so that’s because there are a set of LDL
particles that are lowered by statins that are bad. And so it’s not as if it’s all or none, it’s
just statins could be more effective if they were able to lower the smaller particles. [Rhonda]: The ones that play a bigger role
in heart disease risk. Well, the way I think about it is if you’re
lowering the larger LDL particles, even though, in a way, I don’t think that’s good because
you need larger LDL, but you’re also lowering, you have less of it around to be processed
into lower or smaller LDL particles. [Ron]: Yeah, yeah. Although a part of that effect… Yeah, that’s right. Although part of the effect in the small LDL
is coming through the triglyceride axis, which we’re very interested in that effect, as well. Statins may affect triglyceride metabolism
in ways that could affect small LDL production. But the net effect is less than it could be
if we had a drug that lowered the small LDL particles more effectively. [Rhonda]: What do you think about dietary
changes compared to using statins? Like if a person, I know not everyone’s going
to do a dietary change. So statins obviously have their place, and
they are probably saving, you know, a few years on people’s lives that wouldn’t otherwise
make any dietary change. But what are your thoughts or, you know, on
dietary changes in that modulating heart disease risk as opposed to taking statins? [Ron]: So I have to have a disclosure here,
you know, spending a lot of my time and still doing a lot of work in nutrition, it’s been
frustrating to observe how limited the evidence is that making a dietary change reduces heart
disease risk. The strongest evidence that we have for any
kind of treatment is based on randomized control trials. And as I mentioned, dietary studies, even
measuring lipids, let alone heart attacks, required an enormous investment of time and
energy and funding. So there’s been very little basis for concluding
that a dietary modification, lower fat, lower carbohydrates even reduces heart disease risk. And it partly is because the studies haven’t
been done and partly because the studies that had been done had been limited by a number
of issues, compliance to these studies, it always decays over time. You need to be on these diets for long periods
of time to see an effect, plus which the actual dietary effects are not huge. They vary among individuals, so there’s people
that are really responsive to diet, and I see these in my practice. From diet is extremely important. But if you average it out over the population,
the effect on markers of heart disease risk, lipid, small LDL, or blood pressure, even,
they’re measurable. But in terms of the magnitude of those effects
across the population, they are much smaller than what can be achieved with statins and
their effects on LDL levels. It’s disappointing to have to say that because
I’m a firm believer in lifestyle and lifestyle intervention, both diet and exercise, for
reducing heart disease risk and promoting health overall. But when it comes to people who are at high
risk for heart disease, diet alone is frustratingly difficult to show if there can be a long-term
benefit, not because there isn’t such a benefit, but the studies just aren’t there to help
support that. Statin trials supported by industry, big studies,
tens of thousands, hundreds of thousands, we have assembled data from 40,000 people
in statin trials looking at genetic effects and response, huge amount of data, beautiful
data. Millions that have been used to support these
studies. [Rhonda]: That’s disappointing to me, I mean. [Ron]: Yeah, right. Well, that’s right. So the money has been coming where the profit
comes in. And fortunately, in the case of statins, it’s
been okay because the statins, by and large, have fulfilled their expectations. With the proviso that there’s a huge variation
in response, and even though there’s a 30% to 40% reduction in heart disease risk in
patients who are at risk, or even in the general population, it’s been implied since that happens
to just huge segments in the population, men, women, different ethnic groups, different
lipid levels, and they seem to have a similar benefit across that population, but it’s not
100%, and it’s not even 50% for the most part. So there is that residual risk on statins
that we still have to solve how we best approach that. I think lifestyle is important. I think if we were all fit and lean, a lot
of that residual risk would go away, very hard to prove that, but that seems like a
very plausible and certainly, in my case, actionable advice to give to patients is to
work on things that you can control in your lifestyle. But if you remain at risk for heart disease,
as a physician, I’ll have a statin prescription if I felt it was needed, not to guarantee
that people are going to live forever or anything close to that. But it has a statistically real effect on
risk, and we haven’t gotten there with diet. We don’t have that kind of data for diet. [Rhonda]: So this sort of leads into my next
question is, do you think that statins are overprescribed in a way based on, you know,
