Icariin ameliorates viral myocarditis by inhibiting TLR4-mediated ferroptosis

Objective:To explore the mechanism by which icariin alleviates viral myocarditis.Methods:CVB3-induced cardiomyocytes were used as an in vitro model of viral myocarditis to assess the effects of icariin treatment on cell viability,inflammation,and apoptosis.Moreover,the effects of icariin on ferroptosis and TLR4 signaling were assessed.After AC16 cells were transfected with TLR4 overexpression plasmids,the role of TLR4 in mediating the regulatory effect of icariin in viral myocarditis was investigated.Results:Icariin significantly elevated cell viability and reduced inflammatory factors TNF-α,IL-1β,IL-6,and IL-18.Flow cytometry revealed that icariin decreased apoptosis rate,and the protein expression of Bax and cleaved caspase 3 and 9 in CVB3-induced cardiomyocytes.Additionally,it suppressed ferroptosis including lipid peroxidation and ferrous ion,as well as the TLR4 signaling.However,TLR4 overexpression abrogated the modulatory effects of icariin.Conclusions:Icariin mitigates CVB3-induced myocardial injury by inhibiting TLR4-mediated ferroptosis.Further animal study is needed to verify its efficacy.

Effect of Shengmal Powder(生脉散) on Symptoms and Markers of Inflammatory Damage of Patients with Acute Viral Myocarditis

Objective: To evaluate the efficacy of Sheng-mai Power (SMP) in treating acute viral myocarditis. Methods: 102 patients with acute viral myocarditis were randomized to SMS group (n = 52) and placebo control group (n = 50 ). Semiquantitative integral methods were taken to observe changes of clinical symptoms such as dyspnea, palpitation and chest pain after 4 weeks of treatment, simultaneously EKG, 24h Holter, concentration of serum cardiac troponin-I, cardiac troponin T and neutralizing antibody test to the Coxsackie B virus were determined. Results: Dyspnea improved much more obvious in SMP group than in the placebo

STUDY OF PERSISTENT VIRAL INFECTION IN AN ANIMAL MODEL OF VIRAL MYOCARDITIS BY PCR

Objective To study the role of persistent viral infection in the mechanism of viral myocarditis. Methods A mice model of CVB3m viral myocarditis wes made and the viral RNA in mice myocardium and whole bind sample wes tested by using polymerase chain reaction (PCR ) technique. The pathological changes in mice myocardium were determined. Results De day 3, the viral gene in whole bind and myocardium wes found, which portly became negative on day 8, but the change of myocardial anthology borne obvious. Although the bind specimens wers tested negatively on day 12, the viral gene in mice myocardium remained positive within 120d. Conclusion This study indicates that persistent viral infection plays a role in the pathogenesis of viral myocarditis.

Impairment of Myocardial and Skeletal Mitochondria in Mice with Viral Myocarditis and Their Correlation

In order to investigate the impairment of mitochondrial membrane phospholipid local- ization and DNA3867 (mtDNA3867) deletion and the correlation between cardiac and skeletal muscle cells in mice with viral myocarditis, 50 BALB/c mice were divided into two groups randomly. In ex- perimental group (n=40), the mice were intraperitoneally injected with 0.1 mL Eagle liquid with CVB3 (TCID50=108), while in the control group (n=10), the mice were subjected to equal volume of Eagle liquid. The impairment of mitochondrial membrane phospholipid localization and mtDNA3867 deletion rate of cardiac and skeletal muscle were detected separately at day 3, 11 and 24 after injec- tion. The correlation of mitochondrial membrane phospholipid localization and mtDNA3867 deletion rate between cardiac and skeletal muscle cells cells was analyzed using Spearman method. At the day 3 after injection, in both cardiac and skeletal muscle cells, mtDNA3867 deletion rate was significantly higher in experimental group than in control group (P<0.05), but the localization of mitochondrial membrane phospholipid showed no difference between two groups (P>0.05). At day 11 after injec- tion, the mtDNA3867 deletion rate of both cells in experimental group was increased to the peak level (P<0.05), and the impairment of mitochondrial membrane phospholipid localization of both cells also increased markedly in experimental group as compared with control group (P>0.05). At the day 24 after injection, the impairment of mitochondrial membrane phospholipid localization and mtDNA3867 deletion of both cells showed a recovery tendency, but still severer than those at the day 3 after injec- tion (P<0.05). The impairment of mitochondrial membrane phospholipid localization and mtDNA3867 deletion were consistent and synchronistic between cardiac and skeletal muscle cells, and showed good correlations (P<0.05). The impairment of mitochondria plays an important role in the patho- genesis of viral myocarditis, and the skeletal muscle cells might act as a peripheral 'window' to re- flect the mitochondrial damage of cardiac myocytes.

