Search

A 60-year-old woman with a history of hypothyroidism was referred to our hospital for shortness of breath and a left ventricular ejection fraction (LVEF) of 13%, which required continuous dobutamine injection with intra-aortic balloon pump support. An endomyocardial biopsy obtained from the right ventricle revealed an infiltration of giant cells and eosinophils, indicating giant cell myocarditis. In addition to heart failure treatment, combined immunotherapy with steroids, tacrolimus, and intravenous immunoglobulin was administered. Transthoracic echocardiography demonstrated a dramatic improvement in the LVEF after this therapy, and the patient was discharged home without symptoms on day 72.

We herein report the clinical potential of Impella 5.0 support, which is a catheter-mounted micro-axial left ventricular support device, in a 39-year-old man with recurrent fulminant viral myocarditis complicated with profound cardiogenic shock despite inotropic infusion and an intra-aortic balloon pumping. Switching from these therapies to the Impella 5.0 device provided sufficient systemic perfusion with well-controlled left ventricular diastolic properties to facilitate a prompt recovery from profound cardiogenic shock. The patient was uneventfully discharged on the 27th hospital day. Given its effect of cardiac protection with sufficient systemic perfusion, the Impella device should be considered the first-line therapy for the treatment of fulminant myocarditis complicated with cardiogenic shock.

Prognosis of acute myocarditis is generally benign, but fulminant cases exist which require advanced life support devices, such as percutaneous cardio-pulmonary support (PCPS) and ventricular assist devices (VAD), and lead to fatal outcomes. The purpose of this study was to identify predictors and their values at admission which might foreshadow a fulminant course of myocarditis. Data from 138 patients (mean age 42.0 years, 79 males) with a diagnosis of acute myocarditis in the Tokyo CCU Network database from 2007 to 2009 were analyzed retrospectively. Patients were divided into fulminant (in-hospital death, or PCPS or VAD requirement, N = 42) and non-fulminant groups (N = 96). Clinical data at admission were compared between them. Overall in-hospital mortality was 14.5%. On multivariate analysis, low systolic blood pressure (BPsys, odds ratio (OR)/mmHg 0.97; 95% confidence interval (CI) 0.93-1.00, p = 0.032) and electrocardiographic QRS complex prolongation (OR/10 ms 1.28; 95% CI 1.10-1.59, p = 0.0034) at admission were independent factors associated with a fulminant course. By receiver operator characteristic curve analysis, the area under the curve predicting a fulminant course was 0.769 for low BPsys and 0.821 for prolongation of QRS duration. The optimal cut-off value was 101 mmHg for BPsys (sensitivity 79.5%, specificity 68.0%), and 120 ms for QRS duration (sensitivity 72.2%, specificity 88.0%). Systolic hypotension and prolonged QRS on admission are predictors of a fulminant course of myocarditis.

Myocarditis is a clinically severe disease; however, no effective treatment has been established. The aim of this study was to determine whether cacao bean (Theobroma cacao) polyphenols ameliorate autoimmune myocarditis. We used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. Mice with induced EAM were treated with a cacao polyphenol extract (CPE, n=12) or vehicle (n=12). On day 21, hearts were harvested and analyzed. Elevated heart weight to body weight and fibrotic area ratios as well as high cardiac cell infiltration were observed in the vehicle-treated EAM mice. However, these increases were significantly suppressed in the CPE-treated mice. Reverse transcriptase-PCR revealed that mRNA expressions of interleukin (Il)-1β, Il-6, E-selectin, vascular cell adhesion molecule-1 and collagen type 1 were lower in the CPE group compared with the vehicle group. The mRNA expressions of nicotinamide adenine dinucleotide phosphate-oxidase (Nox)2 and Nox4 were increased in the vehicle-treated EAM hearts, although CPE treatment did not significantly suppress the transcription levels. However, compared with vehicle treatment of EAM hearts, CPE treatment significantly suppressed hydrogen peroxide concentrations. Cardiac myeloperoxidase activity, the intensity of dihydroethidium staining and the phosphorylation of nuclear factor-κB p65 were also lower in the CPE group compared with the vehicle group. Our data suggest that CPE ameliorates EAM in mice. CPE is a promising dietary supplement to suppress cardiovascular inflammation and oxidative stress.

