Heart Fail Rev. 2013 Nov;18(6):703-14.

Dilated cardiomyopathy update: infectious-immune theory revisited.

Chuichi Kawai, Akira Matsumori

Kyoto University, Takeda General Hospital, and Tokyo Medical University, Nonprofit Organization Asian Pacific Society of Cardiology, Kyoto, Japan

 

Abstract

Dilated cardiomyopathy is characterized by dilatation of the left or right ventricle, or both ventricles. The degree of myocardial dysfunction is not attributable to abnormal loading conditions. The infectious-immune theory has long been hypothesized to explain the pathogenesis of many etiologically unrecognized dilated cardiomyopathies. Inflammations followed by immune reactions, which may be excessive, in the myocardium, evoked by external triggers such as viral infections, and/or autoimmune antibodies, continue insidiously and lead to the process of cardiac remodeling with ventricular dilatation and systolic dysfunction. This ultimately results in dilated cardiomyopathy. Hepatitis C virus-associated heart diseases are good examples of cardiac lesions definitely induced by viral infections in humans that progress to a chronic stage through complicated immune mechanisms. Therapeutic strategies for myocarditis and dilated cardiomyopathy have been obtained through analyses of the acute, subacute, and chronic phases of experimental viral myocarditis in mice. The appropriate modulation of excessive immune reactions during myocarditis, rather than their complete elimination, appears to be a key option in the prevention and treatment of dilated cardiomyopathy. The clinical application of an NF-κB decoy and immune adsorption of IgG3 cardiac autoanti- bodies have been used as immunomodulating therapies and may provide novel approaches for the treatment of refractory patients with dilated cardiomyopathy. Conventional therapeutic agents for chronic heart failure such as β-blockers, ACE inhibitors, ARB, and aldosterone antagonists in particular should be reevaluated on the basis of their anti- inflammatory properties in the treatment of dilated cardiomyopathy.

PMID: 23892949

 

Supplement:

We hypothesized that besides genetic abnormalities, dilated cardiomyopathy in man is caused by inflammations in the cardiac tissues, evoked by external triggers such as viral infections and/or autoimmune antibodies, followed by immune reactions sometimes excessive and continuing insidiously. This hypothesis is based on the following animal experiments.

(1) Animal model of dilated cardiomyopathy. Inbred DBA/2 mice were inoculated intraperitoneally with 0.1 ml of the M variant of EMC (encephalomyocarditis) virus. Mice were observed daily for 90 days after inoculation. Myocardial necrosis with calcification appeared on day 4. Thereafter, myocardial necrosis became more extensive and mononuclear cell infiltration was evident and most marked on day 14. On day 90, cellular infiltration had decreased and myocardial fibrosis was prominent. At this stage, the heart weight was significantly greater in the infected mice than in the control. The cavity dimensions of the left ventricle were larger. The diameters of the myocardial fiber of the right ventricle, the interventricular septum and the left ventricle were significantly larger than those of the control (Figure 1) . The temporal changes in murine myocarditis inoculated with virus are diagrammatically illustrated(Fig. 1)in the above text.

fig1Figure 1. Day 90. Dilatation and hypertrophy of the heart. Left; control. Right; inoculated mice. Upper; macroscopic view. Lower; cross sectional view. The cavity dimension of the left ventricle is enlarged and myocardial fibrosis prominent; there is no more mononuclear cell infiltration at this stage, resembling to dilated cardiomyopathy in humans. RV: right ventricle. LV: left ventricle. Reproduced with permission from Reference 1

(2) Myocardial injury in T-Cell-Depleted Mice

The immune T-cell infiltrate peaked on day 7 to 14 after virus inoculation. The inflammatory response continues at a lesser intensity at sites surrounding cardiac necrosis. The cell-mediated immune mechanisms evoked by these infiltrating immune cells play a pivotal role in the ongoing destruction of cardiac tissue, developing to dilated cardio- myopathy.

A marked reduction in myocardial damage is noted in T-cell-depleted nude mice (BALB/c-nu/nu) inoculated with EMC virus. There is a mild mononuclear cell infiltration in the right and left ventricular myocardium. No cavity enlargement is visible (Figure 2)

fig2Figure 2. Day 16. BALB/c-nu/nu mice inoculated with EMC virus. LV;left ventricle. RV:right ventricle (RV, lower left; LV, lower right). Figures 2,3 and 4: Modified with permission from Reference 2.

 

Myocardial damage in BALB/c-nu/+ (intact) mice inoculated with EMC virus is markedly severe, demonstrating prominent mononuclear cell infiltration in the myocardium. There are obvious cavity dilatation and a decrease in wall thickness of both ventricles (Figure 3).

Severe myocarditis is also found in BALB/c-nu/nu mice (nude mice) injected with spleen cells from BALB/c-nu/+ mice (intact mice) (Figure 4). The survival rate of the nude mice inoculated with EMC virus on days 10 to15 is significantly higher than that of nu/+ mice and nude mice injected with spleen cells from nu/+ mice. These studies support the view that the severity and development of myocarditis are mediated by T lymphocytes, which control cell-mediated immunity.

Although the results in animal models cannot be directly extrapolated to humans, the concepts derived from the results of the animal experiments described here will no doubt contribute to the establishment of a new paradigm for the pathogenesis of viral myocarditis and dilated cardiomyopathy and thus to the elucidation of the effective treatments for these diseases, in which currently there are no foreseeable definite life-saving therapeutic options.

fig3

Figure 3. Day 16. BALB/c-nu/+ (intact) mice inoculated with EMC virus. There is obvious cavity dilatation and a decrease in the wall thickness in the right (RV) and left (LV) ventricles. Marked myocardial necrosis and cellular infiltrations are evident (RV, lower left. LV, lower right).

fig4

Figure 4. Day 16. BALB/c-nu/nu* mice (BALB/c-nu/nu mice injected with spleen  cells from nu/+ (intact) mice). There is obvious cavity dilatation and a decrease in wall thickness in the right (RV) and left  (LV) ventricles similar to Figure 3. Marked myocardial necrosis and cellular infiltrations are also evident (RV free wall,  lower left; LV wall, lower right).

 

Reference

1. Matsumori A, and Kawai C. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation.1982;66:355-360.

2. Kishimoto C, Kuribayashi K, Masuda T, Tomioka N, Kawai C. Immunologic behavior of lymphocytes in experimental viral myocarditis: significance of T lymphocytes in the severity of myocarditis and silent myocarditis in BALB/c-nu/nu mice. Circulation. 1985; 71: 1247- 1254.

 

Contact

Chuichi Kawai, M.D.

Professor Emeritus, Kyoto University

e-mail: c-kawai@mbox.kyoto-inet.or.jp

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