Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance.

Intravenous immunoglobulin (IVIG) therapy has been used to treat several autoimmune or inflammatory diseases. We conducted a clinical trial of immunoglobulin therapy for acute myocarditis. The study consisted of two projects: (1) a comparison of prognosis between patients treated with and those not treated with IVIG in a multi-center study; (2) analyses of inflammatory cytokines and blood cell profiles in a substudy. In (1), 15 patients were treated with IVIG (1-2 g/kg, over 2 days), whereas 26 were untreated. There was a statistically significant difference between the survival curves of the patients treated with IVIG and the survival curves of those not treated with IVIG. There was no significant difference between the IVIG-treated and untreated groups in terms of clinical parameters of the acute and chronic phases. In (2), 10 patients were treated with IVIG and 6 were untreated. In both groups, all of the data except for changes in the fraction of lymphocytes and the fraction of monocytes decreased due to the treatment or during the course. In patients in the IVIG group, the percentage of peripheral eosinophils was decreased and the percentage of peripheral monocytes was increased by this treatment when they were compared with the pretreatment data. Therefore, therapy with IVIG seems to be a promising treatment for acute myocarditis given that it improves the clinical course, which may be due to modulation of inflammatory cytokines and the peripheral leukocyte balance.

A 17-year-old male with acute myocarditis following mRNA-1273 vaccination in Japan.

Vaccinations are the main tool being used to control the COVID-19 pandemic. When the Japanese Ministry of Health approved the Moderna mRNA-1273 vaccination in May 2021, it was limited to patients over 18 years old; however, using the additional data of efficacy and safety from clinical trials, vaccination was approved for 12- to 17-year-olds in Japan in July 2021. A previous study reported that myocarditis after the mRNA-1273 vaccination was more prevalent in young men; however, no patients under 18 years old with myocarditis diagnosed by cardiovascular magnetic resonance (CMR) findings after mRNA-1273 vaccination have been reported in Japan. In the present case, a 17-year-old healthy male developed arthralgia and had fever on the day of the second mRNA-1273 vaccination for severe acute respiratory syndrome coronavirus 2. Three days after the vaccination, the patient felt severe chest pain with broad ST elevations on electrocardiography and troponin T elevations. Symptoms and findings rapidly improved; however, on CMR, myocarditis remained. Thus, it is necessary to be vigilant of potential acute myocarditis in young men following mRNA-1273 vaccination. Learning objective: Although it is very rare, acute myocarditis after mRNA-1273 (Moderna) vaccination developed within 3-5 days following the second dose of the vaccine.Most reported cases were mild or moderate in severity, but there were cases of cardiogenic shock. We need to be vigilant of acute myocarditis in young men following mRNA-1273 vaccination.

Ventricular Fibrillation Induced by Takotsubo Syndrome with Congenital Long QT Syndrome.

We herein report a case of congenital long QT syndrome (LQTS) in which the QT interval was prolonged by Takotsubo syndrome (TTS), inducing ventricular fibrillation (VF). The patient was a 55-year-old woman who had been diagnosed with LQTS. Cardiopulmonary arrest occurred while coughing during sleep. VF was observed, and her heartbeat returned after two defibrillations. An electrocardiogram showed marked QT prolongation and large negative T waves. Echocardiography demonstrated hyperkinesis at the base of the left ventricle and akinesis at the apex. As there was no significant stenosis in the coronary artery, she was diagnosed with TTS.

From oxygen sensing to heart failure: role of thioredoxin.