Myocarditis is a clinically serious disease; however, no effective treatment has been elucidated. The P2X7 receptor is related to the pathophysiology of inflammation in many cardiovascular diseases. The P2X7 receptor antagonist is promising as an immunosuppressive treatment; however, its role in myocarditis is still to be established. To clarify the role of the P2X7 receptor, we used a murine experimental autoimmune myocarditis (EAM) model. Mice were immunized on day 0 and 7 with synthetic cardiac myosin peptide to establish EAM. The mice with induced EAM were treated with A740003, the P2X7 receptor antagonist (n = 10), or not treated (n = 11); hearts were harvested on day 21. The P2X7 receptor antagonist improved myocardial contraction of the EAM hearts via suppressed infiltration of CD4+ T cells and macrophages. Similarly, mRNA expression of interleukin 1 beta, the P2X7 receptor and NADPH oxidase 2/4 was lower in the heart of the P2X7 receptor antagonist-treated group compared to the non-treat group. The P2X7 receptor antagonist suppressed EAM development; thus, this inhibition is promising for treating clinical myocarditis.

Myocarditis is a critical inflammatory disorder which causes life-threatening conditions. No specific or effective treatment has been established. DPP-4 inhibitors have salutary effects not only on type 2 diabetes but also on certain cardiovascular diseases. However, the role of a DPP-4 inhibitor on myocarditis has not been investigated. To clarify the effects of a DPP-4 inhibitor on myocarditis, we used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. EAM mice were assigned to the following groups: EAM mice group treated with a DPP-4 inhibitor (linagliptin) (n = 19) and those untreated (n = 22). Pathological analysis revealed that the myocardial fibrosis area ratio in the treated group was significantly lower than in the untreated group. RT-PCR analysis demonstrated that the levels of mRNA expression of IL-2, TNF-α, IL-1β and IL-6 were significantly lower in the treated group than in the untreated group. Lymphocyte proliferation assay showed that treatment with the DPP-4 inhibitor had no effect on antigen-induced spleen cell proliferation. Administration of the DPP-4 inhibitor remarkably suppressed cardiac fibrosis and reduced inflammatory cytokine gene expression in EAM mice. Thus, the agents present in DPP-4 inhibitors may be useful to treat and/or prevent clinical myocarditis.

Objective: Mechanisms of cardiac dysfunction in myocarditis have not been fully elucidated. Though it remains controversial whether angiogenesis is beneficial or harmful in inflammatory disease, significant vascular destruction might possibly impair cardiac function in myocarditis. The prolyl hydroxylase domain-containing protein (PHD) inhibitor is a potential drug for promoting angiogenesis as it stabilizes hypoxia inducible transcription factor (HIF). The authors examine whether the PHD inhibitor TM6008 could affect cardiac function by promoting angiogenesis in experimental autoimmune myocarditis (EAM)., Methods: EAM was induced on BALB/c mice by immunizing them with a synthesized α myosin heavy-chain peptide. Every day, 200 mg/kg of TM6008 or vehicle was administered orally., Results: TM6008 improved left ventricular ejection fraction significantly on the 21st day of EAM. Though TM6008 did not affect the severity of myocardial cell infiltration, it tended to reduce cardiac fibrosis. Immunohistochemistry showed that CD31-positive blood vessels were preserved in the TM6008 group compared to the control group. Immunoblotting revealed that TM6008 increased the expression of HIF-1α, HIF-2α and vascular endothelial growth factor in myocarditis., Conclusion: Inhibition of PHD could ameliorate cardiac dysfunction in EAM, partially through promoting neovascularization. Relief of tissue hypoxia via neovascularization could improve cardiac function in myocarditis.

NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg(-1)·day(-1)) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

Periodontitis is one of the most common infections in humans. Recently, published reports assert that periodontitis is associated with cardiovascular disease. Although it is said that viral, bacterial infections and autoimmune diseases may be the cause of myocarditis, the pathogenesis of it remains unclear. The aim of this study was to investigate the influence of a periodontal pathogen on experimental autoimmune myocarditis (EAM). Porphyromonas gingivalis (P.g.), PBS as a control, were injected into the mice. Histopathological and immunohistochemical analyses were performed. We examined heart mRNA levels using quantitative RT-PCR. The anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared with the PBS-injected group. Histopathological analysis detected that the myocarditis-affected areas and the fibrotic area in the P.g.-injected EAM group significantly increased compared with the PBS-injected EAM group (P < 0.05). Immunohistochemical analysis detected that more CD11b-positive cells were shown in the heart of the P.g.-injected EAM group compared with the PBS EAM-injected group (P < 0.05). Hearts from the P.g.-injected EAM group showed significantly increased expression of monocyte chemoattractant protein-1, IFN-γ, and matrix metalloproteinase-9 (MMP-9) mRNA compared with the hearts from the PBS-injected EAM group (P < 0.05). On day 7, serum levels of IL-6 were significantly enhanced in the P.g.-injected EAM group compared with the PBS-injected EAM group (P < 0.05). These results showed that P.g. injection could deteriorate EAM in mice through CD11b-positive cells, cytokines, and MMP-9 expression.

Recent reports assert that dental health is linked to an increased risk of cardiovascular disease. It is well known that Aggregatibacter actinomycetemcomitans (A.a.) is highly associated with heart disease. Indeed, we previously reported that A.a. affects the development of heart disease in a mouse model. However, no reports have clarified the relationship between A.a. and experimental autoimmune myocarditis (EAM). The aim of this study was to investigate the effects of A.a. on EAM in mice. EAM was induced via the injection of cardiac myosin into the mice. A.a. or PBS was then injected into the mice using a chamber implanted into the back of each mouse. The weight of the organs and echocardiograms were obtained and a pathological analysis and quantitative RT-PCR were performed. Echocardiography showed that no statistical difference was observed between the two groups. A histopathological analysis demonstrated that the number of areas affected by myocarditis in the A.a.-injected EAM group was significantly increased compared to that observed in the PBS-injected EAM group (P < 0.05). The hearts of the mice in the A.a.-injected EAM group exhibited significantly increased expressions of MMP-9 mRNA compared to the hearts of the mice in the PBS-injected EAM group (P < 0.05). These results show that A.a. aggravated EAM via an enhanced MMP expression.

Introduction: Although prognosis in acute myocarditis is generally moderate, giant cell myocarditis shows poor prognosis. Giant cell myocarditis is considered to be an autoimmune disease, however, its pathophysiology and specific treatment is yet to be elucidated., Areas Covered: This article reviews the clinical characteristics of autoimmune myocarditis and its possible future treatments. An animal model of experimental autoimmune myocarditis (EAM) is characterized by severe myocardial damage and multinucleated giant cell infiltration, and this has been used as a disease model for human acute giant cell myocarditis. Using experimental models, we reported that NF-κB, cytokines, adhesion molecules and other factors play a critical role in the development of autoimmune myocarditis., Expert Opinion: Giant cell myocarditis, an autoimmune form of myocarditis, has a high mortality rate unless mechanical support or cardiac transplantation is performed. Therefore, further therapeutic applications of novel methodologies are needed to expand the number of alternative choices for treating autoimmune myocarditis.

Prostaglandins (PG) and their specific receptors for E type PG (EP) play an important role in inflammatory diseases. Although myocarditis results in inflammation of the heart, roles of PG and EP in its pathophysiology is still controversial. To clarify the role of PG and EP on the progression of myocarditis, we used an experimental autoimmune myocarditis model. A selective EP4 (EP4RAG) agonist was administered into both early (Day 0 to 21) and late (Day 14 to 21) -treated groups and the animals were killed on Day 21. We found that improved cardiac function was detected in the EP4RAG-treated groups in comparison to the untreated group. The infiltration area ratio in the early-treated (16.6% ± 4.6%) group was lower than those in the untreated group (32.1% ± 3.5%) (P < 0.05). The fibrosis area ratios in the early-treated (19.2% ± 6.3%) and the late-treated groups (24.4% ± 5.1%) were lower than those in the untreated group (37.4% ± 2.6%), respectively (P < 0.05). Moreover, we found that EP4RAG decreased T-cell proliferation and monocyte chemoattractant protein-1 production in vitro. We concluded that a selective EP4 agonist inactivates T-cells, which turns out to moderate the progression of experimental autoimmune myocarditis. Therefore, EP4 can be an effective target for myocarditis treatment.

