Treatment Of Myocarditis Research Articles

Mechanical Circulatory Support Combined With Immunosuppression for the Treatment of Giant Cell Myocarditis - A Single-Center Experience in Japan.

The therapeutic strategy for giant cell myocarditis (GCM) remains controversial, so we reviewed the clinical status of Japanese patients with GCM.Methods and Results:We retrospectively reviewed 6 consecutive patients with GCM requiring percutaneous mechanical circulatory support (p-MCS), with 3 further requiring ventricular assist devices. One patient died during p-MCS. Cardiac function improved in the other 5 with immunosuppressive therapy, but only 3 patients treated with dual immunosuppressants, including cyclosporine (CyA), achieved >1-year survival. The prognosis of patients with fulminant GCM is poor, but a treatment that combines MCS and early administration of CyA-based immunosuppressants will be useful.

Acute myocarditis in children: problems of diagnosis and treatment

Acute myocarditis by the World Health Organization is an inflammatory disease of the heart muscle, confirmed by histologically, immunologically and immunohistochemically. The diagnosis of acute myocarditis in children remains open due to the presence of a number of reasons. First of all, it is difficult to diagnose myocarditis in children due to the variety of clinical manifestations and the presence of nonspecific symptoms of the disease. What matters is the lack of accessibility in the routine practice of a doctor of certain research methods and a sharp limitation in the use of endomyocardial biopsy. The search for differential diagnostic algorithms of the disease continues. According to modern literature, much attention is paid to non-invasive methods for the diagnosis of acute myocarditis in children. The course of acute myocarditis can be complicated by life-threatening cardiac arrhythmias: ventricular extrasystole, lengthening of the corrected QT interval, atrioventricular block. The appearance of cardiac arrhythmias increases the risk of sudden cardiac death. Recommendations for the treatment of myocardium in children often undergo changes due to the small number of multicenter and controlled studies in the pediatric population. The article provides an overview of modern approaches to the treatment of acute myocarditis in children: the use of antiviral drugs, intravenous immunoglobulin, immunosuppressive therapy, especially the treatment of heart failure in acute myocarditis in children.

P52 Two pathologies one heart: life-threatening lupus myocarditis in a patient with pre-existing dilated cardiomyopathy

Abstract Background Acute myocarditis is a life-threatening complication of systemic lupus erythematosus (SLE) often indicative of severe multisystem disease. Treatment of lupus myocarditis (LM) is well described in the literature with high-dose corticosteroids and cyclophosphamide providing the backbone of induction therapy. Less commonly reported are outcomes of patients with SLE and pre-existing structural heart disease. Methods We present a case of acute LM occurring in the context of established non-ischaemic dilated cardiomyopathy (DCM) presenting a significant diagnostic challenge. Results A 45-year-old woman from Afghanistan with known SLE presented with acute chest pain and dyspnoea. She had a previous mild SLE disease course limited to her skin and joints and was historically non-compliant with immunosuppressive treatment. She also had non-ischaemic DCM diagnosed six years prior to presentation with non-progressive imaging over this time. Upon acute assessment at the referring centre a widespread livedoid rash and cool peripheries were noted. Initial investigations revealed an elevated Troponin-I of 111ng/L and Brain Natriuretic Peptide (BNP) of 4497ng/L. An electrocardiogram revealed no acute ischaemic changes whilst her chest radiograph revealed features in keeping with pulmonary oedema. Transthoracic echocardiogram (TTE) demonstrated a dilated left ventricle with severe global systolic impairment. Her left ventricular ejection fraction (LVEF) was visually estimated at 10-15%, significantly reduced from her last recorded LVEF of 52% on a cardiovascular magnetic resonance (CMR) scan 18-months previously. Intravenous (iv) methylprednisolone, iv diuresis and B-cell depletion therapy were commenced prior to transfer to our department. Once transferred, a CMR scan confirmed an ejection fraction of only 12%. Septal mid-wall delayed enhancement was seen consistent with a non-ischaemic DCM, however, subepicardial delayed enhancement was visualised inferolaterally on native T1-mapping in keeping with perimyocarditis. Additional results on admission were supportive of a multisystem SLE flare. She was lymphopaenic (1.0x109/L), thrombocytopaenic (66x109/L), hypocomplimentaemic (C3 0.33g/L, C4 <0.03g/L), and had elevated dsDNA antibodies (83unit/mL). Serum creatinine had risen from a baseline of 47µmol/L to 110µmol/L and her urine protein: creatinine ratio (414mg/mmol) raised the suspicion of lupus nephritis (LN). Renal biopsy was not performed due to thrombocytopaenia. An MDT discussion with the cardiology, CMR imaging and renal teams took place with CMR imaging proving pivotal in establishing new LM on a background of established DCM. The decision to treat with intravenous (iv) cyclophosphamide was made and repeat TTE at 14 days revealed a significant improvement in LVEF to 25-30%. Conclusion CMR imaging was crucial in delineating acute and potentially reversible myocarditis on a background of chronic cardiomyopathy. This finding supported the escalation in immunosuppressive treatment to a cyclophosphamide-based regimen and led to the rapid improvement in ejection fraction in this young patient. She received 6 fortnightly doses of iv cyclophosphamide and is now maintained on hydroxychloroquine, mycophenolate mofetil and rituximab. Disclosures H. Wilson-Morkeh: None. T. Youngstein: None. S. Shabbir: None. J. Bakshi: None. T. Pihlajavaara: None. M. Bellamy: None. T. Cairns: None.

