The topic of our conference this afternoon

is is a very important one

namely, heart

failure

and its important, as you'll hear
from my colleagues,

for a number of reasons. The sheer
prevalence of heart failure in our population

says that

you're going to deal with a tremendous numbers of patients having

related problems.

The associated

morbidity and mortality is very significant and

heart failure, one way or another,
consumes a very, very significant

fraction of our health care resources.

So it's a problem that you're going to
be dealing with

a lot of the time.

I will spend my time

just introducing the
general concept which we've had a little

bit in lecture, but will try to embellish
that

and illustrate some of the
pathologic anatomy associated with heart

failure one way or another.

Then I'll pass the baton to Dr Matthews

who will make clinical reality out of
this

and translate all of this into signs and
symptom that the patients manifest

and

appropriate strategies

of medical therapy and then we
will conclude the afternoon with

Dr Jonathan Haft

and with the participation of a
patient of his

and discuss the treatment of
advanced heart failure

with mechanical support and
cardiac transplantation.

So that's

the agenda for this afternoon.

Now in its

very simple definition, and there are a
lot of ways to define it, the very simple

definition of heart failure

involves the inability of the heart

to meet

to really pump sufficient
blood to meet the metabolic needs of

the body.

Now this can happen in a in a variety of
ways.

It can come to pass, and this isn't as frequent, that the

heart is putting out a normal or even an excessive amount of blood.

It's really pumping it out there, but it's being

driven by

an increased demand in the peripheral
tissues that it just can't keep up with.

This sort of thing we see in thyrotoxicosis.

It used to be seen,

we don't see it much any more thankfully, in beriberi - vitamin deficiency

with vasodilatation

all over the place and
the heart just couldn't keep up with

that volume

of the

cardiovascular system.

It's seen occasionally with
arteriovenous fistulas

that dump a lot of blood
directly from arteries into the veins in the heart

The heart just can't keep up. Or severe anemia.

Those sorts of things will result in what we call a high output sort of failure,

but much more

often, we're dealing with

the problem of

not enough blood being ejected

for one reason or another

from the heart to support even normal
demands

and this is a combination really of

the loss of systolic umph,

in other words, the contracting
heart just can't get it out there

in the way it should and

often this can be accompanied by

diastolic,

i've listed it here as diastolic failure but
it's a difficulty in diastolic filling

which can impair the heart action. If
the heart muscle can't relax and is ineffective

it's stiff

it won't

accept

the right volume coming into it and
that's going to lead

also to failure.

One way or another, these factors can lead to a constellation

of signs and symptoms,

we'll get to that at the end.

It's really related on the one hand to
congestion of organs which you know all

about now after

your

lectures in pathology and
hypoprofusion of tissues which

we haven't emphasized as much, but it's a

very important point.

Now, when we look at the causes of heart failure
and there are many, many of them, far more

than we can talk about,

but

if we look at those
situations where there is

some unusual demand

on the heart, and the heart just can't meet it, they

fall into a number

of categories, and I will

illustrate each of these in a
moment,

but one very important
category is resistance

to flow, in other words,

if something is keeping the flow of blood from going so

the heart has to work harder to push it
past that resistance

it will come to the point where the
heart could no longer do it and it fails.

Another problem is what we call regurgitant
flow, I mean you like to think of the

blood flowing in one direction through
the cardiovascular system, but

sometimes it comes to pass where, at a point,

there's

regurgitation, instead of things pulsing forward, they slosh

backward, and that

imposes a strain on the heart
as you will see

and thirdly and very importantly there is
disease of various sorts, lots of sorts,

targeting the myocardium itself

so that there's no resistance to flow,
there's no regurgitant flow

perhaps, but the

heart muscle is sick.

And finally, we won't talk

at all about this, I won't, about conduction abnormalities

which can also lead to decompensation

of the heart.