Background: Matrix metalloproteinase (MMP) activity is upregulated in the hearts with myocarditis, and its activation contributes to the changes in left ventricular function. A major macrolide antibiotic, clarithromycin (CAM), has many biological functions including MMP regulation. However, little is known about the effect of CAM in myocarditis via MMPs., Objective: To clarify the role of MMPs regulated by CAM in the progression of myocarditis. Design CAM was given to experimental rats with autoimmune myocarditis (EAM) from day -7 to day 21 (early treated group, n=6) or from day 1 to day 21 (late treated group, n=6) twice a day., Results: Although the non-treated rats showed blood pressure decline and impaired cardiac function, early CAM treatment prevented this progression. Pathologically, severe myocardial cell infiltration (30.5+/-4.2%) and fibrosis (32.2+/-1.1%) were detected in the non-treated group, while early CAM treatment significantly suppressed these changes (infiltration 6.5+/-0.2%, fibrosis 5.9+/-3.9%). Zymography showed that non-treated EAM resulted in enhanced ventricular activities of MMP-9, while early CAM treatment reduced the alteration. However, late CAM treatment was less effective than the early treatment., Conclusions: Early CAM treatment is effective to attenuate myocarditis by suppressing MMP-9.

A 60-year-old man who had serious chest and arm pain died suddenly during hospitalization. He suffered from coronary vasospastic angina complicated by a fatal acute fulminant-type of myocarditis associated with Churg-Strauss syndrome (CSS). The diagnosis at autopsy was acute progressive eosinophilic myocarditis associated with CSS.

4-1BB, a member of the tumor necrosis factor receptor (TNFR) family, binds the 4-1BB ligand (4-1BBL), works as a costimulatory molecule, and regulates T cell-mediated immune responses. Although inflammation is an essential pathological feature of myocarditis, the role of 4-1BB in experimental autoimmune myocarditis (EAM) remains unclear. Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish EAM. 4-1BB-immunoglobulin (4-1BBIg) was administered intraperitoneally (n=6) a total of 9 times (3 times per week). Rats were killed on day 21 to study effects of 4-1BB/4-1BBL pathway blockade. For controls, isotype-matched human IgG was administered in other EAM rats (n=6). Histologic and echocardiographic examination showed development of EAM attenuated by 4-1BBIg. Suppression of mRNA expression for IL-1alpha, IL-1beta, IL-4, IL-6, and TNF-alpha was noted in the heart tissue treated with 4-1BBIg. Treatment with 4-1BBIg reduced production of Th1-type cytokines, and inhibited T cell proliferation in vitro. In the 4-1BB signaling pathway in splenocytes, 4-1BBIg suppressed JNK, p38, and IkappaB activity but not that of ERK1/2. Blockade of T cell activation through the 4-1BB/4-1BBL pathway regulates development of EAM; therefore, 4-1BB may be an effective target for treating myocarditis.

Objective: Myocarditis is a serious disease, however no effective treatment exists. Plasminogen activator inhibitor-1 (PAI-1) is critical in cell recruitment and inflammation. Although inflammation is an essential pathological feature of acute myocarditis, the effects of PAI-1 inhibition on the development of acute myocarditis have not been well studied., Methods: To clarify the role of PAI-1, we used a rat experimental autoimmune myocarditis (EAM) model. Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. The rats with induced EAM were treated with the PAI-1 inhibitor (IMD-1622) (n = 8) or not treated (n = 6); hearts were harvested on day 21. Echocardiograms, heart weight to body weight ratios (H:B), histological examinations and in vitro studies were performed., Results: Echocardiograms indicated that the PAI-1 inhibitor improved left ventricular fractional shortening (50 +/- 3%) compared with controls (36 +/- 4%, p < 0.05). The inhibitor significantly reduced H:B ratios compared with controls. Pathologically, areas of myocardial cell infiltration and fibrosis in the inhibitor-treated group were significantly smaller than those in the control group. Immunohistochemistry revealed enhanced expression of adhesion molecules and inflammatory factors in non-treated EAM hearts, the inhibitor suppressed this expression., Conclusions: The PAI-1 inhibitor suppressed EAM development; thus this inhibitor is promising for treating clinical myocarditis.