Acute Myocarditis in Children: An Overview of Treatment and Recent Patents.

Pediatric myocarditis is rare but challenging. This overview summarized the current knowledge and recent patents on childhood myocarditis. Clinical queries and keywords of "myocarditis" and "childhood" were used as search engine. Viral infections are the most common causes of acute myocarditis. Affected children often have a prodrome of fever, malaise, and myalgia. Clinical manifestations of acute myocarditis in children can be nonspecific. Some children may present with easy fatigability, poor appetite, vomiting, abdominal pain, exercise intolerance, respiratory distress/tachypnea, dyspnea at rest, orthopnea, chronic cough with wheezing, chest pain, unexplained tachycardia, hypotension, syncope, and hepatomegaly. Supraventricular arrhythmias, ventricular arrhythmias, and heart block may be present. A subset of patients have fulminant myocarditis and present with cardiovascular collapse, which may progress to severe cardiogenic shock, and even death. A high index of suspicion is crucial to its diagnosis and timely management. Cardiac magnetic resonance imaging is important in aiding clinical diagnosis while, endomyocardial biopsy remains the gold standard. The treatment consists of supportive therapy, ranging from supplemental oxygen and fluid restriction to mechanical circulatory support. Angiotensinconverting enzyme inhibitors, angio-tensin II receptor blockers, β-blockers, and aldosterone antagonists might be used for the treatment of heart failure while, immunosuppression treatments remain controversial. There are a few recent patents targeting prevention or treatment of viral myocarditis, including an immunogenic composition comprising a PCV-2 antigen, glutathione-S-transferase P1, neuregulins, NF-[kappa] B inhibitor, a pharmaceutical composition which contains 2-amino-2- (2- (4-octyl phenyl) - ethyl) propane 1,3-diol, a composition containing pycnojenol, Chinese herbal concoctions, and a Korean oral rapamycin. Evidence of their efficacy is still lacking. This article reviews the current literature regarding etiology, clinical manifestations, diagnosis, and management of acute myocarditis in children.

Global study of viral myocarditis: A systematic review and meta-analysis

Objective: To investigate the prevalence of viral myocarditis worldwide. Methods: We conducted a systematic search for the prevalence of the most common viruses in myocarditis and 75 studies were included for statistical analysis of the prevalence of adenovirus, hepatitis C virus, cytomegalovirus, Ebola virus, human herpesvirus 6, influenza virus, parvovirus, and non-polio enteroviruses. Results: The highest prevalence was related to B19 (25.0%) and non-polio enteroviruses (18%). The prevalence of human herpesvirus 6, cytomegalovirus, and Ebola virus was12.8%, 5.5%, and 3.1%, respectively. Hepatitis C virus accounted for 6.1% of the disease, the adenoviruses contributed to 5.2% of viral myocarditis. The lowest incidence was related to the influenza virus with 2.0%. Conclusions: Treatment of myocarditis is still problematic and may depend on the etiologic diagnosis. So it is important to know the commonly occurring viral factors in myocarditis and timely diagnosis and treatment are also imperative.