the fact that most physicians don’t look at all the LDL particle sizes, don’t look at
all the genetic factors? They just look at, you know, total LDL cholesterol,
and it gets really high. You know, maybe they have high ApoB, they
may prescribe statins, you know. Whereas if you look at two people, they may
both have high LDL total cholesterol, but one may have no small, dense LDL, and one
may have high. So, and then what about the side effects of
statins? So, are they overprescribed? And are there side effects? [Ron]: Okay, these are great questions which
have a lot of implications. Regarding the prescription of statins, depending
on which hat I choose to wear. I could argue that statins are overprescribed
because a lot of people are taking statins who are not likely to benefit. But I can put on another hat and say there’s
a lot of people out there who should be on statins who aren’t because physicians aren’t
really sufficiently aggressive in taking high-risk patients and lowering their LDL in a way that
still is safe. So there are subsets of the population that
are undertreated and there’s a large segment of the population who are taking statins prophylactically
based on guidelines which have continued to evolve, which I was part of that process for
a while, and then I withdrew from it because I realized I was not happy with the way things
were going in terms of the recommendations, which have evolved to identify even larger
segments of the population that should be taking statins to the point that, I think,
there are a huge number of people that are going to be taking statins who really don’t
need it. And that’s where the adverse effect problem
comes into play. So my current NIH grant, which is, again,
the biggest part of my program right now, is to identify markers for susceptibility,
both to the benefits of statin as well as to the adverse effects. Some of those adverse effects, people tend
to minimize because the benefits for high-risk patients are so evident from the clinical
trials. But as you look at the data, there are some
pretty surprisingly adverse things that are out there that are a little bit below the
radar screen. One of them is muscle effects, which surely
have been recognized. People tend to think about them in the more
extreme case where people get muscle damage and life-threatening complications of muscle
breakdown. That’s very rare, fortunately. Otherwise, statins wouldn’t be out there in
the way they are. But we and others need to develop evidence
that there may be effects on muscle metabolism that might be much more widespread that could
accumulate over time in a way that may not be manifested in an obvious symptom, but could
lead to changes in muscle function, muscle strength. This is a hypothesis that I know has worked
in between now in terms of the adverse effects of statins on muscle. But there is an even bigger problem, which
emerged a few years ago, from one of my colleagues, actually, at Harvard who discovered in a clinical
trial that he organized and then it turned out to be in the literature, people just hadn’t
really recognized it. A significant percentage of people taking
statins go on to develop diabetes, and diabetes is not something you want to acquire as a
result of drug treatment. It, of course, increases heart disease risk. The magnitude of that effect turns out to
be surprisingly high. It’s something on the order of 11% to 12%
of statin users are at risk for developing type 2 diabetes. In women, in particular, we published a paper
that sort of opened this up, actually. In women, the evidence is maybe 2 or 3 or
4 times that, maybe as many as 30% to 40% of otherwise healthy women who are put on
statins could go on to develop type 2 diabetes over time. That’s a very unacceptable number. Now, if you’re a woman that has a high LDL
or a woman that has a predisposition to heart disease risk, that shouldn’t stand in the
way of treatment. But because our guidelines have opened up
statin use to a much larger percentage of the population as a prophylactic, in what
was called primary prevention that is in healthy people who have not yet had a risk of heart
disease, but who are considered at risk, because a high percentage of those individuals, and
women, I would point out in particular, have a relatively higher likelihood of an adverse
effect, type 2 diabetes in particular, than benefit. I think we have to look seriously at finding
ways of improving our selection of patients for statin use, and that, again, is driving
my research. And fortunately, again, as much as I’m wedded
to nutrition and its role in health, and in heart disease in particular, statins are a
lot easier to study. And I think, from the public health standpoint,
especially now with widespread use of statins, almost like a dietary supplement that people
take statins, you know, so it’s like a vitamin, we have to be really careful about that. And that’s where, I think, hopefully, the
studies were embarking on, and this year, in the current phase of our grant cycle, we’re
just starting to do this, where I really feel very committed and passionate about using
