i want to touch on particle size. so someone might put forth well you know total number is this but
let's consider the composition of those particles and they might go on further to posit that well
larger particles are less likely to be trapped within the arterial wall
compared to small dense particles so for that reason if total number is high
but it's mostly large we don't have to worry so much about being trapped and
hence less overall risk but it's a little more complicated than that, like
most claims, right, there is some truth in there but it doesn't exactly cover the whole story
yeah i think that's accurate so i don't blame people for thinking that and it's
not entirely unreasonable when you look at the observational evidence, again, that first pillar
that we talked about, you do see a correlation between particle size and risk and like you said,
people who have lower or smaller particles, smaller LDLs, tend to have higher risk, so it
would be suggestive that that would be protective. the problem is the observational stuff alone
can be misleading so we need to do more confirmation and so we have the same problem
is that these metrics all vary together, it's called collinearity, right, if you think about it
there's no way to change particle size by itself without changing other metrics, it's not possible
if you take larger LDLs and you reduce them you're necessarily trafficking around less cholesterol so
your LDL-cholesterol goes down. or if you want to keep LDL-cholesterol constant and reduce particle
size you have to increase particle number. right? so you're always stuck because always to
change one thing you have to change something else. it's just like the buses, if you reduce the number
of buses traveling around at a certain time you have less passengers traveling inside those buses
and if you want to leave the number of passengers constant and you want to build smaller buses now
you need more buses to carry all those people so because of this reason you, again, you need
to do further analysis to kind of untangle the different parameters, the different confounders
and so when you do multivariate analysis on the observational data what you see is that
when you adjust for the content of the particles and for the number of the particles the effect
of the particle size generally tends to go away, most of the analyses show that, and
then you can confirm that with the genetics, same thing, you can look at which metric tracks best,
is it genetically determined lower size or genetically determined content or genetically
determined particle number? and again you find that the risk tracks best with particle
number, with apoB, and in fact one thing that's come out recently in the last couple of years
out of these genetic studies that's really tantalizing is that even VLDLs, which
are by definition much larger than the largest LDLs, right? even VLDLs are atherogenic and it's
now thought that they're equally atherogenic to LDLs. so all of these apoB-carrying lipoproteins,
they represent roughly the same risk. now, i'm not saying i'm not saying total LDLs
versus total VLDLs because the number as we said previously is very different but particle
by particle they're equally atherogenic, so each VLDL to each LDL, and there's some speculation
on why that would be and the mechanisms behind that, we can we can touch on that if you want
but if this is coming out of the genetics, that even VLDLs that are much larger are equally
atherogenic, to posit that larger LDLs which are kind of intermediate... you'd have to wrap
your head around the fact that risk goes up and then goes down again, it has nothing to do
with size anymore. it's no longer explained by size. but basically yeah when you
do these more detailed analysis where you try to uncouple the different factors
the particle size doesn't seem to play much of a role. now, if people
are in love with the particle size and if they have a way to increase their particle size,
i haven't seen any evidence that that's detrimental
provided that you're not doing that at the expense of increasing particle number, that's
the critical caveat. because that would be jumping from the pan to the fire
so if you have a way to increase your particle size but leave your particle
number constant or bring it down i don't see a problem off the top of my head but
just to suggest that having increased apoB is okay because the particles are
larger, the bulk of the evidence is just not pointing in that direction,
it's pointing in the opposite direction, so i would alert people to heed apoB
and focus on that in terms of protecting themselves and lowering their risk