A case of hypereosinophilic syndrome with eosinophilic myocarditis secondary to nabumetone

Introduction: Hypereosinophilic syndromes are a group of disorders defined by an absolute eosinophil count greater than 1.5 × 109/L that leads to eosinophil-mediated end-organ damage. Cardiac involvement can range from asymptomatic inflammation of the myocardium to endomyocardial fibrosis and irreversible constrictive cardiomyopathy. Case Report: We present the case of a patient who presented with confusion and was found to have an absolute eosinophil count of 8.08 × 109/L as well as clinical findings consistent with eosinophilic myocarditis. It was determined that her clinical presentation was due to a new medication she had taken, nabumetone. Other causes of hypereosinophilia were ruled out. She improved with two days of pulse dose methylprednisolone and subsequent prednisone taper with complete resolution of her cardiomyopathy and normalization of her absolute eosinophil count. Conclusion: While there are no guidelines available for the treatment of eosinophilic myocarditis, corticosteroids should be considered in patients with evidence of cardiomyopathy in the setting of hypereosinophilia. Hypereosinophilic syndrome is an uncommonly recognized adverse event of non-steroidal anti-inflammatory drug (NSAID) therapy.

Qidong Yixin Oral Liquid for Viral Myocarditis: A Systematic Review and Meta-Analysis.

Objective This study aimed to evaluate the efficacy and safety of Qidong Yixin (QY) oral liquid in the treatment of viral myocarditis (VMC). Methods We searched seven databases for randomized clinical trials on QY for treating VMC. The retrieval period was from database establishment to December 31, 2019. Cochrane risk of bias tool in the Cochrane Handbook was used to assess the methodological quality. Review Manager (RevMan) 5.3 was used to analyze the results. Results We included 19 studies comprising 2,608 patients, albeit with low methodological quality. Our meta-analysis revealed that combination therapy with QY and western medicine was more effective than western medicine alone (QY vs other Chinese patent medicines: RR = 1.37, 95% Cl: 1.23∼1.52, P < 0.00001; QY + coenzyme Q10 + routine treatment vs coenzyme Q10 + routine treatment: RR = 1.20, 95% Cl: 1.14∼1.27, P < 0.00001; QY + trimetazidine + acyclovir vs trimetazidine + acyclovir: RR = 1.59, 95% Cl: 1.38∼1.83, P < 0.00001; QY + routine treatment vs routine treatment: RR = 1.09, 95% Cl: 1.03∼1.15, P < 0.003). A study on posttreatment myocardial enzyme levels revealed that QY with western medicine downregulated creatine kinase isoenzyme (CK-MB) (QY + antiviral treatment + routine treatment vs antiviral treatment + routine treatment group: MD = −11.28, 95% CI: −13.33∼−9.22, P < 0.00001; QY + routine treatment vs routine treatment: MD = −4.96, 95% CI: −5.56∼−4.32, P < 0.00001), creatine kinase (CK) (MD = −32.10, 95% CI: −35.63∼−28.57, P < 0.00001), and lactate dehydrogenase (LDH) (QY + antiviral treatment + routine treatment vs antiviral treatment + routine treatment: MD = −48.76 95% CI: −58.18∼−39.33, P < 0.00001; QY + routine treatment vs routine treatment: MD = −23.52, 95% CI: −30.10–16.94, P < 0.00001) rather than western medicine alone, with no evidence of aspartate aminotransferase (AST) downregulation on treatment with QY with western medicine (MD = 2.88, 95% CI: −0.95∼6.71, P < 0.00001) in patients. Two studies reported adverse events, indicating that QY is relatively safe. Conclusion Although QY may have potential advantages in treating VMC, they remain unclear owing to the poor methodological quality of most studies. Larger, multicenter, high-quality randomized controlled trials are required to verify the effectiveness of QY.

A closer look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.

