[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, low HDL cholesterol is a stronger predictor of heart disease risk overall than
is high LDL.
And 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.