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Cytokines may induce or exacerbate myocarditis through several mechanisms. They may activate cytotoxic T cells. They may induce cell adhesion molecule (CAM) expression and other proinflammatory phenomena. They may induce nitric oxide synthetase (NOS), resulting in increased local nitric oxide. Nitric oxide and some cytokines can directly damage myocytes and cause reversible depression of contractility.

Cytokines mediate activation and the effector phase of innate and specific immunity, which are both important in controlling viral infection. The innate immune response not only has an important protective function but also serves to initiate and regulate subsequent specific immune responses. There are 2 principal mechanisms of innate immunity against viruses. 1) Viral infection directly stimulates the production of type I IFN (IFN-alfa and -beta) by infected cells. Type I IFN inhibits viral replication by initiating the synthesis of enzymes, which collectively interfere with replication of viral RNA or DNA. 2) Natural killer cells lyse a wide variety of virally infected cells and are probably one of the principal mechanisms of immunity against viruses early in the course of infection, before specific immune responses have developed.95

In specific immunity, various cytokines, chemokines, and adhesion molecules are involved in regulating migration and activation of T- and B-cell responses, including migration and activity of macrophages. Interest has focused on tumor necrosis factor (TNF) -a, interleukin (IL)-1, and IL-6, because increased concentrations have been reported in plasma of patients with myocarditis. Moreover, plasma values of TNF-a and IL-6 correlate with clinical signs of heart insufficiency in patients with dilated cardio-myopathy.96

Increased concentrations of TNF-a have been reported in the serum of patients with chronic heart disease,97 including a subset of patients with myocarditis or DCMI.96 TNF-a is able to potentiate the immune response and induce apoptosis in cells, both of which appear to hold special importance in the pathogenesis of myocarditis. Other inflammatory mediators, including IL-1 and granulocyte colony-stimulating factor, also have increased values in myocarditis patients.96

Kubota et al.98 described a transgenic mouse model of myocarditis in which TNF-a is expressed specifically in the myocardium, under the control of the a-myosin heavy-chain promoter. These animals developed gross lymphocytic infiltrates in the myocardium and interstitial edema. In addition, globular dilation of the heart and cardiomegaly were noted.

Satoh et al.99 reported the expression of IL-6, IL-8, IL-10, and TNF-a in all myocar-dial samples of 6 patients with acute myocarditis. In the same patients, however, analysis of repeated biopsy samples, at the time when DCM with enteroviral RNA persistence had developed, identified IL-6 (3 patients) and IL-8 (4 patients). In 21 DCM patients studied, only IL-6 (5 patients), IL-8 (8 patients), and TNF-a (12 patients) were detected, and enteroviral RNA was detected in 9 patients.

The ability of IL-12 to protect mice from encephalomyocarditis virus-induced myocarditis has also been reported.100 IL-12 has been shown to augment cytotoxic activity and induction of Th1-specific immune responses. Shioi et al.100 used IL-12 treatment in mice with encephalomyocarditis virus-induced myocarditis and this therapy reduced viral replication, inflammation, and myocyte necrosis, with a concomitant increase in survival. Successive administration of 10 ng of IL-12 from the day of virus inoculation to 5 days thereafter decreased mortality, myocardial damage, and viral replication in the heart tissue. The gene expression of IL-12p35 and IL-12p40 was enhanced in the hearts of mice inoculated with encephalomyocarditis virus. Treatment with neutralizing anti-IL-12 resulted in increased mortality of inoculated mice. Because both Th1 and Th2 immune responses were augmented, it was not possible to associate recovery with a predominant type of response. Further, it would be interesting to know if the virus was completely cleared after IL-12 treatment and whether dilated cardiomyopathy subsequently developed, as has been shown in an encephalomyocarditis virus model of myocarditis.101 In this model, persistent expression of IL-1P and TNF-a occurred during the development of DCM after myocarditis healing.

One possible effect of cytokine expression is the activation of inducible nitric oxide synthase (iNOS). Increased expression of NOS has been proposed to account for some of the dilation associated with DCMI102 and has been demonstrated in a murine CVB3-induced myocarditis model.103 In a study of a cardiac myosin-induced myocarditis model in mice, NOS expression was induced in macrophages and cardiomyocytes.104 However, nitric oxide synthesis did not appear to be essential for the development of pathologic conditions because myocarditis developed in mice lacking interferon regulatory transcription factor (IRF)-l, a transcription factor that controls iNOS expression. Despite the failure to synthesize NOS in the myocardium, the prevalence and severity of disease in IRF-1-deficient animals were similar to those in control animals. In addition, no difference was detected in animals lacking the IRF-2 gene, a negative regulator of IRF-l-induced transcription.

In contrast to these data, Ishiyama et al.105 found nitric oxide expression played a critical role in the resultant pathologic condition produced in a rat model of autoimmune myocarditis, after induction with cardiac myosin. Rats treated with aminoguanidine, an inhibitor of iNOS, had only focal mononuclear infiltration and reduced numbers of cardio-myocytes positive for iNOS compared with untreated animals that had considerable inflammatory infiltration and myocyte damage. In addition, serum concentrations of creatine kinase were significantly decreased in the treated animals, indicating decreased muscle damage. In a separate study of autoimmune myocarditis in the rat,106 IL-2 appeared early, whereas IL-3, TNF-a, and iNOS were present later, during the period of peak inflammation. IL-10 was detected only once inflammation began to subside and persisted during recovery. These data support the notion that changes in the Th1 and Th2 responses are important for controlling outcome, as previously suggested for CVB3-induced myocarditis.

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