Now, I'd like

to illustrate some of these
very quickly, don't get lost in the details,

just

let it flow over you, you're going
to get these details later on

in the year

later on in your careers, but just
for a little orientation,

I'll give you an example first of resistance to flow,

there is a good hallmark for

it, I can't show you
hypertension obviously

but think of

the situation when a patient
has established significant hypertension,

it means that 24/7

every minute, every beat of the
heart

that poor left ventricle is having to
force against an increased resistance to flow,

that's what hypertension

is all about. The result

one of the results you see here is
is this rather massive

myocardial hypertrophy which i'm sure
you all recognize,

so that's one

kind of resistance to flow. Here's another one, this takes a

little explaining, it's an unusual plane of section of the heart,

but what attracts your
attention right away is that the left ventricle

is immensely hypertrophied, very thick

and very heavy, and the reason

for it is not terribly
well shown here

but here is the aortic outflow, this is the aorta here, and this would be the aortic valve

which you can't get a good view
of, but

a common lesion is stenosis of the aortic valve,

and obviously, in that situation, it's very
analogous to hypertension, every time

the ventricle contracts, it's got to push that blood

through a stenotic valve

and it's a lot of work.

I'll show you one of these valves from
above, this is an interesting one,

this is a pretty typical example of
aortic stenosis,

you're standing in the ascending
aorta, looking back

towards the left ventricle, and

you're aware from your gross anatomy
that this should be a three cusp valve

and you're seeing a couple of things here,

first of all this is only two cusps

and that was a congenital problem

and it's a fairly frequent one
in our population, there are probably a

couple of so-called

bicuspid valves in this room

and

whatever the case

the aortic valve is very susceptible to calcification

and stiffening with age, and if you

plot it against the aging
population, we see an increasing

incidence of stenotic

aortic valves even if they're not

bicuspid, if they're congenitally bicuspid like this they get wrecked

very frequently

earlier on so that

instead of maybe in the
seventies or eighties, it might be in the

fifties and sixties that the patient
would suffer from such stenosis.

But you can see

that every time

the ventricle is trying to push
blood through that orifice, and it's really like brick

it doesn't move.

It's going to be a

tremendous load on
the left ventricle.

here's another valve stenosis for you,
we don't see this as much anymore,

it's a result usually of old rheumatic fever
in childhood, but the mitral valve

here is reduced to
a fish mouth, it's all puckered up

and scarred, and frequently calcified,

and the valve leaflets

can't move at all,

so that the blood coming out of the lungs into the

into the left atrium trying to get through

into the left ventricle, you're looking down towards the left ventricle,

it's got to pass by that stenotic slit.

The result is damming back,

very obviously you know about passive
congestion, you can see this immensely dilated

left atrium

and you can imagine

what was happening in the
lungs

behind that sort of obstruction.

Now as far as

regurgitant flow, hold on with me

and i'll try to explain
it, here is another mitral valve, we've chopped off the

the atrium and you're
looking right at the

mitral valve, and

think about what you saw in gross anatomy, the
mitral valve leaflets usually come together

like that and keep the blood, during systole,

keep the blood from
flowing back into the atrium so all the blood goes out

the aorta like it should.

Here,

and this happens for a variety of
reasons, but here this leaflet of the valve

is sort of pooched up and

and with every ventricular systole, blood is able to force its way back

into the atrium, which means

the poor old left ventricle is
pumping some of that blood more than once

in other words it's putting part of it out
the aorta, part of it back up the atrium,

and that comes

sloshing down for the next

beat of the heart

and it consists,

it induces a volume overload on the valve

and

on the ventricle

and it may fail.

Now when you get to the realm of myocardial
abnormality per se, in other words disease of the myocardium

there are lots

and lots of examples, and the most frequent one and most important one is myocardial ischemic disease

in other words, the result of coronary artery disease, atherosclerosis

and its complications, and what happens when the myocardium

becomes ischemic.

Clearly many patients who have a
myocardial infarct, an acute heart attack

will go into

acute failure if enough of
the myocardium is involved right then and there in the

emergency room.