Myocarditis as a lupus challenge: two case reports

BackgroundMyocarditis is an uncommon manifestation of systemic lupus erythematosus in which the clinical presentation can range from subclinical to life-threatening. We report cases of two patients who presented to our hospital with myocarditis as an initial manifestation of systemic lupus erythematosus despite negative results of extensive workup that excluded other diagnoses. The mainstays of treatment are corticosteroids, immunosuppressive agents, and anti-heart failure medications, with use of the latter being case-specific. Mycophenolate mofetil was the cornerstone of the proposed treatment for induction of remission, although it is well known to be used as a maintenance therapy in lupus myocarditis.Case presentationBoth Emirati patients described satisfied the diagnostic criteria for mixed connective tissue disease (systemic lupus predominant) and systemic lupus erythematous. Other differential diagnoses of myocarditis were excluded. The patients were started on pulsed steroid followed by oral steroid, with hydroxychloroquine, mycophenolate mofetil, and anti-heart failure medications used as needed. Dramatic responses were noted in the first few weeks in terms of symptoms.ConclusionEarly recognition and treatment of lupus myocarditis is needed to avoid fatal consequences.

Protective effect of Shenmai injection on doxorubicin-induced cardiotoxicity via regulation of inflammatory mediators

BackgroundDoxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators.MethodsMale ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection.ResultsA cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement.ConclusionsSMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.

Early Treatment of Coxsackievirus B3-Infected Animals With Soluble Coxsackievirus-Adenovirus Receptor Inhibits Development of Chronic Coxsackievirus B3 Cardiomyopathy.

Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model. NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection. Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dtmax, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dtmin, -4046.9±776 versus -3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury. Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.

Advance on early diagnosis and treatment of fulminant myocarditis in children

Fulminant myocarditis is characterized by acute hemodynamic disorder, with rapid progress and high mortality.This article reviewed the current diagnostic criteria, the development of diagnostic techniques, as well as the development of current immunological, antiviral, and mechanical circulation adjuvant therapy for fulminant myocarditis in children. Key words: Fulminant myocarditis; Early diagnosis; Therapy; Children

Improvement of insulin signalling rescues inflammatory cardiac dysfunction

Inflammation resulting from virus infection is the cause of myocarditis; however, the precise mechanism by which inflammation induces cardiac dysfunction is still unclear. In this study, we investigated the contribution of insulin signalling to inflammatory cardiac dysfunction induced by the activation of signalling by NF-κB, a major transcriptional factor regulating inflammation. We generated mice constitutively overexpressing kinase-active IKK-β, an essential kinase for NF-κB activation, in cardiomyocytes (KA mice). KA mice demonstrated poor survival and significant cardiac dysfunction with remarkable dilation. Histologically, KA hearts revealed increased cardiac apoptosis and fibrosis and the enhanced recruitment of immune cells. By molecular analysis, we observed the increased phosphorylation of IRS-1, indicating the suppression of insulin signalling in KA hearts. To evaluate the contribution of insulin signalling to cardiac dysfunction in KA hearts, we generated mice with cardiac-specific suppression of phosphatase and tensin homologue 10 (PTEN), a negative regulator of insulin signalling, in the KA mouse background (KA-PTEN). The suppression of PTEN successfully improved insulin signalling in KA-PTEN hearts, and interestingly, KA-PTEN mice showed significantly improved cardiac function and survival. These results indicated that impaired insulin signalling underlies the mechanism involved in inflammation-induced cardiac dysfunction, which suggests that it may be a target for the treatment of myocarditis.

Exosomes derived from cardiac progenitor cells attenuate CVB3-induced apoptosis via abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways

