00:02
Another interesting point,
in any vessel
in the body,
it has been exposed,
theoretically uniformly,
to all of the things that drive
the production of atherosclerosis.
00:16
So if there is hypertension,
the entire vascular tree
is pretty much susceptible to that
same level high blood pressure.
00:23
If there's hypercholesterolemia,
pretty much the entire
vascular tree susceptible
or is being exposed to that
same level of cholesterol.
00:32
If you are a smoker,
whatever the evil humours are,
that are in that
cigarette smoke,
that's also been distributed
and exposed everywhere
within the vascular tree.
00:43
And yet,
when we look at atherosclerosis,
it is not a uniform process.
00:50
That is to say,
only certain parts
of certain vessels
are impacted.
00:55
It's a non random distribution.
00:58
So the lesion that are the..
01:00
The image that we're looking
at in the middle there,
that has black, that's an aorta.
01:06
And we have taken the aorta out,
and then labelled it with a
compound called Oil Red O.
01:13
And that will stain lipid deposits
in atherosclerotic plaque.
01:18
That red is only
in certain areas.
01:21
It's not everywhere.
01:23
Even though this entire
aorta was subjected
to the same evil humours
in cigarette smoke and
hypertension, in diabetes all about.
01:33
The image on the far right
is a coronary artery.
01:37
And the circle all
the way around it
is the typical medial smooth
muscle of the normal arterial wall.
01:45
That kind of semi circle
of pink that's in the upper
two thirds of the vessel.
01:51
That's atherosclerotic plaque.
01:53
Note,
that part of the vessel
has atherosclerosis,
the bottom part of the vessel
is absolutely pristine.
02:00
It's thin walled,
there's no athero.
02:03
And the difference between
the top and the bottom
were flow characteristics.
02:08
So that's the next
thing I want to say,
flow influences where
plaque develops.
02:13
And in the image in the middle,
you can see at branch points,
particularly up again,
around the arch vessels
up near the top,
where there's branching,
there's a lot more athero.
02:23
And there tends to be more
athero as we go more distal.
02:26
And at branch
points, all that red,
through the thoracic aorta,
is because we have little
tiny branch point vessels,
and it's at those bifurcations,
where we have turbulence,
that we're getting
atherosclerosis.
02:40
So it's not just all the
other things we talked about,
including not just inflammation,
but it's also
influenced by flow.
02:48
Let's look at this a
little bit more closely.
02:50
Just because this is near
and dear to my heart,
no pun intended.
02:54
If we look at say the
carotid bifurcation,
so this is a model of
the carotid bifurcation
into the internal and
external carotids.
03:03
We see that there are
areas up near the top
of that bifurcation
where flow is now
physiologically laminar
at a certain pressure
and flow rate.
03:13
And the flow is going
in straight lines.
03:16
In that region of the
bifurcation near the top
where it's laminar flow,
we tend not to get
atherosclerosis.
03:26
If we look at this,
and it's been modeled very carefully
with MIT undergraduates
and a lot of very
interesting studies.
03:35
There's a certain
flow characteristics.
03:37
Remember,
this is pulsatile flow.
03:39
So you can have a heartbeat,
and we're seeing the
shear stress shown there
as a function of time
throughout the cardiac cycle.
03:46
The athero-protective waveform
is tears your shear stress
shows that particular waveform.
03:53
Now if we go and look at that
same carotid bifurcation,
and we look at a lower
area, lower down,
where we are more prone
to get atherosclerosis,
so it's athero prone,
there is turbulence
or low shear.
04:08
And the waveform
looks quite different.
04:12
And we can actually
model those waveforms
in Vitro experiments.
04:19
So we can take endothelial cells
and see show they behave if we
give them an athero-protective
shear stress waveform,
or an athero prone
shear stress waveform.
04:30
To really get at our hypothesis,
that flow also determines
where atherosclerosis develops.
04:37
That's what's shown
here and this is just,
this is a real experiment,
but we'll walk through it.
04:44
So if we have a vessel
shown on the right,
and we have an inflammatory
cell, a monocyte,
flowing through that area,
the endothelial cells have relatively
flatter cells top and bottom.
04:56
The middle of that is the lumen
in the thing with the white rim around
it, it is a monocyte.
05:02
And if we don't have any
endothelial cell treatment,
there is no expression
of adhesion markers,
and we don't recruit
inflammatory cells
remember inflammation and major
driver of atherosclerosis.
05:15
If we hit thate ndothelium
with interleukin-1,
a pro inflammatory mediator,
then we will get some degree
of VCAM, vascular cell
adhesion molecule expression,
and we will get some
binding of monocytes.
05:31
And they will then crawl
across and become macrophages.
05:33
And we'll start the inflammatory
part of the atherosclerosis cascade.
05:39
Cool.
05:40
And that's what happens.
05:40
I mean, it's just inflammation
driving that initial expression.
05:44
Now,
if we do our different flows
over the surface of the
endothelial, what happens?
So if we take interleukin-1,
and an athero-prone,
you can see that
squiggle down the middle.
05:56
That's the
athero-prone waveform,
those endothelial cells
become incredibly sticky.
06:02
Make lots and lots of vascular
cell adhesion molecule,
and we get lots, lots more of
inflammatory cell recruitment.
06:10
Wow.
06:11
All we've changed here is Flow.
06:14
Now, you're thinking okay,
now what happens if I take interleukin-1
and I have athero-protective waveform?
We don't make any VCAM.
06:23
We do not recruit and activate
those inflammatory cells.
06:28
So flow clearly also influences
the development of
atherosclerotic plaque.
06:38
With that, we've kind of
looked at risk factors,
traditional and
not so traditional.
06:43
And we'll go on from there and
look at what plaques look like.