the tools of what we call precision medicine or genomic medicine as well as more refined
laboratory tools such as particle measurements, I’ll come to that in a minute, to better identify
those people who are most likely to benefit. So I think physicians, getting back to your
question, who are using LDL cholesterol as the barometer of statin efficacy are potentially
going in the wrong direction. And we need better attention to the particles
and the measurements of the particles themselves rather than LDL cholesterol. When we, as physicians, are recommending,
particularly drug treatment, we should be monitoring those particles as a primary target
of treatment because they are, and particularly smaller particles give us a much better handle
on therapeutic benefit of any treatment. [Rhonda]: So the test that you played a role
in developing, which is, I believe, used by Quest Diagnostics and it’s, like, based on
physics, essentially, right? Just throwing these particles through the
air, and, based on their way they’re going through the air, you can figure out their
density. But why is that not used in medicine? And can we get physicians to start adopting
this? [Ron]: Yeah, well, of course, I’ll, you know,
disclose here that along the way, because of my interest in lipoprotein metabolism and
where I’ve been able to do my work, initially at the Lawrence Berkeley lab and now here
at Children’s Hospital, I’ve been able to work with people that have had analytic capabilities
that have led to methodologies, the most recent is the one you mentioned, I’ll come back in
a minute to that particular method. So we brought this to the public through industry. And so, you know, we do have patents and they’ve
been licensed to do this methodology. So that’s a disclosure. But that’s the way you get things out there,
is through that kind of partnership. And it has penetrated a certain segment of
the preventative cardiology community. There are lipidologists, in particular, who
are proliferating, fortunately. There’s a lot of lipid education going on,
and the people that are really skilled and understand lipid metabolism are at least thinking
about lipoprotein particles, not necessarily yet about sub-fractions, but at least a particle
versus the LDL cholesterol is taking you in the right direction, because that’s really
the first step in terms of narrowing down the focus on what you should be treating. That’s being understood, but it’s still a
relatively small percentage of the entire medical community that would consider themselves
lipidologists or cardiologists. What about the rest of the physician community? Well, they’ve been confused. And a part of that is because there’s been
a number of methods that have been out there, not just the ones that I developed and others
that have used different systems and different calibration, different ways of organizing
the data, different ways of trying to educate the public, a lot of it driven by the companies
that have promoted these methods. And so physicians were getting a rush and
still are with competing claims for this or that method, not as well standardized, certainly,
as the LDL cholesterol measurement. So it’s been kinda given a backseat in part
because of that confusion, in part because a lot of people are still not convince and
even my colleagues, even the lipidology community is not fully convinced that the smaller particles
are that much worse than the larger particles despite all the data we have. So I’m always on the trail trying to sort
of remind people of what the data show. I give a talk called “Not All LDL Particles
Are Created Equal,” and people just need to understand that. So there’s been a slow uptake because of the
confusion, a scientific confusion, a methodological confusion. And at one point, it was a price issue, as
well. Is it really cost-effective to be using this
test and, you know, hundreds of thousands and millions of people, why did it cost an
arm and a leg? Well, this new method that we’ve… It’s not so new anymore, I’ve been working
on it for, like, over 10 years, but Quest did partner with us and has been now more
actively engaged in supporting the development of this methodology improvement and methodologies
to be more refined, since it’s one of the more refined measurements… In fact, it is the most refined measurement
we have for lipoprotein analysis. Using this technique called ion mobility,
which sprays particles into air, and then we count them as a function of size and it’s
really elegant, it’s based on physics. And it works, and it gives us data that is
entirely consistent with everything we’ve known from our previous methods. Its standardization is in progress, but it’s
relatively easily standardized, and its cost has come down to something, you know, that’s
not that much more than doing a standard cholesterol panel. So none of those things should be barriers
anymore. So I’m hoping that as time goes on, hopefully
within my lifetime, that physicians will see the role of this in their clinical practice,
certainly when they’re trying to make a treatment decision, if they’re considering a patient