Viral myocarditis is potentially fatal and lacking a specific treatment. Exosomes secreted by cardiac progenitor cells (CPCs) have emerged as a promising tool for cardioprotection and repair. In this study, we investigated whether CPCs-derived exosomes (CPCs-Ex) could utilize the mTOR signal pathway to reduce the apoptosis in viral myocarditis. In vitro, exosomes were, respectively, added to H9C2 cells after CVB3 infection to detect the anti-apoptosis effect of CPCs-Ex. Compared with the controls, the apoptosis rate was reduced, accompanied with the depressed expression of viral capsid protein 1 (VP1) and pro-apoptosis factors of Bim/caspase families. Meanwhile, the phosphorylation of Akt, mTOR, and p70S6K were promoted, but that of 4EBP1 was suppressed. In vivo, the results of apoptosis, expression of CVB3 and pro-apoptosis factors, and phosphorylation of Akt/mTOR factors of CVB3-infected cardiomyocytes were consistent with that of vitro. Following that, we use Rapamycin and MK-2206 to inhibit the Akt/mTOR signaling pathway, meanwhile, Rattus 4EBP1, p70S6K, Akt1 and Akt2 were transfected to H9C2 cells to establish the stably transfected cell lines. In the group with Rapamycin or MK-2206 pretreatment, CPCs-Ex also could decrease the apoptosis of H9C2 cells and expression of CVB3 mRNA, followed by decreased expression of apoptosis factors. In Akt2, p70S6K and 4EBP1 overexpression groups, CPCs-Ex promoted CVB3-induced apoptosis, VP1 expression and cleavage of caspase-3. Our results therefore identify CPCs-Ex exerts an anti-apoptosis effect in CVB3-infected cells by abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways as well as the expression of Bcl-2 and caspase families. Viral myocarditis, mainly caused by CVB3 infection, is lacking a specific treatment. Our study identified an anti-apoptosis role of CPCs-Ex in CVB3-infected cells and rats, which shown that CPCs-Ex may be an effective tool to treat viral myocarditis. We believe that with more in-depth research on the functionality of CPCs-Ex, there will be a breakthrough in the treatment of viral myocarditis.

The efficacy observation of ulinastatin combined with creatine phosphate sodium in pediatric viral myocarditis.

This study aimed to compare the efficacy and safety of ulinastatin combined with creatine phosphate sodium and ribavirin combined with creatine phosphate sodium in the treatment of pediatric viral myocarditis. 155 children with viral myocarditis in the Xuzhou Children's Hospital, were retrospectively analyzed. 80 of them received ulinastatin combined with creatine phosphate sodium, and were regarded as observation group; other 75 patients received ribavirin combined with creatine phosphate sodium and were regarded as the control group. The therapeutic efficacy of the two groups was observed, the improved condition of myocardial enzyme indicator and myocardial troponin I (cTn I) in the two groups were compared before and after the treatment. The total effective rates of the patients in the observation group and the control group were 93.75% and 76.00%, respectively. The clinical efficacy of the observation group was better than that of the control group (p<0.05). The electrocardiogram improvement condition of the observation group was better than that of the control group (p<0.05); after the treatment, the expression levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), Creatine Kinase (CK-MB), and cTn I in the observation group were (313.37±9.42) U/L, (29.38±4.97) U/L, (23.67±2.89) U/L, (0.12±0.02) μg/L, respectively. The expression levels of LDH, AST, CK-MB, and cTn I in the control group were (322.43±12.32) U/L, (33.43±5.14) U/L, (26.22±3.37) U/L, (0.24±0.04) μg/L. The levels of myocardial enzyme and cTn I in the observation group and the control group after the treatment were lower than that before the treatment (p<0.05), while the level of myocardial enzyme and cTn I in the observation group after the treatment was significantly lower than that in the control group (p<0.05). The results indicated that, compared with ribavirin combined with creatine phosphate sodium, ulinastatin combined with creatine phosphate sodium had better clinical efficacy in the treatment of pediatric viral myocarditis. It could significantly improve the level of myocardial enzyme indicator and cTn I, and had certain clinical and promotional values and application values.

Rapid Recovery of Acute Giant Cell Myocarditis with Hypereosinophilia with Combined Immunosuppression and Benralizumab