But chronically it can become a big problem
even when the

situation heals. Here, for example,

a slice of a heart, this is left ventricle over here,

and this individual sustained a
myocardial infarct, I don't know how long ago,

it could be years ago,

months ago, and you see a lot of scar

throughout the ventricular wall, a little
bit back there, a little bit in the septum,

but a tremendous scar here

and when this involves enough of the
ventricular myocardium, it puts a strain

on what's left of viable myocardium, because this

obviously doesn't contract.

Patients can sustain a lot of myocardial infarcts,

here's serial sections of the same heart,
and you can see at least a couple of infarcts

that involve

a tremendous

fraction of the

left ventricle

and again when

that happens, the rest of

this can't keep up with it, and the left

ventricle fails.

Here is a heart that was

was removed from a patient
who was still alive

happy and well as far as i know

This is an explant to the heart, in
other words, taken out of the time of transplantation

and this was also

ischemic disease, and this

individual had scraped through

with this much of the heart converted into

what amounted to a fibrous sack, totally

non-contractile

and you can see there's even a clot in there because it wasn't moving

and that had

produced failure of the remaining myocardium.

So that's a

good sample of

ischemic

disease leading to chronic failure of the left ventricle.

Now, beyond

ischemic disease there are a whole lot of them,
don't worry about the details

I'll show you this as an example
of an inflammatory process targeted at

the myocardium. We see this

with certain viral infections, certain protozoan infections,

with bacterial

infections, but you can
get inflammation of the myocardium

and you can almost literally hear

these cells chewing at the myocytes

and obviously

obviously that can produce failure.

We see that not infrequently,

then the heart can be involved in a
variety of systemic diseases, in other words

you can have something
going on affecting many tissues in

the body, but that something may affect the heart and produce

failure. Here's an example

now I don't know

if I want to dart in the
auditorium completely to show you this

did you discuss hemochromatosis in genetics? Yes? Not a complete blank.

It's an ineffective storage
disease because the body absorbs too much iron

from the gut,

and the iron

gets stored in a variety of
issues and one of the tissues it gets stored in

is the heart,

and you recognize instantly that this is myocardium

and as you stare at it a little bit, you'll pick out some nice golden brown pigment

there and there and there, you see a little
more over there, and little bit down there and over there.

and one of the pigments

you'd think of in the heart, someone asked me a question about this last week,

it would be lipofuscin (wear and tear pigment)

but another pigment you got to think about is iron, and this is stored iron

in this myocardium. Here is

that blue

Prussian blue iron stain, tremendous iron

load, iron is bad for you

if it gets deposited in certain tissues. This can produce myocardial failure.

This was from a relatively young man who presented with

very advanced heart failure

because of his unrecognized

hemochromatosis.

One other that you will hear about

probably next year

is amyloidosis. Amyloid

is an abnormal protein that could
get deposited in a number of tissues

for a number of reasons, which I won't go into.

But all of this

sort of translucent, gray stuff surrounding the

myocytes, you're looking at a cross-sectional view of myocardium,

and you can see that each myocyte is enveloped in this

casing

of amyloid.

And this is

a marvelous example of
something that renders the heart rigid

and unable to

expand diastolically, and it can be

a cause of heart failure.

Finally,

this is not a complete list, I'm just showing

the examples, there are

a number of genetic diseases
of the heart muscle itself, where from

the get go, because of

abnormal genetic endowment

the heart is

made wrong. Here's an example

of something we call hypertrophic cardiomyopathy.

Cardiomyopathy means
heart muscle disease.

This particular heart was immensely
hypertrophic, you can see that left ventricle

it's really tremendous with no

valve disease, no hypertension to explain that,

but look at the

goofy muscle, you know

what myocardium is supposed to look like, and the histology people never show you

the kind of

disarray and criss-crossing of
fibers like that.

This is the result of the genetic
abnormality of this myocardium.

All right, these are just a few examples
of the things that can go wrong

and most frequently,

if I had to pick from this whole list, I'd say hypertension and

ischemic disease

are the big actors at least in our population.