Oxidative stress has been widely recognized to be involved in the pathogenesis of cardiopulmonary disorders. In ischemic heart diseases, it is involved not only in the development of atherosclerosis but also in ongoing ischemic injury, especially in the reperfusion process. Cardiomyopathy is another cardiac disorder in which oxidative stress is involved. In diabetic cardiomyopathy, homocysteine, a well-known source of oxidative stress, is believed to play major roles in its development. Thioredoxin (TRX) is a redox-acting protein ubiquitously present in the human body. It also is inducible by a wide variety of oxidative stresses. TRX is a multifunctional protein and has anti-inflammatory and antiapoptotic effects, as well as antioxidative effects. It is therefore feasible to think that TRX is a potential therapy for cardiac disease. Moreover, serum TRX is a well-recognized biomarker of various diseases involving oxidative stress, and this is also the case for cardiac disorders. Here we discuss how TRX is useful as a biomarker of and therapeutic agent for cardiopulmonary disorders, especially focusing on ischemic heart disease, myocarditis and oxygen sensing, and acute respiratory distress syndrome.

Aortic valve replacement with a 17-mm mechanical prosthesis in octogenarian or older patients.

OBJECTIVE: Few studies have reported on aortic valve replacement (AVR) in patients aged >80 years who have small aortic annuli. Various surgical techniques have been proposed for treating such patients. We investigated AVR using small-diameter mechanical valves, in patients aged >80 years, to determine its effectiveness. METHODS: Eighteen consecutive patients (15 women; 3 men) aged >80 (mean: 83.3 ± 2.7) years underwent surgical AVR with a 17-mm prosthesis. The clinical status and results of pre- and post-operative echocardiography were evaluated. Midterm examination was conducted at 12.0 ± 1.0 months after AVR. RESULTS: The average preoperative body surface area of the patients was 1.39 ± 0.15 m(2); the average New York Heart Association functional class was 3.28 ± 0.75. Echocardiography showed a peak pressure gradient of 99.1 ± 38.4 mm Hg. Operative mortality was absent. A significant decrease in the peak pressure gradient was found on early (22.6 ± 7.2 mm Hg) and midterm (22.2 ± 8.0 mm Hg) postoperative echocardiography, compared with that in the preoperative period. During this follow-up, 16 patients improved to class I, a significant change in each perioperative period compared with the preoperative period. No mortality was observed at 1 year postoperatively. CONCLUSIONS: In patients aged >80 years who have small aortic annuli, AVR using a 17-mm prosthesis showed satisfactory clinical and hemodynamic results and provided a satisfactory remote prognosis.

Successful Catheter Ablation for Paroxysmal Atrial Fibrillation in a Patient with Double-chambered Right Ventricle.

We herein describe an adult case of double-chambered right ventricle (DCRV) with symptomatic drug-intolerant paroxysmal atrial fibrillation (PAf). The woman was referred to undergo radiofrequency ablation (RFA), and mapping of the pulmonary veins (PVs) demonstrated that a spontaneous spike potential originating from the left inferior PV (LIPV) induced sustained Af in the second procedure. Accordingly, the LIPV was regarded as the arrhythmogenic PV. Since complete isolation of the PVs, the sinus rhythm has been maintained for at least two years. This is the first report to describe that RFA for drug-intolerant PAf was useful in a patient with DCRV.

Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity.

BACKGROUND: Adriamycin (ADR) is an anticancer drug known to cause severe cardiac toxicity by generating free radicals. We investigated the role of a redox-regulating molecule, thioredoxin-1 (TRX1), in ADR-induced cardiotoxicity. METHODS AND RESULTS: The in vitro study showed that TRX1 was dose-dependently increased concomitant with the formation of hydroxyl radicals in ADR-treated neonatal rat cardiomyocytes. Lactate dehydrogenase-releasing assay showed that treatment with recombinant human TRX1 suppressed cardiomyocyte injury in ADR-treated cardiomyocytes. To examine the biological significance of TRX1 in vivo, we used transgenic mice expressing increased levels of human TRX1 (TRX1-TG mice). Electron microscopy revealed that mitochondria, myofibrils, and other cellular details were much better maintained in ADR-treated TRX1-TG mice than in ADR-treated nontransgenic (WT) mice. The increase in the protein carbonyl content, a marker of cellular protein oxidation, was suppressed in ADR-treated TRX1-TG mice compared with ADR-treated WT mice. The formation of hydroxyl radicals in ADR-treated heart homogenates of TRX1-TG mice was decreased compared with WT mice. For the survival study, all WT mice treated with ADR died within 6 weeks, but 5 of 6 TRX1-TG mice treated with ADR survived >8 weeks. CONCLUSIONS: TRX1 is upregulated by intracellular oxidative stress generated by ADR. TRX1 has a protective role against ADR-induced cardiotoxicity by reducing oxidative stress.