Introduction Myocarditis is often an elusive diagnosis as the clinical presentation can be nonspecific and definitive diagnosis can be challenging due to the low sensitivity of endomyocardial biopsy. Additionally, treatment of myocarditis is controversial with no guidelines and limited data available regarding efficacy. Nevertheless, recent studies have demonstrated a treatment benefit with immunosuppression, particularly in giant cell myocarditis (GCM). This report highlights a unique case of histologically confirmed GCM in which the patient also had a significant peripheral hypereosinophilia, and examines the response of combined immunosuppression with rabbit anti-thymocyte globulin (RATG), corticosteroids, cyclosporine, and benralizumab–an interleukin-5 receptor antagonist–that resulted in rapid recovery. Case Report A 25 year old woman with a history of asthma for 3 years and a recent diagnosis of heart failure with reduced ejection fraction (40%) presented with acute chest pain and worsening left ventricular (LV) dysfunction with a reduction of her left ventricular ejection fraction (LVEF) to 25-30% within 2 weeks. Laboratory studies revealed a 40% peripheral eosinophilia. Further workup was negative for infection, eosinophilic granulomatosis with polyangiitis, or malignancy. A cardiac MRI showed late-gadolinium enhancement and an endomyocardial biopsy confirmed significant eosinophilic tissue infiltration, myocyte necrosis, and the presence of giant cells. She was treated with a combined immunosuppression regimen of RATG induction, corticosteroids, cyclosporine, and benralizumab. Despite this regimen, she had a recurrence of peripheral eosinophilia during the course of her hospitalization. Nevertheless, she had significant clinical improvement in symptomatology, functional status, and hemodynamics. Her peripheral eosinophilia resolved over the following days with increased corticosteroids and thereafter remained negligible. A repeat echocardiogram 3 weeks after initial initiation of immunosuppression demonstrated significant improvement in her LVEF to 53%, improvement of global strain, and reduction of left atrial dilatation. Discussion Emerging data suggests that treatment with immunosuppression can improve outcomes in patients with GCM. Indeed, this patient did have a marked improvement in LV function within 3 weeks of initiating treatment. Additionally, the use of benralizumab to treat her peripheral eosinophilia demonstrates potential implications for use in other hypereosinophilic syndromes. However, given that her serum eosinophila recurred despite being on a multi-drug immunosuppression regimen, including benralizumab, identifies potential focus areas of future research including further examination of the exact mechanism of action, the relevance of expanded use in other hypereosinophilic syndromes, and delineation of appropriate end points for measuring response.

Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: A systematic review and meta-analysis

The treatment of pediatric myocarditis is controversial, and the benefits of intravenous immunoglobulin (IVIG) are inconclusive due to limited data. We searched studies from PubMed, MEDLINE, Embase, and Cochrane Library databases since establishment until October 1st, 2018. Thirteen studies met the inclusion criteria. We included a total of 812 patients with IVIG treatment and 592 patients without IVIG treatment. The meta-analysis showed that the survival rate in the IVIG group was higher than that in the non-IVIG group (odds ratio = 2.133, 95% confidence interval (CI): 1.32–3.43, p = 0.002). There was moderate statistical heterogeneity among the included studies (I2 = 35%, p = 0.102). However, after adjustment using Duval and Tweedie’s trim and fill method, the point estimate of the overall effect size was 1.40 (95% CI 0.83, 2.35), which became insignificant. Moreover, the meta-regression revealed that age (coefficient = −0.191, 95% CI (−0.398, 0.015), p = 0.069) and gender (coefficient = 0.347, 95% CI (−7.586, 8.279), p = 0.93) were not significantly related to the survival rate. This meta-analysis showed that IVIG treatment was not associated with better survival. The use of IVIG therapy in acute myocarditis in children cannot be routinely recommended based on current evidence. Further prospective and randomized controlled studies are needed to elucidate the effects of IVIG treatment.

体温変化に伴う心電図変化からBrugada症候群であることが判明した1症例(A patient with Brugada syndrome characterized by various electrocardiographic and body temperature changes)

要旨 突然死の家族歴がない28歳の男性に，発熱を契機に発症した心室細動症例を経験した。患者は1週間前から感冒様症状，胸部痛，発熱（39.8℃）を認め当院救急外来を受診した。診察終了後，突然心室細動になり，蘇生に約30分を要した。心拍再開時の体温は39.1℃で，Brugada型心電図type 1を呈していた。臨床経過から劇症型心筋炎の治療および脳低温療法を開始した。心原性ショックおよび高ミオグロビン血症も認めIABPおよび持続的血液浄化療法を併用した。体温の低下とともにBrugada型心電図type 3から正常波形に変化した。その後の治療経過中にも体温とは関係なく同様の心電図変化を認めた。ウイルス性心筋炎が否定された後の上位肋間での右側胸部誘導でBrugada型心電図type 3を認めBrugada症候群の精査を考慮したが，患者および家族の強い拒否のために確定診断には至らず退院となった。他院でのセカンドオピニオンの結果，埋め込み型除細動器を留置した。留置後，熱発を契機に再度心室細動を発症したことから，Brugada症候群が最初の心停止の原因であったと考えられた。Brugada症候群患者における特徴的な心電図異常は，様々な外的要因によって顕在化し，致死的な不整脈イベントが惹起され，またその心電図異常は経時的に正常化するため注意が必要である。