Whatever the cause, as the heart is

overburdened,

there are certain compensatory
mechanisms that kick in

for a while, in other words, enable
the heart to keep up

with the abnormal strain,

and some of these you know about, you've
heard about I'm sure about the Frank Starling

mechanism,

where the myocyte is stretched by
increased filling pressure, it's stretched

and contracts then

with greater vigor,

in other words, it can put out more UMPH

if it starts from a slight stretch. The
trouble with that mechanism is that it fails.

In other words, for a while

it's adaptive, you get more and more UMPH for each

contraction and then it peters out

for a variety of reasons.

A second compensation is hypertrophy,

and you know about this, we talked about
it last summer I guess.

It's a situation where the same number

of muscle cells are there

but more sarcomeres are added

and the muscle cells enlarge the whole

tissue grossly

enlarges and there's more UMPH.

I mean it's very definitely

a compensatory mechanism.

A third compensation

mechanism I've listed

is activation of neuro-humoral systems and we're not going to go into that

in much detail, just enough detail

so you know that

they are there.

Now here's hypertrophy!

Normal size myocytes you see over here

and each one is on the average just a
little bit thicker

than the normal

That's because of addition of sarcomeres, not much change in the number of cells

and you can imagine these cells having
more UMPH like a weight lifter,

imagine that, like a weight lifters arm

This is maybe what we see

grossly, there's an increase in
the muscle, increase in the weight of the heart,

and sometimes

we see concentric hypertrophy, meaning

the chamber is not enlarged, it may even be a
little smaller, gross thickening of the walls

and its

concentric.

We see that usually with
pressure overload.

With a volume overload, we may see

what looks like no hypertrophy

at all except that's a lot more muscle

than there is normal, it's just that it's
dilated.

That also happens in very advanced
failure

from any cause, you see this sort of
eccentric picture.

When it comes to the neuro-humoral
mechanisms, I'm just going to race through these now,

there is

first of all

all of these things tend to be triggered
by pressure and

stretch receptors that are
scattered through the heart

the aorta, the carotids,

and the kidney even there is such sensing.

When the cardiac output
begins to drop, these receptors say UH OH

and they trigger a number of things, one of the things they trigger is

a central nervous system,

i'm sorry, the sympathetic nervous
system

with release of norepinephrine

and this can produce

a contractile boost for the heart

this can produce an increased heart
rate

these things will help meet
an abnormal load

and also this will produce vasoconstriction peripherally.

This is designed,

this evolved this way presumably to

to make sure that
blood gets shunted to essential organs

so there's peripheral
vasoconstriction

which increase, well we'll talk about
what the bad things it does.

Vasopressin is released

from the hypothalamus, that's also a vasoconstrictor,

and we talked in class previously about

the renin-angiotension-aldosterone system.

The kidney senses the decreased flow
that's coming to it, secretes renin which

acts on angiotensinogen which is
circulating protein

forms angiotensin I

and then there's angiotensin
converting enzyme which takes angiotensin II

that in turn

stimulates the production

in the adrenals of aldosterone.

The importance of all of this is first of all angiotensin II

is also a vasoconstrictor

and

between angiotensin II and aldosterone, there is

sodium retention, salt
retention, sodium retention and water retention

and that has

some important consequences.

I just listed, I don't have time to go into it, the natriuretic peptides

secreted by the heart which
tend to counteract the renin-angiotensin-aldosterone

system to some extent.

Unfortunately, all of these

mechanisms

are limited in how much help they can provide and there's a downside

to a lot of them.

Now

problems with hypertrophy, it just gets bigger and

bigger and bigger muscle,

it doesn't work out that way because
the capillary network in the muscle

does not increase in parallel and you

end up with perfusion problems
so there's a limit to how much hypertrophy

the tissue can stand.

Same is true for the ratio between mitochondria and

and contractile protein, so to speak,
the mitochondria-to-meat ratio

does not keep up to what it should be so
the energy is a problem.