for some sort of intervention, I think that’s where the particle analysis really is important. For screening the population, I think one
can argue, the standard lipid tests do a fairly good job. But if you’re having somebody, if you or,
in my case, my patients, are on the cusp about whether they should be dealing with their
lipids, I think these measurements add enormously to our ability to target those people who
would benefit from certain kinds of treatments, statins, diet, and then monitoring them as
they’re undergoing treatment. [Rhonda]: So, if anyone that’s had a standard
lipid panel done, and let’s say their LDL cholesterol was high, they can go to Quest
Diagnostics and get that test done, or do they need a doctor’s prescription for [crosstalk
01:11:01] ? [Ron]: No, no, yeah, no. This is all done by medical orders. There has to be not only a doctor’s prescription,
but there’s gotta be a diagnosis. [Rhonda]: Diagnosis? [Ron]: Yeah. To get insurance reimbursement, you have to
have a defined basis for doing those tests. Insurance policies, Medicare are starting
to, have been reimbursing for those tests, but you have to have a medical reason. And that gets back to the issue of what criteria
should be used to identify someone who should have this test done. One could argue that if one has a really high
LDL cholesterol, one might not even need this test because if the LDL cholesterol is enough,
it’s almost always going to have some of the small LDL particles in it. I’m talking about very high LDL. The people that really are most likely to
get benefit from knowing what their particle profile looks like are those that have sort
of the garden variety levels of LDL cholesterol. [Rhonda]: What’s that considered to be? [Ron]: Well, the average in the population
is something like 115 or 120 milligrams per deciliter. If you take a population of heart attack patients,
it’s going to be slightly higher than that. So that’s another one of the important messages
that we and others try to convey, is that LDL cholesterol, because of this particle
difference, does not discriminate heart disease patients from the general population as well
as does the particle measurements, which are more specifically related to disease risk. So, in those individuals who have LDL cholesterol
in that sort of borderline range between “normal,” you know, unaffected people at low risk for
heart disease versus those that have heart disease, there’s a relatively tight range
occupying the middle of the LDL cholesterol distribution. That’s where I think this particle measurement
really has the greatest potential for refining risk assessment and identifying people that
should be considered candidates for treatment, with whatever one can use to help lower those
particle concentrations. [Rhonda]: I don’t want to take too much more
of your time because you’ve been so generous and we’ve covered so much. But this brings me to one… What about someone, as a follow-up to that,
what about someone that has, you mentioned, genetic risk factors? Let’s say they have a genetic risk factor
like, you know, they would have an ApoE4 allele, which means they can’t recycle the LDL cholesterol
back to the liver as efficiently. And so they have more LDL cholesterol around,
and they have a level of, let’s say, 150, which is much higher than what you said the
average would be, but they don’t eat a lot of refined carbohydrates or added sugars,
things like that. Do you think they could still benefit from
this, you know, particle test? [Ron]: Well, those that have ApoE4, you know,
have a sort of additional dimension to risk. We don’t understand all the reasons for that. But the determination of small LDL particles
is driven by many other factors, including other genes, that are probably even more important
than ApoE, actually. So the ApoE4 axis sort of amplifies the risk
associated with small LDL or any other lipid, or heart disease risk factor. But the recommendations for trying to monitor
or manage small LDL particles, I thought about this a lot recently, I think they represent
sort of a separate axis from the ApoE. I think the ApoE axis amplifies the risk,
but it doesn’t necessarily change the fundamental biology for the production of the small LDL
particles. [Rhonda]: But if someone were to have their
lipid panel done by their physician, and it was 150, let’s say they didn’t know they were
ApoE4. Their physician would look at them and go,
“Whoa, that’s really high.” [Ron]: Right. And I think, you know, it’s not just on the
LDL, but there’s a range. If you want to actually pick a number, the
sort of consensus number that the lipid community, the cardiology community has accepted as mandating
attention for genetic reasons is an LDL actually at 190. So it’s even higher than that. So I’ll start with that. If your LDL is 190 and greater, the particle
measurement probably isn’t going to affect the treatment decision because in almost all
cases, those patients have genetic abnormalities. ApoE may be part of it, but not the cause
of those very high levels, that’s usually an LDL receptor abnormality. Those patients are at, sufficiently, a high