STAT4 silencing underlies a novel inhibitory role of microRNA-141-3p in inflammation response of mice with experimental autoimmune myocarditis.

As an inflammatory disease afflicting the heart muscle, autoimmune myocarditis (AM) represents one of the foremost causes of heart failure. Accumulating evidence has implicated microRNAs (miRNAs) in the process of inflammation and autoimmunity. Hence, the current study aimed to investigate the mechanism by which miR-141-3p influences experimental AM (EAM). An EAM mouse model was established using 6-wk old male BALB/c mice, after which the expression of miR-141-3p and STAT4 was measured. Gain-of-function and loss-of-function investigations were performed to identify the functional role of miR-141-3p and STAT4 in EAM. Heart weight-to-body weight ratio, cardiac function, and degree of inflammation, as well as the levels of inflammation factors (IFN-γ, TNF-α, IL-2, IL-6, and IL-17) in the serum were detected. STAT4 was subsequently verified to be upregulated, and miR-141-3p was downregulated in the EAM mice. Furthermore, the overexpression of miR-141-3p or silencing of STAT4 was observed to reduce the heart weight-to-body weight ratio of EAM mice and improve cardiac function, while alleviating the degree of inflammatory cell infiltration in the myocardial tissue. Meanwhile, the overexpression of miR-141-3p was identified to diminish serum inflammatory factor levels by downregulating STAT4. Additionally, miR-141-3p could bind to STAT4 to downregulate its expression, ultimately mitigating inflammation and inducing an anti-inflammatory effect in EAM mice. Taken together, upregulation of miR-141-3p alleviates the inflammatory response in EAM mice by inhibiting STAT4, providing a promising intervention target for the molecular treatment of AM.NEW & NOTEWORTHY miR-141-3p is poorly expressed, and STAT4 is upregulated in experimental autoimmune myocarditis (EAM) mice. Overexpressing miR-141-3p inhibits EAM. miR-141-3p binds to and suppresses STAT4 expression. miR-141-3p overexpression inhibits inflammatory factors by downregulating STAT4. This study provides new insights into the treatment of autoimmune myocarditis.

Cardiotoxicity of Immune Checkpoint Inhibitors.

Immunotherapies, particularly immune checkpoint inhibitors (ICI), are revolutionary cancer therapies being increasingly applied to a broader range of cancers. Our understanding of the mechanism, epidemiology, diagnosis, and treatment of cardiotoxicity related to immunotherapies remains limited. We aim to synthesize the limited current literature on cardiotoxicity of ICIs and to share our opinions on the diagnosis and treatment of this condition. The incidence of ICI-associated myocarditis ranges from 0.1 to 1%. Patients with ICI-associated myocarditis often have a fulminant course with a case fatality rate of 25-50%. The diagnosis of this condition poses many challenges because independently a normal electrocardiogram, biomarkers, or a preserved left ventricular function do not rule out ICI-associated myocarditis. Endomyocardial biopsy should be pursued when clinical suspicion remains despite normal non-invasive tests. Data on optimal screening and surveillance tools are lacking. Cessation of ICIs, combined with high dose corticosteroids and other immunosuppressant approaches are the cornerstones of the treatment of ICI-associated myocarditis. This condition may recur when patients are re-challenged with these agents and the decision to resume ICIs should be made through a multidisciplinary discussion. Immunotherapies have changed the landscape of cancer treatment. Recognizing and managing cardiotoxicity related to ICIs is of critical importance. Our understanding of ICI-cardiotoxicity has improved, but large information gaps remain for further research. Due to the high case fatality rate, any type of cardiac symptoms or signs in a patient who has recently started an ICI should prompt consideration of ICI-cardiotoxicity.