Then very importantly

we're learning that there is altered
gene expression

and alteration in the

proteins that are produced, and these may involve

contractile proteins,

segmentation

contraction coupling them, they may involve energy utilization,

but some abnormal proteins are made

there's an increase in apoptosis

in a hypertrophic myocardium

and, under the influence

of all of this is actually driven by the various hormonal

things that i've mentioned

and with something

we call remodeling occurs, there's a
change in geometry of the ventricle

which can have implications of tugs on the chordae tendinae of the mitral valve

the wrong valve, you can get mitral regurgitation,

it's a disadvantageous thing

often associated with a lot of fibrosis, that blue-green tissue racing through the myocardium

is a fibrosis in the remodeled ventricle

which causes problems of its own as you
can imagine, I don't have to go into any detail

So that's a problem

and there's a problem

with neurohumoral activation,

vasoconstriction increases the

afterload that this poor
old failing heart has to pump against.

It sounds like

a nice mechanism, but it

bites the heart

Various of these humoral
substances are

cardiotoxic

chronically

in other words, they are
responsible for the increase in apoptosis

they drive the remodeling and it's a bad thing for the heart

in the long run,

and we know about the

implications of sodium and
water retention and how that

overloads the heart.

All of these things

contribute to the downward spiral

and I've simplified a very
complex business, but

there are many

consequences for the
peripheral tissues and that's what we're

really talking about when we talk about
heart failure, what's going on

in the peripheral tissues.

These consequences we can
talk about in a number of ways, we talk

about sometimes forward failure and backward failure.

Forward failure being the idea that

the failing heart does not perfuse the
tissues well enough, and

backward failure you're familiar

with the idea of passive
congestion and we talked about that in class

so you have a good image of that.

We speak of left heart failure and
right heart failure,

most processes that cause

heart failure start out on the left

but it's a closed plumbing system

so as the left heart fails, the right heart is going to fail.

The commonest

cause of right heart failure then is left heart failure.

There are some of the examples where the
right heart fails primarily and it has to do

with things happening in the lungs,

they're relatively less common and you'll
hear more about them some other time,

but the backward consequences
of left and right heart failure are very

familiar to you already, we know that when the left heart fails you get

pulmonary congestion and edema,

when the right heart fails, you get

elevation of hydrostatic

pressure in a variety of
tissues

with associated

congestive changes in
organs and accumulation of edema

fluid and this

is when we start to speak of congestive heart failure.

We're throwing that adjective very frequently

What we're not emphasizing, and I'll just conclude by mentioning this,

are the forward changes

associated with left heart
failure, in other words, when the left

heart fails, things begin to

happen because tissues
in a variety of places simply aren't being perfused.

And you're familiar already with

the activation of the

renin-angiotensin-aldosterone system

from forward failure to

supply enough blood to the kidney,

I would point out that as the
perfusion drops more and more,

the kidney can really shut down as far as
its excretory function and nitrogenous

waste can pile up.

Sometimes they speak,

people speak, of a cardio-renal syndrome because of this.

Well many other

tissues suffer from this lack of perfusion in the same way.

We've shown you for instance the liver,

and the liver gets caught in a one-two punch,

there's resistance to outflow from the liver

the fact is that the poor old failing left
ventricle isn't delivering enough blood

to this, the central

lobular area,

and it undergoes a sort of hemorrhagic

necrosis which you remember that, you never forget

that kind of a picture.

Now something, a little wrinkle that I'll point out here,

is that the aldosterone

levels in patients in
failure are way way up there

and part of it

obviously is because it's been
triggered by the production of angiotensin II

and so forth, but the liver

when it's in that kind of a state,

does not catabolize aldosterone the way it should,

and the patient may end up with a twenty fold increase in aldosterone level partly because

of synthesis and partly because of

"non tearing down"

by the liver

One more example, the gut

may suffer in very advanced cardiac

failure, patches of mucosa

in the bowel may undergo

necrosis because they're furthest from the blood supply

and we speak of ischemic colitis, a bit
of a misnomer as it is an inflammatory condition,

but actually that sort of thing

can be a problem.

Other organs and in fact even the
central nervous system in very advanced failure

we see problems

with CNS function.

Well I turn the baton over

to Dr. Matthews

you just keep some of
these images in mind and she will flesh them out,

as they say, with the clinical realities

and with some of the

therapeutic strategies

that make sense I hope.