life-long risk of heart disease that they are candidates for statin therapy almost in
all cases. It’s very difficult to achieve a significant
approach towards optimizing LDL levels in those patients. So that’s 190. One-fifty, sort of halfway in between. So that’s a gray zone. And so it depends not just on the LDL, but
the overall risk, blood pressure, diabetes, family history. [Rhonda]: Triglycerides? [Ron]: And triglycerides have not entered
into the equation. So, you know, there’s epidemiologists that
do all this number crunching, and they come up with risk assessment tools. Triglyceride hasn’t entered into it because
it’s so tightly related to everything else. And so it’s a very bouncy measurement. It’s much less stable over time, even from
day-to-day, as LDL cholesterol and HDL cholesterol. So it sort of falls out of these equations. But it’s part of this atherogenic dyslipidemia
phenotype, it’s part of that trait. It’s important. But as a measurement, it doesn’t stand up
to the LDL particles in terms of its association with risk or even HDL. So, anyway, this risk assessment is done,
and then you decide, “Well, is this patient at sufficiently high risk using these,” you
know, if you’re in the swing of things with the guidelines, you do these assessments of
likelihood of having a heart attack over the next few years, and if it’s high enough, then
you jump in with aggressive treatment. And I think if the risk was high enough, you’d
probably use statins. You need to use statins for those patients,
as well, but it’s not an automatic decision. That’s where the particle measurement hasn’t
yet achieved the level of acceptance to enter into those risk calculation formulas, partly
because the risk assessment tools that we have work pretty well by themselves. And this is actually a very interesting point
from sort of a, how should I say, a conceptual standpoint. So I’m just going to say this because that’s
maybe a little bit complicated. But when you have some very strong predictors
of heart disease risk, blood pressure, diabetes, even LDL cholesterol, HDL cholesterol, use
standard measurements. And you throw them into a risk formula and
you add in age and sex, you can explain a lot of risk that way. We can argue what that explanatory number
is, whether it’s 50% or 70%, it’s very high. So if you add LDL particles or these more
refined measurements of particle concentrations into those formulas, you don’t get much additional
explanation of risk, because a lot of these things are interrelated with one another. And so there is a confusion between the magnitude
by which you can improve risk prediction by these measurements versus what’s really important
biologically that you should be treating. And so people think, “Well, because the particle
measurements don’t add that much to the risk assessment, but it adds to the measurable
amount, it’s not just a lot.” People say, “Well, let’s not worry about that.” But from a biological standpoint, that may
be the driving factor. So if you turn that whole process around,
and you throw out the standard factors, and you just use the particle concentrations and
maybe a few other things like age and sex, you can also explain a lot of the risk. So you can choose your weapon, but don’t confuse
the ability to predict risk with what you should be treating, because those are not
always the same. I hope that’s not too complicated, but that,
to me, is a very interesting point. [Rhonda]: It is very interesting. It is very interesting. It is a little complicated. [Ron]: It is complicated, so we may not want
to get too far into that. And then there’s also the issue of relative
risk versus absolute risk, which is an important… That’s something that I think people should
be able to understand because it’s really important, as well. If your absolute risk of heart disease is
very low, if you’re, like, a super-healthy person that has immaculate blood pressures,
lean, fit, blood sugar is great, and their LDL cholesterol or even small LDL particles
are elevated, it may increase the risk by two or three-fold. But if it’s two to three times a very small
number, that’s still a very small number. And people sort of confuse that with how much
benefit you’re likely to get from lipid lowering, it really depends on the absolute risk. [Rhonda]: Right. No, that’s actually a really good point, and
I think we’ll end on that point. Ron, thank you so much. I know that you don’t have a website, but
you are, you know, people can find you at CHORI. What about talks? You mentioned “Not All LDL Particles are the
Same.” Were there certain talks people can look up
and find if they want to hear you speak? [Ron]: Yes, there have been some webcasts
that I can’t give you chapter and verse, but I’m Google-able, I guess. [Rhonda]: Ron Krauss, Google. [Ron]: Yeah, something like that. [Rhonda]: And, also, they can find you at [Ron]: Right, exactly. [Rhonda]: So, thank you so much, Ron. [Ron]: Okay. Nice talking to you. [Rhonda]: Really, really interesting conversation. [Ron]: Great questions. Okay.

Randall Smitham