Dilated Cardiomyopathy: Etiology

00:01 of the genetic basis, The autosomal dominant inheritance pattern is the predominant pattern not exclusively, however.

00:10 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.

00:21 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.

00:33 So you can have those proteins that are defective.

00:37 You can have other cytoskeletal proteins that are involved in maintaining the normal structure function of the myocyte be defective.

00:44 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.

00:54 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.

01:11 And if those are defective, then that can also be a cause of a cardiomyopathy.

01:18 Those are the the autosomal causes, there are x linked inheritance mutations as well.

01:25 The dominant one are those associated with dystrophin.

01:29 So the same mutations that can cause muscular dystrophy also can cause cardiomyopathy.

01:39 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.

01:53 Those are the genetic basis, let's talk about some of the non genetic basis, so infectious disease.

01:58 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.

02:10 Rheumatic heart disease caused by streptococcal infections with the development of cross-reactive antibodies and T-cells to antigens present on certain streptococcal infections.

02:23 HIV can cause a dilated cardiomyopathy primarily by infecting inflammatory cells, but also to some extent, cells of the myocardium.

02:35 And then enteroviruses, and for example, Coxsackie B virus, and also adenovirus and others that are causes of viral myocarditis.

02:46 An important toxic exposure is alcohol.

02:49 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.

03:01 It can also be due to alcohol associated thiamine deficiency, so this is beriberi heart disease.

03:07 when you are not taking in adequate levels of B1.

03:13 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.

03:29 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.

03:40 All of those are potentially toxic to cardiac myocytes.

03:44 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.

04:10 Heavy metals, exposure to things like cobalt can also be cardiotoxic.

04:16 Inhalation of organic solvents, as associated with glue sniffing, for example.

04:22 All of those are causes of a toxic cardiomyopathy.

04:27 Ischemia.

04:28 Cocaine, in some instances can cause a very impressive microvascular spasm.

04:33 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.

04:47 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.

05:08 So cocaine can be a cause of ischemic cardiomyopathy which can lead to a dilated cardiomyopathy.

05:14 Recurrent use with microvascular spasm, microvascular infarct all over the myocardium over time may accumulate to give you a dilated cardiomyopathy.

05:24 In the same fashion, pheochromocytoma by the release of epinephrine from adrenal medullary tumors recurrently over time will give you exactly the same phenomena.

05:35 Takotsubo, already mentioned that, the broken heart syndrome.

05:39 Takotsubo is high stress, increased catechols because of emotional duress gives you exactly the same phenotype.

05:48 Thyrotoxicosis can do this too by increasing cardiac myocyte contraction and also causing microvascular spasm.

05:57 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.

06:10 Other causes: 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.

06:29 And on the right, all the areas of white represent those areas of scarring with a granulomatous inflammation.

06:36 As the heart becomes damaged in this kind of multi-focal pattern, the chambers tend to dilate.

06:42 This also tends to be a rather profound cause of arrythmias.

06:48 Dilated cardiomyopathy also occurs with hemochromatosis.

06:51 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.

06:58 It turns out that that brown pigment is accumulation of iron, which we can highlight with a Prussian blue stain shown on the right.

07:07 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.

07:23 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.

07:41 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.

07:54 In both cases, we then kind of funnel in through primary myocyte injury and we end up with a dilated cardiomyopathy.

08:02 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.

08:14 And over time, we may turn a dilated cardiomyopathy into something that is much more restrictive.

08:24 Other causes, so peripartum cardiomyopathy is very interesting.

08:27 And fortunately, as I said before, relatively rare cause of a dilated cardiomyopathy.