00:01
The most common cause of restrictive
cardiomyopathy is cardiac amyloidosis.
00:05
So this is an extracellular deposition of
proteins and there are a variety of proteins
that can form amyloid.
00:11
Amyloid is any of a variety of proteins
that will form insoluble beta pleated sheets
that's just demonstrated there on the right,
so it kind of looks like a corrugated tin roof.
00:23
And that material can then undergo non-enzymatic
crosslinking which makes it very insoluble,
and that can accumulate over time and compress
and basically make for a very stiff wall.
00:36
The most common cause of amyloid-associated
cardiomyopathy is going to be transthyretin.
00:43
That's the protein, and it's
interesting, it's produced by the liver.
00:47
Its normal function is to transport thyroxin,
and retinal hence the name Trans-thy-retin.
00:55
So you can remember that.
00:56
It's a normal protein, and we
make it our entire lifetime.
01:01
But what happens as you get older and
older and older, into the 70s, 80s and 90s,
you don't break it down.
01:08
And probably because of the nature of the normal
extracellular matrix within the myocardium,
you get a deposition of this protein that
then undergoes non-enzymatic cross-linkage
and leads to the deposition, increasing
amounts of the amyloid protein.
01:25
We can also see amyloid
deposition due to other proteins.
01:30
Transthyretin just happens to be the
most common in the aged population,
but if a patient has multiple myeloma, and
is making abnormal amounts of light chain,
light chains can also deposit as an AL,
amyloid light chain type amyloidosis.
01:48
Besides depositing it as amyloid, it turns out
that light chains are also directly cardiotoxic.
01:55
So in very early amyloid deposition, may actually
even have somewhat of a dilated cardiomyopathy
due to the toxic nature of amyloid light chains.
02:06
Predominantly,this overload of
amyloid can be in multiple tissues.
02:14
In fact, if we see it in the heart,
we'll also find it to some extent in lung
and we can find it in valves and
we can find it in other tissues.
02:21
But the symptomatology of this transthyretin,
the senile cardiac amyloidosis,
the symptomatology is related to effects due
to deposition of the amyloid in the heart.
02:34
Interestingly, you can have normal
forms of transthyretin that deposit
as you get older and older, because you're
just not breaking them down as effectively,
or you can have mutant forms of
trans they written that deposit.
02:47
And interestingly, in the African American
population, roughly 4-5% of that group
carry specific mutations that increase
the risk of amyloid deposition,
and they will tend to have amyloid
accumulating at a younger age, say 60 to 70.
03:04
What does it look like?
The darker pinker cells that you see
there represent normal cardiac myocytes.
03:12
That lighter pink material in
between is the amyloid deposition.
03:17
So I kind of like to think about this as
pavement stones with mortar in between
and the mortar being the amyloid, you can see
that that forces the cardiac myocytes apart,
so that they don't have really
normal connections to each other.
03:32
So they may be prone to arrhythmia, but by having
this stiff material that is not contractile,
you end up with a restrictive cardiomyopathy.
03:42
The classic study that one does to confirm
on histology that you have amyloid deposition
is a Congo red stain, and that
will appear on the boards.
03:52
It's just one of those
things that they like to ask.
03:55
It's an easy one to remember.
03:56
You know, it's just Congo red for amyloid.
03:59
When you shine polarized light
on this, the Congo red molecules
will they’re in a kind of crystalline array to the amyloid
and you shine polarized light and they bend it
in a refractile way and we get an apple green,
which is indicated there birefringence.
04:18
Okay, so that's, that's the classic
histology for cardiac amyloidosis.
04:25
Let's step away from the geriatric
population with senile cardiac amyloid
and talk about the pediatric population.
04:31
So in that group, the most common
cause of restrictive cardiomyopathy
is going to be endomyocardial fibrosis.
04:38
This occurs mainly in certain geographical
regions, tropical and subtropical regions
can affect the valves in addition
to thickening the endocardium
and making for a stiffer endocardial surface.
04:54
We don't really understand
the pathogenesis of this.
04:58
Possible things that have been
implicated in nutritional deficiencies,
such as inadequate magnesium.
05:05
There may also be parasitic infections
leading to hypereosinophilia.
05:09
And in the moment, we'll talk more about increased
eosinophils causing endocardial fibrosis.
05:15
So maybe that's one of the components of
this pediatric endomyocardial fibrosis.
05:20
Unclear.
05:22
Certain viral infections can also
lead to this endocardial fibrosis
and exposure to certain elements,
certain compounds, so cerium for example,
These are all implicated, none of them are proven.
05:38
We just see this in a particular
population and we typically see it
in again the tropical and subtropical regions.
05:46
This is to be compared and contrasted with the
adult, mostly adult form of endocardial fibrosis.
05:55
This is Loeffler's endomyocarditis, so it is an
inflammation of the endomyocardium predominantly,
named after the physician who
first described it Dr. Loeffler.
06:06
As opposed to the endocardial
fibrosis associated with little kids,
there's no geographic or population
predilection,but what is associated with it
as shown on the right, lots
and lots of eosinophils.
06:17
So there is typically not exclusively not always,
but there's often peripheral eosinophilia,
being elevated eosinophils in the peripheral
blood, and what we will see as the driving force,
eosinophilic infiltration of various
tissues and particularly of the endocardium.
06:37
So, as we are getting eosinophilic degranulation
and damage to the endocardial surface
due to these eosinophils, we
are causing endothelial damage,
and we will tend to get than large
mural thrombi that then also organize
to form increasing thickness of theendocardium.
06:58
Potentially for some forms of Loeffler
endomyocarditis, those that may actually have a
low grade malignancy potential,
tyrosine kinase inhibitors can help.
07:09
They are not helpful in all cases.
07:12
So, the pathogenesis here, it's
hypereosinophilia and it can be malignant
or premalignant hematologic disorders
such as acute promyelocytic leukemia.
07:22
It can be allergic and autoimmune diseases, again,
other causes of increased peripheral eosinophilia.
07:28
It can be certain infections that drive
an eosinophilic response in particular,
many parasites, some helminths, some protozoa.
07:37
You get an eosinophilic infiltration of the
endocardium, and there they release their granules,
major basic protein and others causing
endothelial and endocardial damage.
07:48
And as a result of that,
you get then this fibrosis.
07:52
And because of the damage to the endothelium,you
get layering of thrombus and as that organizes,
then you get more thickening of the walls.
08:03
Combination of the fibrosis and
the organization of the thrombus
leads to a very thickened and
non-contractile endocardial surface,
and hence a restrictive cardiomyopathy.
08:13
And with that, we've covered a
rather broad range of topics.
08:17
Hopefully you now have a better way of
thinking about dilated, hypertrophic
and restrictive cardiomyopathy.