00:01
So let's talk about the timing of events
that occur after loss of perfusion,
specifically to the heart.
00:07
And we're going to emphasize the heart
because, in fact, cardiovascular death
is going to be one of the major forms of ischemic
infarction injury across the human population.
00:20
So within seconds, after we cut off the blood
supply, say with a thrombus or a plaque rupture
in a coronary artery, within seconds, the
tissues, the myocardium, that is being perfused,
by that blood supply turns
over into anaerobic metabolism.
00:41
So we are now not, no longer
using oxygen to generate ATP.
00:48
Within a couple minutes, even that is
not able to maintain ATP generation,
at a level sufficient to maintain contractility.
00:58
So within a couple minutes, we have lost
the ability of the heart to contract.
01:02
It's not dead, but it's not functional.
01:06
And therefore, we will be having
problems with regard to generating
enough blood supply to go to the brain or whatever.
01:14
The ATP is reduced to 50%
of normal within 10 minutes.
01:19
So all the things we've been doing before the anaerobic
metabolism, cutting down the amount of contraction,
everything that we're doing
to maintain ATP at some level,
significantly reduced, is significant
reduced within 10 to 40 minutes.
01:35
Once we get to less than about 10
percent, that's when the tissues will die.
01:41
So we will have irreversible cell injury,
death, infarction beginning at 20 to 40 minutes.
01:49
Now, interestingly, if you think about
the heart, it's not just cardiomyocytes.
01:53
There are fibroblasts, which are
relatively resistant to ischemic injury.
01:58
But there's also vessels, endothelial cells.
02:02
And beginning to about an hour,
they will also begin dying.
02:07
That means if we restore blood supply,
after about an hour of ischemia,
or when we are having infarction,
death of the endothelial cells,
then if we restore blood supply by giving a
clot buster, tissue plasminogen activator,
we will in fact, get bleeding into the heart.
02:26
Okay, so let's look at this,
let's look at what looks like.
02:31
We have a heart, we have a thrombus, we have a
kind of a brownish area where we're not getting
enough blood supply.
02:39
What is going on at the vascular
level is what is shown most commonly.
02:43
On the left hand side, we've seen
this image in a prior session.
02:47
We have an atherosclerotic plaque,
that was probably not flow limiting.
02:52
It was somewhere less than a 70% chronic stenosis.
02:56
And at some unpredictable
point, that plaque ruptured.
03:01
The thin fibers cap over the surface
of the atheromatous core broke.
03:06
And then we expose the underlying thrombogenic
materials to all the blood, and we got a clot.
03:12
That thrombus limits blood supply downstream.
03:15
The consequence is shown on the right hand side,
and the arrow is pointing to an area of infarct,
a territorial area of infarct, where
we've actually even had some reperfusion
in an attempt to save this patient's life,
and that's why we have the hemorrhage.
03:32
So that territory with the arrow
is a rather large area of infarct,
and is going to lead to probably a
combination of things, including arrythmias
but also diminished cardiac output.
03:48
The rest of the heart is not going to
be able to maintain sufficient squeeze
to provide blood supply to the
rest of the body or to the brain.
03:55
And as a consequence, the patient has expired.
03:59
How do we measure, how do we
identify this as it's happening?
That's where we bring in biomarkers.
04:06
So there are a number of components within cardiac
myocytes that we can measure in the circulating blood
that will give us an idea whether
or not we have irreversible damage.
04:18
So these are the biomarkers of acute infarction.
04:21
So on the left hand side, we have onset of
myocardial infarction, that tissue is dying.
04:27
At the periphery of that zone, there are still blood
vessels that are able to exchange at the periphery,
things that are in the myocardium
with oxygen and other stuff,
As the muscles are dying in that peripheral area,
the various components of the cardiac myocytes,
as demonstrated here, some of the
proteins - the myosins the actins,
the creatine kinase MB fraction, the CKMB,
troponins which are part of the actin-myosin complex
and allow the filaments to slide over one another.
05:04
All of these are released into the blood supply.
05:09
And we can by drawing blood out of an arm
vein, see how much damage has been done.
05:15
Clearly, if we reperfused this area, now
we have lots of blood supply coming in,
and we will get a big surge in these markers.
05:24
The markers are not necessarily created equal.
05:28
So we think cardiac myocytes, there is myoglobin.
05:32
Myoglobin is one of the very first
proteins that we can use to measure
an incipient or ongoing myocardial infarct, but
it comes up and it goes down very, very quickly.
05:43
So it's not really a very good marker.
05:45
Most patients don't appear at time
zero when they're having an infarct,
and we can watch them and see
at peak at about five hours.
05:52
The other problem about myoglobin
is it's found in skeletal muscle.
05:55
It's found in a variety of tissues so
it's a relatively nonspecific marker.
06:00
The next marker that has been used very
commonly traditionally for many, many decades,
is the creatine kinase MB fraction.
06:08
Creatine kinase, important protein
for driving and generating ATP.
06:16
That creatine kinase is also found in other
tissues, but there are different isoforms.
06:23
So there's an MM isoform that's
found in skeletal muscle.
06:27
There's a BB isoform, that's found in brain.
06:31
The MB fraction or the MB isoform, is found
predominantly, but not exclusively in cardiac muscle.
06:37
And again, this one has been used
traditionally, to be a good marker
for a specific injury to the cardiac myocytes.
06:46
The one now that we use most commonly
in hospitals, clinics around the world is troponin
and there are various subforms,
isoforms of troponin that we use,
but most of the ones, all the ones that
we use, are specific to myocardium.
07:01
They are so much better
biomarkers, they last much longer.
07:07
And we will traditionally measure,
a patient comes in with chest pain.
07:11
We're not sure whether or not they're having
a heart attack, a myocardial infarction.
07:16
We will measure over the next 24 to 48 hours, 3
or so troponins, each at about 12-hour intervals,
identifying one - if there is an infarct,
two - how much of an infarct there is,
the more troponin you have released,
the greater the size of the infarct
and making sure that that infarct is a one time only,
and that the troponin trends down at the end.
07:42
So this is what you will use on a regular basis.
07:46
And here's the reason that you use it and
why we use troponins much more commonly now
than CKMB and why we never use myoglobin.