Thioredoxin-1 ameliorates myosin-induced autoimmune myocarditis by suppressing chemokine expressions and leukocyte chemotaxis in mice.

BACKGROUND: Cardiac myosin-induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM. METHODS AND RESULTS: EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days -1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti-TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1alpha, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1alpha were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1alpha- or MIP-2-induced leukocyte chemotaxis. However, real-time reverse transcription-polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice. CONCLUSIONS: TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.

Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression.

OBJECTIVE: Thioredoxin (TRX) is a redox regulatory protein that protects cells from various stresses. Angiotensin-converting enzyme (ACE) inhibitor was reported to enhance endogenous antioxidant enzyme activities. This study was carried out to investigate whether temocapril, a novel non-sulfhydryl-containing ACE inhibitor, reduces the severity of myocarditis via redox regulation mechanisms involving TRX. METHODS AND RESULTS: In normal rat myocytes in vitro and in vivo, Western blot showed that temocapril enhanced cytosolic redox regulatory protein TRX expression, but that neither mitochondrial TRX2 nor antioxidant enzymes, such as copper-zinc superoxide dismutase (Cu/Zn-SOD) or manganese superoxide dismutase (Mn-SOD) expression, was up-regulated by the preconditioning treatment. In rats with experimental autoimmune myocarditis (EAM), the severity of myocarditis and the protein carbonyl contents were less increased in temocapril treatment (10 mg/kg/day, orally) from day 1 to day 21, but not in temocapril treatment from day 15 to day 21. An immunohistochemical study showed that TRX stain was enhanced in infiltrating inflammatory cells and in damaged myocytes. Considering the characteristics of this model that myocardial inflammation begins around day 15 and increases until day 21, temocapril treatment for 3 weeks might be thought of as a preconditioning treatment. CONCLUSIONS: The results suggest that TRX and the redox state modified by TRX may play a crucial role in the pathophysiology of EAM. Temocapril ameliorates myocarditis associated with inducing TRX up-regulation in a preconditioning manner, although the mechanism of TRX up-regulation by temocapril remains to be elucidated.

Redox regulation by thioredoxin in cardiovascular diseases.

Increasing evidence has indicated that the modulation of intracellular redox states has important aspects to cellular events, such as cellular proliferation, activation, growth inhibition, or death via the regulation of intracellular signal transduction and gene expression. Thioredoxin (TRX) is a multifunctional stress-inducible protein, which protects cells from various types of stresses. TRX has not only a scavenging activity of reactive oxygen species, but also a regulating activity of various intracellular molecules including transcription factors. We demonstrated that the serum TRX levels are correlated with the severity of heart failure, and are negatively correlated with left ventricular ejection fractions of patients with heart failure. The expression of TRX is enhanced in endothelial cells and macrophages in human atherosclerotic plaques, in balloon-injured rat arteries, and in damaged cardiomyocytes of rats with acute myocarditis. Overexpression of TRX in transgenic mice attenuates adriamycin-induced cardiotoxicity by reducing oxidative stresses. These findings suggest that TRX and the redox system modulated by TRX have an important role in cellular defense against oxidative stress in cardiovascular diseases.

Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats.

