The knowledge about myocarditis and ICMP is still limited. It is determined by their varied aetiology and sometimes not quite cleared autoimmune processes which have been detected in myocarditis. Most of the information about the pathogenesis of these conditions comes from experimental mouse models whereas the best explored is myocarditis caused by enteroviruses and adenoviruses.
Generally, pathogenesis of myocarditis is classified into three successive phases: acute phase (viremia), subacute phase and chronic (sometimes called myopathic) phase.
It is presumed that a number of aspects contribute to the development of myocarditis and/or ICMP like genetic predisposition supported by the fact that in some individuals whose encountered with an infectious agent causing myocarditis, the disease did not develop [85].
Acute phase (viremia)
This phase lasts for approximately first three days of the disease and it is characterized by the development of the viral infection and internalization of the virus into cardiomyocytes. In enteroviral and adenoviral myocarditis model, viruses use for their entrance into cells CAR (Coxsackie-adenovirus receptor) receptor. Adenovirus uses for its internalization even co-receptors, specifically integrins. On the other hand, enteroviruses use co-receptor DAF (Decay Accelerating Factor), called also as CD55 [36]. Receptor ICAM-1 is also related to the connection with the internalization of Coxsackie viruses into cardiomyocytes. Together with CAR, it belongs to the group of immunoglobulins. The results of the analysis of the expression of CAR receptors in patients with DCMP confirmed increased expression of these receptors whereas in other patients with severe heart failure these results were not observed. The increased expression could be genetically predisposed [36].
However, it is not a rule, that a viral agent attacks the cardiomyocytes directly. For example, in the case of PVB19, endothelial cells of the blood vessels are affected and the damage of the myocardium is mediated indirectly [23].
The viral internalization is followed by the damage of inner structures of cardiomyocytes. In enteroviral myocarditis, damage of dystrophin was observed what lead to the interruption of the dystrophin-glycoprotein complex what resulted in the disruption of the cytoskeleton and decay of the cell structure [26].
In the phase of viremia, cardiomyocytes are damaged by the direct toxic viral activity and its lytic activity. At the same time, this activity causes the exposure of the inner cell structures, primarily cardiac myosin antigens [26].
Via Toll-like receptors (TLR), inner cell signal pathways are activated including besides other things the activation of nuclear transcription factors what leads in the production of cytokines (primarily of interferons, interleukins and TNF factor) and also in the activation of the immune system [26, 37]. The leading role have primarily TLR-3 and 4 which are widened in the cardiovascular system bountifully [22, 26].
Subacute phase
Subacute phase is characterized by the immune response caused by the viral internalization into cardiomyocytes. It is in motion approximately between the 4th and 14th day of the disease. The immune response goal is the elimination of the viral agent. This phase is important even from the point of view of the further course of myocarditis. In the case of an excessive immune response, viral persistence even after the immune response, development of the autoimmune reaction or their combination, structural and functional damage of the myocardium may develop what could lead to the development of DCMP, or rather ICMP and chronic heart failure [22, 86].
Innate immunity reaction is characterized by the immune response activation and the production of cytokines and interleukins (in the initial phase especially of IL 1beta and TNF alpha), [26, 29] decreasing the viral replication [26].
It is followed by the humoral and cellular immune response. NK-cells activated by IL-2 infiltrates the myocardium and eliminates cardiomyocytes attacked by the virus [29].
The inflammatory response includes both cellular and later as a result of T cells activation even humoral part of the immune system when B cells activate and start the production of specific antibodies [24]. From the cellular immunity, macrophages, B lymphocytes, CD4 and CD8 T lymphocytes are involved in the inflammatory reaction [26]. CD4 T lymphocytes differentiate in several cellular subtypes like Th1 and TH2 and T regulating cells (Treg) which have together with other factors an important role in the suppression of the immune response [26].
In this phase, the production of anti-myosin and other autoantibodies may occur what happens as a result of the destruction of cardiomyocytes and the exposure of their inner structures on the principle of the molecular mimicry of the infectious agent and components of the host cell [26].
Chronic (myopathic) phase
This phase begins approximately with the 15th day and ends 90th day from the beginning of the disease (it could sometimes last even distinctively longer) and is highly important for the future disease course. After the elimination of the virus, suppression of the immune reaction should begin and myocarditis should heal up without any severe consequences for the patients what occur in 50 to 70 % of cases [96]. In the remaining part of patients, the disease may lead either to death or the heart transplant or the disease progresses in chronicity.
There are a lot of factors influencing the structure and function of the heart, primarily of the left heart ventricle. One of them is the extent of the myocardial damage because damaged and necrotic myocardial tissue is replaced by fibrous tissue which is not able to fulfill highly specialized functions of the myocardium. These changes are accompanied by the left ventricular remodelation which gradually reach the stage of the DCMP [22, 26]. Fibrous changes and remodelation are initiated already in the subacute phase of the disease by the activity of pro-fibrous cytokines, especially of TNF alpha, IL 1beta, IL 4, IL 17 and TGF beta 1 [41]. This damage is not caused just by the lytic activity of an infectious agent, but also by the elimination of cardiomyocytes attacked by the agent by the immune system, which in some cases may cause even more extensive damage of the tissue than the agent itself, however, at the cost of stopping the infection. There are of course even other aspects that have a share in the development of the DCMP on the grounds of a suffered myocarditis like if the elimination of the infectious agent was successful or not what may lead to other lytic activity of the agent or long-term immune system stimulation.
Last but not least, immune system activity has a crucial influence on a patient´s state of health. Continuing myocardial inflammation leads to further damage to cardiomyocytes and it may initiate even the production of autoantibodies against the inner cellular components of cardiomyocytes as mentioned in the previous paragraph. Most frequently autoantibodies are created against myosin, sarcolemma components, beta-adrenergic receptors, muscarine receptors, tropomyosin etc. [39]. Antibodies against some of the previously mentioned components were detected in serum in up to 59 % of patients with myocarditis. Moreover, even other changes may be observed like for example cardiomyocytes hypertrophy, increase of the extracellular space connected with the fibrous replacement and other changes which are described even in the left ventricular remodelation connected with the heart failure like for example changes of the ATP metabolism in the myocardium etc. [26, 40].
Author of the opening picture: BruceBlaus
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References:
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