00:00
In this talk, we're going to cover a very important pathophysiologic set of consequences
that lead to a lot of morbidity and mortality. This is heart failure. Fundamentally, this is
pump failure and we're not able to pump blood adequately to the body and we're not
able to also keep blood flowing in a unidirectional fashion so we end up with a retrograde
flow which has a lot of manifestations. With that, let's get started. As I've already
eluded to, the definition of heart failure is the inability of the heart to supply the body
with its normal cardiac output to meet the metabolic demands. It can have a variety of
causes, but that is the final important consequence. And if we're not providing adequate
nutrition and oxygenation to the brain, you will have a consequence. If you're not making
it to the liver, you will have problems with synthetic function. If you're not making
adequate blood flow to the bowel, you're not absorbing nutrition. So there are a lot of
different consequence depending on the tissue. It is the end stage of chronic heart
disease not otherwise specified, meaning we can get there by a variety of different
mechanisms. It is also something that can happen with acute insults. As we'll see in a
couple of slides, this is a fatal disease. Heart failure that is not treated effectively will
lead to death within 2-3 years and it is one of the major causes of morbidity and
mortality in the world. Okay. This is showing a curve that you will see in your various
physiology courses particularly in cardiovascular physiology. This is the Frank-Starling
curve and on the x axis it is the ventricular filling volume that's occurring during diastole.
01:58
On the y axis is the stroke volume. That's how much the muscle squeezes during
systole. As we go up to Frank-Starling curve, we are getting more and more output
and we can do that by a variety of mechanisms. We can do it 1) by increasing the
volume that is in the ventricle. So we can squeeze with exactly the same vigorousness
and get more cardiac output. Okay, so we've dilated the heart during diastole. We fill
it better. We squeeze just as well. We get more stroke volume. That's how you are
able to go from resting to running a marathon. You have to increase your stroke volume.
02:37
Now we're going to come back to this Frank-Starling curve because you see it trends
down and on the other side you can have maladaptation that will lead to actually
diminished stroke volume as we increase the diastolic filing. Okay, so it is not something
that goes up and up and up and up. We can exceed the capacity of the heart to respond
appropriately. So this is just showing you one way that we can increase cardiac output,
increase the stroke volume by increasing the volume that occurs during diastole.
03:11
In order to take advantage of that, we have to squeeze as vigorously as we have at
lower volume filling. Okay. So, that's the Frank-Starling curve. Again there is a
downside. We'll come back to that. Okay, so what is a mechanism by which we can get
increased organ perfusion or increased squeeze of the heart? Well, one of the ways
that we can do that is to make more sarcomeres and make for hypertrophied myocytes.
03:42
With more sarcomeres lay down in parallel next to each other, we get a concentric
hypertrophy that will give us more bang for our buck. We cannot increase cell number.
03:52
Remember that myocardium, myocytes in the heart are a terminally differentiated cell
and for all intents and purposes we cannot make more of them. So if we want to get more
squeeze, we can increase the volume but we can increase the size of the cardiac
myocytes by increasing the sarcomere content. That will give us a better squeeze.
04:17
Other ways that we can maintain cardiac function to adapt to increased demands and
what is being shown here is the sympathetic trunk that lies along the aorta, the
descending aorta. And there is going to be important neurohumoral mechanisms that will
also help to drive cardiac adaptation if we need to increase cardiac output. Name
amongst these are going to be norepinephrine release. So, if we detect diminished
pressure, if we detect a decreased oxygen content, if we detect increased acidosis.
04:57
All of those are potentially going to trigger the neurohumoral system to release
norepinephrine. When we do that, we'll increase heart rate and we'll squeeze more
effectively. So even if we haven't made individually enlarged myocytes, this is an acute
mechanism by which we can increase cardiac output. Now, we may also want to reduce
cardiac output. So, whatever acute kind of stimulus has driven us to have more output,
at some point we may want to reduce that again. So one of the mechanisms, there are
others, but one of the mechanisms is by a volume overload of the atrium detected by the
atrium as increased stretch. And that atrium makes atrial natriuretic peptide.
05:42
That peptide, a hormone released by cardiac myocytes, wow a hormone, causes increased
vasodilation and diuresis. So that is a way for us to decrease blood volume and therefore
reduce cardiac output. Okay, so there are these various mechanisms in play. So, the
main mechanisms overall are the neurohumoral mechanisms that we've just seen
and also the renin angiotensin aldosterone system, RAAS. This is going to be a system
that is going to be kind of bring together the kidney, the liver, and the adrenals to
maintain blood pressure. So let's start with a drop in blood pressure or a drop in fluid
volume. This is detected at the level of the kidneys, at the level of the afferent arteriole
in the glomerulus and you have cells of the juxtaglomerular apparatus that are
going to be making a hormone renin if they detect a decrease in blood pressure.
06:52
That renin acts on angiotensinogen, a hormone secreted by the liver constitutively.
07:00
That renin acting on angiotensinogen makes angiotensin I. So it cleaves it to a smaller
peptide. And then as that smaller peptide circulates around the body, endothelial cells
making angiotensin converting enzyme or ACE, will act on that to make the main peptide
that's responsible for regulating blood pressure. That's angiotensin II. So it's a smaller
peptide. It cleaves it one more time. That angiotensin II will cause vasoconstriction.
07:32
Remember what's strict at this entire series of events was a drop in blood pressure or a
perceived drop in blood pressure at the level of the kidneys. Angiotensin II will squeeze
the blood vessels. So now that will raise blood pressure, but it will also act on their
adrenal cortex to increase aldosterone synthesis. So here we brought together the kidney,
the liver, peripheral endothelial cells, and now the adrenal and that aldosterone
produced by the adrenal cortex will cause an increased reabsorption of sodium and
chloride and obligate water by the kidney. Now we've increased volume. So we have tried
to fix the drop in blood pressure or the perceived drop in blood fluid volume by squeezing
the vessels more vigorously and by increasing the volume of the blood. Okay, those
mechanisms, the neurohumoral mechanisms and the more vigorous squeezing of the
heart due to hypertrophy gives us an ability to adapt to increased demands but we can go
further out on the Frank-Starling curve and as we get more and more dilated, so the
ventricular filling volume gets bigger and bigger and bigger we actually stretch the
sarcomeres and there is a more tenuous connection between the actin and myocin chains
within the sarcomeres and we do not get as much of a good contractile force. So that's
the down curve on the Frank-Starling mechanism. And just because we have a bigger
volume doesn't necessarily mean that we're going to have maintenance of the output.
09:16
There is a maladaptation that can occur. So there are limits to how much we can dilate
up the heart in order to get more of a stroke volume. Okay, and in this particular instance
we've doubled the chamber size compared to normal or non-stressed and as a result
though we have stretched the sarcomeres to the point where they are no longer
interacting effectively to give us the most squeeze.