As oxidative stress plays a crucial role in the development and pathogenesis of hypertension, we analyzed the redox (reduction/oxidation) status in tissues from Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). Expressions of 8-hydroxy-2'-deoxyguanosine, a marker for oxidative stress-induced DNA damage, and protein carbonylation, a marker for oxidation status of proteins, were enhanced in aorta, heart, and kidney from SHR and SHRSP compared with WKY. The expression of redox regulating protein, thioredoxin (TRX), estimated by immunohistochemistry and western blot, and expression of TRX gene estimated by real-time RT-PCR were markedly suppressed in those tissues from SHR and SHRSP compared with WKY. Induction of TRX was impaired after angiotension II treatment in peripheral blood mononuclear cells isolated from SHR and SHRSP compared with those isolated from WKY. Although previous reports have shown that TRX is induced by a variety of oxidative stress in tissues, the present study shows the impaired induction of TRX in tissues from genetically hypertensive rats despite the relative increment of oxidative stress. Redox imbalance in essential organs may play a crucial role in the development and pathogenesis of hypertension.

Heterozygous disruption of CMA1 does not affect blood pressure.

OBJECTIVE: It has been suspected that the mast cell chymase gene (CMA1) is important for the generation of angiotensin II and therefore might be associated with the pathogenesis of hypertension. METHODS: We sequenced the promoter region, exons, and exon-intron junctions of CMA1 and found 13 single-nucleotide polymorphisms, two of which were loss-of-function mutations. The loss-of-function mutations resulted in: (1) a premature stop codon; and (2) atypical splicing which creates a frame-shift and a stop codon. To elucidate the role of CMA1 in blood pressure regulation, we conducted an association study using these polymorphisms, including the loss-of-function mutations. The study population consisted of 1859 subjects, selected consecutively from the Suita study, an epidemiological cohort representing the general population in Japan. RESULTS: There was no difference in the genotype distribution of the polymorphisms we studied between hypertensive and normotensive subjects, among either men or women. Moreover, neither of the heterozygous loss-of function mutations had a significant effect on blood pressure values. CONCLUSION: Our data suggest that CMA1 is unlikely to influence blood pressure levels in the Japanese population.

Genetic analysis of 22 candidate genes for hypertension in the Japanese population.

OBJECTIVE: We performed association studies between 118 single-nucleotide polymorphisms (SNPs) of 22 candidate genes (or gene family) and hypertension in a Japanese population. DESIGN AND PARTICIPANTS: The study population consisted of 1880 subjects representing the general population in Japan, recruited from the Suita study. The candidate genes were selected based on their functions, including insulin resistance (APM1, CD36, HSD11B1), oxidative stress (CYBA, GPX1, GSTMs), steroid hormone (ESR1, ESR2, HSD11B2), renal functions (PTGS2, KLK1, NPHS1, NPHS2, SGK, SLC12A1, PTGES), and others related to cardiovascular physiology (GJA4, NOS1, NTRK3, P2RX4, SPP1, ALDH2). RESULTS: Multiple logistic analyses, with age and body mass index as covariates, indicated that 13 SNPs (eight genes), six SNPs (four genes) and 11 SNPs (four genes) were associated with hypertension (P < 0.05) in the total, male, and female populations, respectively. PTGS2 seems to be a promising candidate gene for hypertension in men. GSTM3 and SLC12A1 seem to be promising candidate genes for hypertension in women. Especially, a polymorphism in SLC12A1 was significantly associated with hypertension in women even after correction by the Bonferroni method (corrected P = 0.0236). Multiple logistic analyses, with age and body mass index as covariates, indicated that the prevalence of hypertension in females was significantly higher in subjects with the CC genotype than in those with the TT + TC genotypes (P < 0.0001, odds ratio = 1.967, 95% confidence interval = 1.430-2.712). CONCLUSION: Although the present results should be replicated in other study populations for confirmation, the present results suggest that SLC12A1 may contribute to hypertension in Japanese women.

Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension.

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A > G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p = 0.0223), age (p < 0.0001), body mass index (p < 0.0001), alcohol consumption (p = 0.0002), and the Promoter 3 genotype (AA = 1, AG + GG = 2) (p = 0.0090) were predictive of hypertensive status. The odds ratio of the AG + GG genotypes for hypertension was 1.35 (95% confidence interval: 1.08-1.69) over the AA genotype. SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure.

Association between hypertension and the alpha-adducin, beta1-adrenoreceptor, and G-protein beta3 subunit genes in the Japanese population; the Suita study.

