Myocarditis: Definition and Etiology

00:00 Welcome back. We're going to talk now about inflammatory diseases of the myocardium.

00:06 This can be a cause of heart failure. It can be acute, it can be chronic, it can be fatal.

00:12 So it's an important entity to be able to recognize. Myocarditis, simply stated, is an inflammatory disease of the myocardium, that's all we're saying. It's an itis, inflammation of the myocardium, has multiple different causes. It can be idiopathic. In most cases, it is probably an autoimmune myocarditis but we don't know necessarily what drives In most cases of myocarditis in the US, in European population, that's going to have a viral cause. The most common amongst these include Coxsackievirus B, influenza virus, HIV, echovirus and, there's a big question mark that we'll come back to the end is whether corona virus can be a cause of myocarditis. I'll tell you, the answer right now is no but we'll talk more about that. We can also have bacterial forms of myocarditis. One is associated with the Corynebacterium diphtheriae causing the diphtheric myocarditis that is really due to the elaboration of diphtheria toxin. You can have staphylococcus or streptococcus myocarditis and that can cause lesions that you might expect in any other tissue where there is an infection. We can have Lyme myocarditis. That's the spirochete that you see there on the right due to borrelia.

01:34 We can have parasitic infections and in many places in developing parts of the world, Trypanosoma cruzi is a major form of myocarditis so called Chagas disease. You can also have Toxoplasma gondii which is also a very common form of myocarditis in the immunocompromised host. So, there are other forms. In addition, you can have a fungal myocarditis, aspergillus and candida are common players in that world. And you can have immune-mediated myocarditis; things associated with lupus, rheumatoid arthritis, sarcoidosis, other vasculitides and hypersensitivity myocarditis due to drug administration and not illicit drugs. Any of a variety of drugs can elicit a hypereosinophilic or and not illicit drugs. Any of a variety of drugs can elicit a hypereosinophilic or hypersensitivity myocarditis. What are the underlying etiologies? So there is a genetic predisposition. There is some increased susceptibility to myocyte damage or there can be genetic polymorphisms in immune function that predispose an individual to getting inflammation of the heart. There are also a variety of drugs that we know quite a bit about that can cause an ongoing myocardial injury, doxorubicin used for many chemotherapeutic regimens, cyclophosphamide in the same general category, cocaine, and other drugs In terms of the general mechanisms, we talked about etiologies, we talked about the mechanism. So there are kind of 3 general flavors. One is antibody mediated, the other is cell mediated, and then there is mediator-mediated dysfunction. For humoral, we have our vessel here and on the outside of the vessel is going to be myocardium.

03:21 If we have antibodies that recognize either endothelial cell antigens or myocardial cell antigens, they can bind and activate compliment. They can also then recruit Fc receptor bariant cells causing endothelial damage and we can also then get direct myocardial damage if the antibodies happen to be directed against the myocardium. But when we get endothelial damage, we're going to get movement of plasma so we're going to see a lot of edema. Edema in the heart is not a good thing. It means the heart is going to be boggy and not as tightly contractile. So that's going to be a problem. And then, with an injury to the endothelium we're also going to get thrombus. And that can become completely occlusive so that we end up with downstream infarction, things that have gone gray there. So we can have cell death like regular old myocardial infarct but at a microvascular level due to humoral-mediated injury. There is the cellular component.

04:18 We can have lymphocytes, T-cells, and then the recruited macrophages that are recognizing either endothelial and/or myocardial antigens. And you can see them here both attacking the endothelial cells as well as the underlying myocardium. When those cells attack the myocytes, they can be directly cytotoxic. When they attack the endothelial cells, they cause them to die and as a result of that we get thrombus and then oh my goodness, now we get ischemic injury on top of that. So we can have direct cellular injury causing both myocyte killing, cytotoxicity. But also microvascular thrombosis causing ischemic injury. And then finally, all these inflammatory cells that are coming in, they are elaborating a variety of cytokines. Those cytokines may actually cause a lot of dysfunction and as we'll see in a subsequent slide, that dysfunction may be way out of proportion to how many inflammatory cells we actually see. So, the various cytokines that are being elaborated include interleukin II, that causes increased vascular permeability so we get that boggy heart again. You can have tumor necrosis factor that's being made by the macrophages in particular that causes cellular death and dysfunction. You can have interferon gamma made predominantly by the T-cells.

05:38 Interferon gamma acts on inducible nitric oxide synthase, INOS, of the myocytes and causes them to become less contractile, it become more relaxed and they don’t generate as much contractile force. And then you can have TGF beta, transforming growth factor beta, that causes increased fibrosis, it drives the fibroblasts that are part of the normal myocardium to make more scars, you end up with a stiff heart. All of those mediators combine to make the heart really very dysfunctional and way out of proportion to any amount of inflammatory cells that we may see on a biopsy or even at autopsy.