Mesenchymal stem cells (MSCs) have various effects, including angiogenic, myogenic, and paracrine actions. In this study, we determined whether MSC transplantation attenuates experimental autoimmune myocarditis (EAM). The mechanisms involved were also investigated. Male Lewis rats were immunized with myosin to establish EAM on day 0. MSCs, isolated from isogenic rats, were injected directly into the myocardium on day 14 (group MSC-2W), day 21 (group MSC-3W), or day 28 (group MSC-4W). In the MSC transplantation groups, cardiac systolic function detected by echocardiography was significantly improved, the EAM affected area determined by histological examination was significantly decreased, and capillary density was increased compared to that in the control groups. Expression of hepatocyte growth factor protein was enhanced by MSC transplantation. MSC transplantation inhibited myocardial expression of interleukin-2, -6, and -10 mRNAs. MSC transplantation reduces the severity of EAM by inducing neovascularization and inhibiting inflammatory cytokine production. Enhanced expression of hepatocyte growth factor was associated with these effects. Autoimmune myocarditis may be a good clinical target for MSC transplantation.

Chemokines play an important role in induction of chemotaxis of immune cells. CCR1 is a chemokine receptor expressed on neutrophils, monocytes, and T lymphocytes. The role of CCR1 in immunity is not well examined. We demonstrated the role of CCR1 on T lymphocytes and the effect of a CCR1 antagonist, BX471 in myocarditis. Lewis rats were immunized with cardiac myosin on day 0 to establish experimental autoimmune myocarditis. Rats were then administered BX471 subcutaneously every day (group BX0: n = 7) or from day 14 (group BX14: n = 7) and were killed on day 21. We confirmed expression of CCR1 in cells infiltrating the myocardium by immunohistochemistry and FACS analysis. The development of myocarditis was almost completely prevented in group BX0, and myocarditis-affected areas were significantly decreased in size in group BX14. Cardiac function was markedly improved. Ribonuclease protection assay showed that the CCR1 antagonist treatment suppressed mRNA expression for IL-6, IL-1beta, and TNF-alpha in the hearts. An antigen-specific T cell proliferation assay was performed with CD4-positive T cells isolated from control rats immunized with cardiac myosin. T cell proliferation was inhibited by the CCR1 antagonist. Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression. The CCR1 antagonist reduced the severity of EAM by inhibiting cytokine expression and inducing T cell inactivation. Thus, the CCR1 antagonist may provide a novel therapeutic strategy treatment of myocarditis.

Acute myocarditis is a clinically serious disease; however, no effective treatment has been elucidated. Cyclooxygenase (COX)-2 is a key factor for progression of inflammation. Although inflammation is an essential pathological feature of acute myocarditis, the role of COX-2 in this process remains unclear. Thus, the purpose of this study was to clarify the role of COX-2 in acute myocarditis. We used a rat experimental autoimmune myocarditis (EAM) model and a specific COX-2 inhibitor in this study. Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. We administered the COX-2 inhibitor (meloxicam, 0.1 mg/kg per day) daily; the rats were killed on day 21. Echocardiograms, body and heart weight, heart rate, blood pressure, and histological and molecular examinations were performed. Cytokine expression in the hearts and cell proliferation against cardiac myosin were also analyzed. The COX-2 inhibition during the immune response (late) phase attenuated EAM development; however, the inhibition during the antigen priming (early) phase did not attenuate EAM. The COX-2 inhibitor altered Th1/Th2 cytokine balance and inhibited cell proliferation in vitro. The COX-2 inhibitor suppresses the development of EAM. COX-2 regulation is promising for treating acute myocarditis.