This study focused on 3 genetic polymorphisms that have previously been implicated in hypertension: the alpha-adducin (ADD1/Gly460Trp), beta1-adrenoreceptor (ADRB1/Arg389Gly), and G-protein beta3 subunit (GNB3/C825T) gene polymorphisms. We determined genetic variants using the TaqMan system in a large cohort representing the general population in Japan (867 males, 1,013 females). Logistic analysis indicated that the ADD1/ G460W polymorphism was associated with hypertension in female subjects. The odds ratio of the WW genotype for hypertension was 1.53 (95%Cl, 1.12-2.08) over the WG+GG genotype (p=0.0070, p corrected (p(c)) =0.0420 corrected by the Bonferroni method). The ADRB1/R389G polymorphism tended to be associated with hypertensive status in male subjects (p=0.0117, p(c)=0.0702). The odds ratio of the GG genotype for hypertension was 0.38 (95%CI, 0.167-0.780) over the RR+RG genotype. The GNB3/C825T polymorphism was not associated with hypertensive status in either male or female subjects. The present results do not agree with those in previous reports. Almost all common variants may have only a modest effect on common diseases, and a single study even employing 1,880 subjects may lack the statistical power to detect a real association. Accordingly, it will be necessary to verify the association between these three genes and hypertension using a larger number of subjects from the Suita cohort or another population.

Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress.

Although an autoimmune mechanism has been postulated for myocarditis and dilated cardiomyopathy, immunosuppressive agents had not been shown to be effective. Potential benefits of intravenous immunoglobulin (IVIg) in the therapy of patients with myocarditis and recent onset of dilated cardiomyopathy were reported. Also, experimental studies showed that IVIg is an effective therapy for viral myocarditis by antiviral and anti-inflammatory effects. Accordingly, in the current study, the effects of IVIg in the patients were investigated with the analyses of inflammatory cytokines and oxidative stress. Nine patients (six in myocarditis, three in acute dilated cardiomyopathy) were treated with high-dose intravenous IVIg (1-2 g/kg, over 2 days). All were hospitalized with New York Heart Association (NYHA) class III to IV heart failure, left ventricular ejection fraction (LVEF) <40%, and symptoms for <6 months at the time of presentation. Five patients were diagnosed using endomyocardial biopsy. LVEF determined by echocardiography improved from 19.0+/-7.5% (mean+/-S.D.) at baseline to 35.4+/-9.1% at follow up (12.2+/-5.8 days after the treatment) (P<0.01). C-reactive protein and plasma inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) were decreased by this treatment. In addition, plasma level of thioredoxin, which regulates the cellular state of oxidative stress, was decreased by the treatment. All nine patients improved functionally to NYHA class I to II, and were discharged without side-effects. There have been no subsequent hospitalizations for heart failure during the course of follow-up (3 months-4.5 years). LVEF improved 16% of EF in the patients with myocarditis and acute dilated cardiomyopathy with the reduction of cytokines associated with improvement of oxidative stress state by high-dose of IVIg. Thus, IVIg seems to be a promising agent in the therapy of acute inflammatory cardiomyopathy in view of not only suppression of inflammatory cytokines but a reduction of oxidative stress.

Increased oxidative stress with elevated serum thioredoxin level in patients with coronary spastic angina.

