Shurjo Sen: In our lab, we study coronary artery disease,
or CAD, which is the single largest cause of death worldwide.
Many of us don’t know that CAD begins in our late teens, early 20s.
As a 35-year-old former smoker, I’m actually a really good candidate myself.
But advanced CAD mainly manifests in people 55 years of age and older, and it takes two
very distinct forms.
In panel A, what you see is what we call stable plaques.
And these are plaques where, although the artery has become narrower, the plaque itself
is at lesser risk for rupturing and releasing its contents into the lumen.
Contrasting with this is what we see in panel B, which are much more dangerous, vulnerable
plaques.
And what distinguishes them from stable plaques is the thin, fibrous cap, which you’ll see
right above the black arrow.
And so in a vulnerable cap, when that thin, fibrous cap ruptures, what happens is what
we see in panel C, where the contents of the necrotic core spill out into the lumen.
And these usually form a thrombus, which occludes blood flow to the heart muscle, leading to
a myocardial infarction and unfortunately most often a fatal myocardial infarction.
So one of the big, big unknowns of cardiology is what exactly causes a vulnerable plaque
to go into the rupture state.
If we understand this, this helps us immensely in managing advanced cardiovascular disease.
So my specialty is in applying RNA sequencing to the study of cardiovascular phenotypes
such as plaque rupture, which is what we see here.
And one of the things I’m doing to understand this question is, I’m sequencing RNA from
subjects who died from sudden cardiac death.
And what sudden cardiac death is, is a person doubles up symptoms -- usually chest pain
-- and then within the next hour, they’re dead.
And during autopsy they’re found to have a ruptured plaque like the ones we see here,
which caused the myocardial infarction that led to their dying.
So we want to use RNA sequencing as a tool for studying the changes leading up to this
event.
The experimental design we use for this project is about half pathology and half sequencing.
First we collect hearts from the autopsy procedure.
And then we put these hearts through a pretty detailed protocol to isolate the lesions,
characterize them, understand what caused the death, and by getting the data from that
procedure, we have formed a matched set of 10 hearts, which had both vulnerable and ruptured
plaques.
And then from 10 other hearts, we have 10 stable plaques like the one in panel A, which
we use as controls.
So our next challenge is to sequence the RNA from these plaques, and that is unfortunately
a little harder than it sounds because the hearts were originally not for sequencing,
but for pathology procedures.
And the chemicals used for the histology staining usually degrade the nucleic acids pretty badly.
So I’m, however, quite happy because we’ve been able to recover substantial amounts of
RNA in a size range that, although it’s not perfect, is still usable for sequencing.
So in panel D, what you see is relative to the highly quality in near-perfect RNA on
the extreme right.
The other A samples, which are in the two other boxes to the left, are the samples we
get from these autopsy hearts.
And as you can see, they’re pretty fragmented compared to the control sample.
But the good news here is that if you look at the box in the middle, which is RNA, those
200 base pairs are greater in size.
We still have a substantial amount of RNA in that size range, and that’s actually
want we need to use sequencing on these samples.
So I’m really, very optimistic that one we have the results from sequencing these,
we’ll be in a pretty good position to understand from the transcriptor [spelled phonetically]
point of view what went on that led a stable plaque to go in the direction of becoming
vulnerable and, even more importantly, what happened between the vulnerable plaque and
the rupture event that caused sudden cardiac death.
If we understand that, that gives us a good starting point to be able to manage this disease,
hopefully lower rates of cardiovascular mortality, which, as I mentioned, are highest in the
world.
Thank you.
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