Hepatocyte growth factor (HGF) plays a role in cell protection, antiapoptosis, antifibrosis, and angiogenesis. However, the role of HGF in the immune system is not well defined. We examined the influence of HGF on T cells and the effects of HGF therapy in acute myocarditis. Lewis rats were immunized on day 0 with cardiac myosin to establish experimental autoimmune myocarditis (EAM). Human HGF gene with hemagglutinating virus of the Japan-envelope vector was injected directly into the myocardium on day 0 or on day 14 (two groups of treated rats). Rats were killed on day 21. Expression of c-Met/HGF receptor in splenocytes and myocardial infiltrating cells was confirmed by immunohistochemical staining or FACS analysis. Myocarditis-affected areas were smaller in the treated rats than in control rats. Cardiac function in the treated rats was markedly improved. An antigen-specific T cell proliferation assay was done with CD4-positive T cells isolated from control rats stimulated with cardiac myosin. HGF suppressed T cell proliferation and production of IFN-gamma and increased production of IL-4 and IL-10 secreted from CD4-positive T cells in vitro. Additionally, TUNEL assay revealed that HGF reduced apoptosis in cardiomyocytes. HGF reduced the severity of EAM by inducing T helper 2 cytokines and suppressing apoptosis of cardiomyocytes. HGF has potential as a new therapy for myocarditis.

Objective: This study tested the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor affects T cell-mediated autoimmunity through inhibition of nuclear factor-kappaB (NFkappaB) and reduces the severity of experimental autoimmune myocarditis (EAM)., Methods: EAM was induced in Lewis rats by immunization with myosin. High-dose or low-dose fluvastatin or vehicle was administered orally for 3 weeks to rats with EAM., Results: Fluvastatin reduced the pathophysiological severity of myocarditis. Fluvastatin inhibited expression of NFkappaB in the nuclei of myocardium in EAM. Fluvastatin reduced production of Th1-type cytokines, including interferon (IFN)-gamma and interleukin (IL)-2, and inhibited expression of inflammatory cytokine mRNAs in the myocardium. Infiltration of CD4-positive T cells into the myocardium and T cell proliferative responses were suppressed by fluvastatin. Plasma lipid levels did not differ between the groups., Conclusions: Fluvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB, and this activity is independent of cholesterol reduction.

Objective: Inducible costimulator (ICOS) is a member of the CD28 family. Although inflammation is an essential pathological feature of myocarditis, the role of ICOS in myocarditis remains unclear., Methods and Results: Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis (EAM). Flow cytometry was used to examine expression of ICOS on myocardial infiltrating cells. Anti-ICOS antibody or ICOS-immunoglobulin (ICOSIg) was administered intravenously, and rats were killed on day 14 or 21 to study effects of ICOS/ICOS-ligand (ICOSL) pathway blockade during the antigen priming phase (days 0-14) or immune response phase (days 14-21), respectively. The heart weight to body weight ratio was determined, and histological examination and echocardiogram were performed to evaluate the severity of the disease. Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed. Flow cytometry revealed that the majority of infiltrating cells, especially CD4-positive cells, expressed ICOS. Blockade of the ICOS/ICOSL pathway during the immune response phase attenuated EAM development. However, blockade of the ICOS/ICOSL pathway during the antigen priming phase did not attenuate and exacerbate EAM. Blockade of T cell activation through ICOS suppressed expression of cytokines including INF-gamma, IL-4, IL-6, IL-10, IL-1 beta, and TNF-alpha and inhibited T cell proliferation in vitro., Conclusions: Blockade of T cell activation through ICOS during the immune response phase regulates development of EAM, and therefore, ICOS may be an effective target for treating myocarditis.

Although fulminant myocarditis is known as a fatal disease, patients have been able to recover and return to normal life with the help of mechanical cardiopulmonary support. However, therapeutic guidelines for using percutaneous cardiopulmonary support (PCPS) for fulminant myocarditis have not been established, and the clinical course and long-term prognosis of such patients are still controversial issues. The present national survey considered the current situation of patients as the basis for proposing therapeutic guidelines. Thirty of 52 patients (57.7%) survived and returned to social life. Important factors concerning the prognosis were the severity and grade of cardiac and renal dysfunction, the adjusted support flow rate to enable recovery from circulatory failure, and prevention of circulatory disturbances of the legs and multiple organ failure directly associated with PCPS. With regard to the long-term prognosis of patients treated with PCPS, the readmission rate was 10%, the exacerbation rate was 3.3%, and mortality was 10% during the average follow-up period of 962 days. Optimal management of the mechanical cardiopulmonary support and curative treatment for the myocarditis further improve the outcome of this disease.

