of the genetic basis,
The autosomal dominant inheritance pattern is
the predominant pattern not exclusively, however.
And again, most of these are defects in various
proteins involved in the contractile apparatus,
but also can involve proteins that
link the sarcomere to the cytoskeleton.
Clearly, you just can't have a sarcomere
doing this in the middle of the myocyte,
without linking it to the plasma membrane, so
that the cell itself gets shorter or longer.
So you can have those proteins that are defective.
You can have other cytoskeletal proteins
that are involved in maintaining the
normal structure function of
the myocyte be defective.
And desmin is a good example of that that's
actually part of a plasma membrane complex
that's going to interact with cytoskeleton actin.
Mitochondrial proteins, so did you have
defective ATP generation can be a cause,
and you can have mutations in
nuclear lamins that are responsible
for maintaining normal nuclear architecture and
normal nuclear transcription and translation.
And if those are defective, then that
can also be a cause of a cardiomyopathy.
Those are the the autosomal causes, there
are x linked inheritance mutations as well.
The dominant one are those
associated with dystrophin.
So the same mutations that can cause muscular
dystrophy also can cause cardiomyopathy.
And the dystrophins are a complex of proteins that
link the outside world, the extracellular matrix
to the intracellular cytoskeleton
and that's just represented there schematically.
Those are the genetic basis, let's talk about some
of the non genetic basis, so infectious disease.
And in parts of South America and other portions
of the world, Chagasic myocarditis due to T. cruzi
is a cause of a dilated cardiomyopathy.
Rheumatic heart disease caused by streptococcal
infections with the development of
cross-reactive antibodies and T-cells to antigens
present on certain streptococcal infections.
HIV can cause a dilated cardiomyopathy
primarily by infecting inflammatory cells,
but also to some extent, cells of the myocardium.
And then enteroviruses, and for example,
Coxsackie B virus, and also adenovirus and others
that are causes of viral myocarditis.
An important toxic exposure is alcohol.
So alcohol use disorder via a direct
toxic effect on the myocardium,
a suppressive effect over long periods of time,
may well lead to a dilated cardiomyopathy.
It can also be due to alcohol associated thiamine
deficiency, so this is beriberi heart disease.
when you are not taking in adequate levels of B1.
Cardiotoxic drugs and this includes the
anthracyclines, doxorubicin and daunorubicin
that are used for treating various
malignancies as is of thymidine,
which was used early on in the
HIV therapeutic kind of window.
And trastuzumab, which is a monoclonal
antibody against a tyrosine kinase
that's used very commonly in the treatment of
certain malignancies, in particular breast cancer.
All of those are potentially
toxic to cardiac myocytes.
It's a bit idiosyncratic and different
patients are going to be much more susceptible
than other patients, but it will say with the
anthracyclines, doxorubicin and daunorubicin,
we know that if we get up to a certain threshold
of about 500 milligrams per meter squared,
lifetime exposure, that the vast majority
of patients will have a cardiotoxicity.
Heavy metals, exposure to things
like cobalt can also be cardiotoxic.
Inhalation of organic solvents, as
associated with glue sniffing, for example.
All of those are causes of a toxic cardiomyopathy.
Cocaine, in some instances can cause
a very impressive microvascular spasm.
This is a very, very powerful catecholamine
and that cocaine will actually,
in causing the microvascular
spasm, lead to diminished perfusion
in a localized area for up to 20 to 30 minutes.
If that occurs due to the cocaine ingestion,
then you will get microscopic infarcts
and then as the cells die and calcium rushes
in, then you can get hyper contractions
such as is demonstrated here this is
a so-called contraction band necrosis.
So cocaine can be a cause of ischemic cardiomyopathy
which can lead to a dilated cardiomyopathy.
Recurrent use with microvascular
spasm, microvascular infarct
all over the myocardium over time may
accumulate to give you a dilated cardiomyopathy.
In the same fashion, pheochromocytoma
by the release of epinephrine
from adrenal medullary tumors recurrently over
time will give you exactly the same phenomena.
Takotsubo, already mentioned
that, the broken heart syndrome.
Takotsubo is high stress, increased
catechols because of emotional duress
gives you exactly the same phenotype.
Thyrotoxicosis can do this too by
increasing cardiac myocyte contraction
and also causing microvascular spasm.
Vasculitis by being inflammation of the small
vessels can lead to microvascular infarction
that can look exactly like this and over
time lead to ischemic cardiomyopathy.
Sarcoidosis, which is a chronic
granulomatous disease of unknown etiology,
represented here on the left by
having large areas of fibrosis
associated with granulomas,
often with giant cells.
And on the right, all the areas of
white represent those areas of scarring
with a granulomatous inflammation.
As the heart becomes damaged in this kind of
multi-focal pattern, the chambers tend to dilate.
This also tends to be a rather
profound cause of arrythmias.
Dilated cardiomyopathy also
occurs with hemochromatosis.
So the H and E that you see on
the left hand side, that image,
there's kind of a brown pigment
that's within the cytosol.
It turns out that that brown
pigment is accumulation of iron,
which we can highlight with a Prussian
blue stain shown on the right.
Elevated levels of iron lead to a number of
effects but predominantly an increased amount
of free radical generation, which is presumably
the etiology for the cardiomyocyte dysfunction
and the heart failure that occurs.
Iron overload cardiomyopathy can
occur with hereditary hemochromatosis,
relatively infrequent overall in population,
but is much more associated in iron overload
with things like thalassemia
and sickle cell disease,
where patients receive
multiple multiple transfusions.
In all cases, you get an iron overload,
whether it's primary or secondary,
that leads to the activity of
metal dependent enzyme systems,
which will lead to dysfunction but also
the production of reactive oxygen species.
In both cases, we then kind of funnel
in through primary myocyte injury
and we end up with a dilated cardiomyopathy.
Again, because we have damage to the
myocytes, they may individually die,
we are also going to have free radical injury
to the cardiac fibroblast that are in there,
so the interstitial fibrosis will also increase.
And over time, we may turn a dilated cardiomyopathy
into something that is much more restrictive.
Other causes, so peripartum
cardiomyopathy is very interesting.
And fortunately, as I said before, relatively
rare cause of a dilated cardiomyopathy.