BACKGROUND: Increased oxidative stress has been implicated in the pathogenesis of coronary vasospasm. Thioredoxin (TRX) is a redox-active protein that is known to be induced by oxidative stress. HYPOTHESIS: The serum TRX level may be high in patients with coronary vasospasm. METHODS: The serum TRX level was determined using an enzyme-linked immunosorbent assay in 21 patients with the active stage of coronary spastic angina (CSA), in 18 patients with the inactive stage of CSA (iCSA), in 24 control subjects without coronary artery disease (Control), and in 20 patients with stable effort angina (SEA). RESULTS: Serum TRX levels (mean +/- standard deviation ng/ml) were significantly higher in CSA (64 +/- 44) than in iCSA (28 +/- 26), in Control (34 +/- 15), and in SEA (36 +/- 16). In contrast, serum alpha-tocopherol levels (mg/g lipids) were significantly lower in CSA (2.8 +/- 0.7) than in Control (4.0 +/- 1.2) and in SEA (3.2 +/- 0.4). Current smoking was significantly more prevalent in CSA (76%) than in any of the other groups. No significant correlation was found between the serum level of TRX and alpha-tocopherol in the study subjects. In nine patients with CSA, the serum TRX level decreased (93 +/- 41 --> 41 +/- 35 ng/ml) and the alpha-tocopherol level increased (2.7 +/- 0.6 --> 3.2 +/- 0.7 mg/g lipids) significantly under medication with calcium entry blockers after an at least 3-month angina-free period. CONCLUSIONS: Patients with coronary spastic angina had a higher serum TRX level associated with a lower serum level of antioxidant vitamin E, with redox equilibrium appearing to be related to the disease activity of coronary vasospasm in these patients. Oxidative stress may be related to the genesis of coronary vasospasm.

Immunohistological analyses of myocardial infiltrating cells in various animal models of myocarditis.

Animal models of myocarditis are of great value for studying the pathophysiology of the disease. To clarify the key factors for determining the severity of myocarditis, we analyzed immunohistological surface markers of myocardial infiltrating cells in various animal models, and the relationship between myocardiogenic antigens and abnormal behaviours of infiltrating cells was discussed. Myocarditis was induced in mice and rats by cardiotropic viruses and by porcine cardiac myosin. Animals were sacrificed at the peak of their disease. Pathological examinations were performed, and the severity of the lesions was scored semiquantitatively. There were striking differences in the severity of viral and autoimmune giant cell myocarditis among different animal models. However, the majority of myocardial infiltrating cells were comprised of macrophages and CD4+ T cells. Different immunological behaviours of myocardial infiltrating cells were demonstrated in these models of myocarditis. However, the development of severe myocardial lesions may depend on the macrophage-CD4 cell lineage in these animal models.

Antiatherosclerotic effects of the Fc portion of immunoglobulin in apolipoprotein E-deficient mice.

The mechanisms and importance of the Fc portion of immunoglobulin on experimental atherosclerosis in apolipoprotein E-deficient mice were examined. Experimental atherosclerosis was induced in mice fed a high fat diet containing 0.3% cholesterol. Over eight and 16 weeks, the mice were treated with intraperitoneal injections (1 g/kg/day) of either human intact immunoglobulin or F(ab')(2) fragments of human immunoglobulin on alternate days. Fatty streak formation and fibrofatty plaques were markedly suppressed in mice that received intact immunoglobulin for eight and 16 weeks. In contrast, atherosclerotic lesions did not improve in mice that received F(ab')(2) fragments. Differences in lesion area did not correlate with any significant alterations in serum lipid levels. Immunoglobulin therapy markedly suppressed atherosclerosis due to Fc receptor-mediated anti-inflammatory and immunomodulating actions.

Cardioprotective effects of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), a novel free radical scavenger, on acute autoimmune myocarditis in rats.

BACKGROUND: Recent evidence suggests that oxidative stress may play a role in myocarditis. PURPOSE: To test the hypothesis that 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone or MCI-186), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats. METHODS: MCI-186 was administered intraperitoneally (1 mg/kg/day, 3 mg/kg/day or 10 mg/kg/day) in rats with EAM for three weeks. The results were compared with those from untreated rats with EAM. RESULTS: MCI-186 treatment did not affect the hemodynamics of the rats, but did reduce the severity of myocarditis when the heart weight:body weight ratio and the pathological scores were compared. There were significantly fewer myocardial interleukin-1beta-positive cells in rats with EAM treated with MCI-186 (at 3 mg/kg/day and 10 mg/kg/day) than in the untreated rats with EAM. CONCLUSION: MCI-186 ameliorated acute EAM in rats, suggesting that free radicals may be involved in the development of myocarditis.