Korean Circ J.  2023 Dec;53(12):795-810. 10.4070/kcj.2023.0042.

Thalidomide and a Dipeptidyl Peptidase 4 Inhibitor in a Rat Model of Experimental Autoimmune Myocarditis

• Kim KJ
• Park JB
• Lee SP
• Kim HK
• Kim YJ

• KMID: 2548786
• DOI: http://doi.org/10.4070/kcj.2023.0042

Abstract

Background and Objectives
Myocarditis is a potentially fatal disease, but curative treatments have not yet been established. Myocardial inflammation is an important pathogenesis of this disease, and immunosuppressants such as methylprednisolone and immunoglobulin have been used for treatment; however, the effectiveness needs to be improved. Thalidomide and dipeptidyl peptidase (DPP) 4 inhibitors were recently investigated regarding their immunomodulatory properties. This study aimed to test whether thalidomide or a DPP4 inhibitor (evogliptin) can improve the effectiveness of myocarditis treatment using a rat model of experimental autoimmune myocarditis (EAM).
Methods
Rats with or without myocarditis were administered thalidomide at 100 mg/ kg/day and DPP4 inhibitor at 10 mg/kg/day orally. Measurement of echocardiography, serum inflammatory cytokines, myocardial histopathological examination, and immunohistochemical staining for leukocytes, macrophages, CD4+ T cells, and cytoskeleton were performed after 3 weeks, and the fibrosis area was measured after 3 and 6 weeks.
Results
Thalidomide and DPP4 inhibitor did not reduce the severity of myocarditis compared with the EAM without treatment rats by comparing the echocardiographic data, myocardial CD4 + , macrophages, neutrophil infiltrations, and the heart weight/body weight ratio in 3 weeks. The levels of inflammatory cytokines were not lower in the thalidomide and DPP4 inhibitor-treated group than in the untreated group in 3 weeks. In 6 weeks, thalidomide and DPP4 inhibitors did not reduce the fibrosis area compared to untreated groups.
Conclusions
Although thalidomide and the DPP4 inhibitor had an immunomodulatory effect and are used against inflammatory diseases, they did not ameliorate myocardial inflammation and fibrosis in this rat model of EAM.

Keyword

Myocarditis; Thalidomide; Dipeptidyl peptidase 4 inhibitor; Immunomodulatory therapy

Figure

• 

  Figure 1 The experimental schedule.DPP = dipeptidyl peptidase; ELISA = enzyme-linked immunosorbent assay; H&E = hematoxylin and eosin.

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  Figure 2 Disease manifestations in EAM rats after 3 weeks.EAM = experimental autoimmune myocarditis.

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  Figure 3 Kaplan–Meier survival curves in the 3-week and 6-week experiments.(A) Kaplan–Meier survival curves of EAM rats in the 3-week experiment. (B) Kaplan–Meier survival curves of EAM rats in the 6-week experiment.DPP = dipeptidyl peptidase; EAM = experimental autoimmune myocarditis.

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  Figure 4 Differences in the ratio of heart weight to body weight. (A) Differences in the ratio of heart weight to body weight (g/kg) after 3 weeks in the 3-week experiment. (B) Differences in the ratio of heart weight to body weight (g/kg) after 6 weeks in the 6-week experiment.

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  Figure 5 The time course of changes in body weight among rat groups during 6 weeks in the 6-week experiment.DPP = dipeptidyl peptidase; EAM = experimental autoimmune myocarditis.

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  Figure 6 Differences in the area of Masson’s trichrome staining showing the extent of fibrosis in the left ventricle after 6 weeks in the 6-week experiment.DPP = dipeptidyl peptidase; EAM = experimental autoimmune myocarditis.

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