Background The renin angiotensin system (RAS) plays an important role in the pathogenesis of cardiovascular diseases and inflammation. Myocarditis is an inflammatory disease of the heart, and the role of the RAS in its pathophysiology is unknown. Because the direct renin inhibitor, aliskiren, is thought to block RAS completely, we investigated the cardioprotective effect of aliskiren in mice with experimental autoimmune myocarditis (EAM). Methods A cardiac α-myosin heavy chain peptide was injected in mice on days 0 and 7. Aliskiren 25 mg/kg per day ( n = 10) or vehicle ( n = 10) was administered to EAM mice starting on day 0 and the animals were killed on day 21. Results Aliskiren significantly prevented the progression of left ventricular wall thickening in EAM hearts compared to the vehicle-treated group. Histologically, the inflammatory cell infiltration and fibrosis area ratios in the aliskiren-treated group were lower than that in the vehicle-treated group. Immunohistochemistry revealed that aliskiren suppressed CD4 positive cell infiltration in EAM hearts compared to vehicle. Moreover, aliskiren decreased mRNA levels of interleukin (IL)-2, interferon-γ, tumor necrosis factor-α, and collagen 1. In vitro study showed that aliskiren inhibited T cell proliferation and IL-2 production induced by myosin stimulation. Conclusion Our results suggest that aliskiren ameliorates EAM by suppressing T-cell activation and inflammatory cytokines, and has potential as a treatment for myocarditis. [ABSTRACT FROM AUTHOR]

NF-kB, which is activated by the inhibitor of NF-kB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg-1·day-1) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-B activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation. [ABSTRACT FROM AUTHOR]

SUMMARY Macrolide antibiotics are broadly used for the treatment of various microbial infections. However, they are also known to have multiple biologic effects, such as alteration of inflammatory factors and matrix metalloproteinases (MMPs). Because of controversial results in clinical trials, the effects of macrolides on cardiovascular diseases are still to be elucidated. It has been reported that MMP activity is upregulated in various cardiovascular diseases, such as myocarditis, cardiac transplant rejection and myocardial infarction. However, little is known about the effects of macrolides on cardiovascular diseases. We have reported that clarithromycin suppressed the development of myocarditis, cardiac rejection and myocardial ischemia using animal models. In this article, we reviewed the roles of MMPs in cardiovascular diseases and the effects of macrolides on the prevention of adverse tissue remodeling. [ABSTRACT FROM AUTHOR]

Background: Myocarditis is a clinically serious disease. Tea catechins have been shown to reduce inflammation; however the effects of catechins on the development of myocarditis have not been well studied. Aims: To clarify the role of catechins, using an experimental autoimmune myocarditis (EAM) model. Methods and Results: Lewis rats were immunized with porcine cardiac myosin to establish EAM. Tea catechins were administered orally from day 0 to day 21 (Group A, n=12), from day 14 to day 21 (Group B, n=8), or saline (Group C, n=9) daily. Rats were killed on day 21. Echocardiograms indicated that Group A showed significantly improved cardiac function compared to Group C. Pathologically, non-treated EAM hearts showed severe myocardial cell infiltration and fibrosis; however Group A showed significantly less area. Immunohistochemistry revealed enhanced expression of NF-kappaB and ICAM-1 in non-treated EAM hearts, which was suppressed by catechin administration in Group A. mRNA levels of TNF-alpha were decreased and Th2 cytokines were markedly enhanced in Group A compared with the control group. Late catechin administration (Group B) showed limited effects on EAM. Conclusion: The catechins suppressed ventricular remodelling in EAM; thus catechin treatment might be a promising option for the prevention of EAM myocarditis. [ABSTRACT FROM AUTHOR]

There is growing evidence of the potential role of hepatocyte growth factor (HGF) in various cardiovascular diseases. In addition to the beneficial effects of HGF in myocardial infarction, heart failure, and occlusive peripheral arterial disease, administration of HGF effectively suppresses acute and chronic cardiac allograft rejection and autoimmune myocarditis. The present review summarizes recent advances in the utility of HGF for heart diseases, especially immune-mediated heart diseases. Possible mechanisms of action in the suppression of T-cell-mediated immunity are also discussed. [Copyright &y& Elsevier]