[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 and others 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.