Effect of Astragalus Injection on Levels of Blood Selenium and Immunity Function in Children with Viral Myocarditis

Objective: To observe the effect of Astragalus Injection (AD on levels of blood selenium (Se) and cytokines, and T cellular immune function with viral myocarditis (VM) in children. Methods: Eighty children with VM were randomly divided into 2 groups. The control group consisted of 38 patients, to whom conventional therapy, including energy mixture, vitamin C and coenzyme Q10, etc. were given. The treated group (n = 42), to whom combination therapy of conventional therapy and Al were given. The levels of blood Se and cytokine, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and also evaluation of T lymphocyte subsets and cardiac function were observed. Results: The results showed that after treatment, the levels of blood Se were significantly higher (P<0.01), while IL-1,IL-6 and TNF-a were significantly lower (P<0.01) than those before treatment in the control group. The left ventricular end diameter (LVED) were significantly decreased (P<0.01), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly increased than those before treatment in the treated group(P<0.01, P<0.05). T lymphocyte subsets got normalized (P<0.01), and compared with the control group, the difference was significant (P<0.01). Conclusion: Astragalus membranaceus possesses anti-viral effect, adjusts the balance of cytokine and T cellular immunity, and improves the clinical manifestation and cardiac function. It is an effective approach in treating viral myocarditis.

Effect of intravenous gamma globulin on short- and mid-term clinical outcome in acute viral myocarditis in children

Acute viral myocarditis is an extremely diverse disease with a predictable good outcome with supportive therapy. The objective of this study was to look at the clinical outcome of patients receiving additional intravenous gamma globulin compared to those receiving conventional anti-congestive therapy alone. Patients and methods: This is a retrospective review of charts of children admitted with acute myocarditis. Group 1 was children who received intravenous gamma globulin (IVIG) along with conventional anti-congestive therapy. Group 2 were patients who received the conventional anticongestive therapy alone. Short-term outcome was survival to hospital discharge, and mid-term outcome was improvement of left ventricular ejection fraction at 6 months and one year follow-up. Results: A total of 36 patients were enrolled and 18 were males. The mean age of all patients was 2.3 ± 2.6 years and the mean duration of illness for the whole group was 6.7 ± 3.8 days. Group 1 comprised of 16 patients. There was no difference in short-term outcome with mortality of 2 patients in Group1 (12.5%) and 3(15%) in Group 2 (p = 0.2). At intermediate term follow up, recovery of ejection fraction in Group 1 was in 4/14 (28%) and in Group 2 it was 9/17 (55%) and at 12 months it was 10/13 (77%) in Group 1 and 15/16 (94%) in Group 2 (p = 0.02 and 0.19 respectively). Conclusion: Acute myocarditis has a high spontaneous cure rate. Our study did not show any significant difference in the short-term or midterm outcome between children receiving IVIG compared to those who did not.

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.

Observation on Therapeutic Effects of Shengmai Powder (生脉散)in Treating Acute Viral Myocarditis

Objective: To evaluate the clinical efficacy of Shengmai Powder (SMP, 生脉散) in treating a-cute viral myocarditis objectively. Methods: One hundred and twenty-four patients with acute viral myocarditis were randomized into the treated group (SMG, n = 64) and the control group(CG, n = 60 ). Such myo-cardial nutrient medicine as ATP, CoA , Vit-C, were given to both groups. And to the treated group, 40 ml of Shengmai Injection per day was given intravenously for 2 weeks, which was followed by oral intake of Shengmai granule, one package three times daily for another 2 weeks in total. The same anti-arrhythmia agents were applied to both groups, and no fructose-1, 6-diphosphate (FDP) for either. Semi-quantitative scoring method was adopted to observe such symptoms as chest stuffiness, palpitation and chest pain before treatment and four weeks after treatment. Meanwhile, EGG, dynamic ECG by Holter monitor, left ventricular end-diastolic dimension (LVEDD), left ventricular ejection fraction (LVEF), serum neutralizing antibody of virus Coxsackie B, cardiac troponin I (cTnl) and cardiac troponin T (cTnT) were examined. Results: (1) Compared with the control group, more significant improvement was got in SMG in respects of chest stuffiness, palpitation, chest pain and arrhythmia (P<0.05 or P<0.01). (2) Negative converting rates of cTnl ,cTnT in the two groups were 59.46% vs35.48%, 68.75% vs42.31% respectively ( P<0. 05). (3) LVEDD before and after treatment in SMG was 52. 44 ± 3. 40 mm and 48. 81 ± 2. 23mm respectively, while that in the control group was 52. 31 ± 3. 74 mm and 49. 92 ± 2. 67mm respectively; LVEF before and after treatment in SMG was 60.67 ± 4. 62 % and 65. 02 ± 4. 16 % respectively, while that in the control group was 60.91 ± 4. 26 % and 63. 67 ± 3.17 % . There was obvious improvement in the two parameters in both groups, but the improvement in SMG was superior to that in the control group ( P<0. 05). Conclusion: SMP shows a good effect in improving clinical symptoms and signs, heart function, abnormal ECG and inflammatory injury indexes in patients with acute viral myocarditis.

Phenotype Analysis of Mononuclear Cells in Endomyocardial Biopsy Specimens from Patients with Viral Myocarditis and Dilated Cardiomyopathy

This study investigated the distribution and phenotype of mononuclear cells in endomyocardial biopsy(EMB)specimens from patients with viral myocarditis (VMC,25 cases) and dilated cardiomyopathy (DCM, 10 cases).T lymphocytes,including Th/i cells in VMC and Tc/s cells in DCM, predominated in the infiltrating mononuclear cells in these specimens. The morphological relationship between infiltration of T lymphocytes and pathological changes of myocardia was also observed and neither macrophages nor B lymphocytes were found.

Clinical value of high-dose VitC + immunoglobulin for the treatment of viral myocarditis in children

Objective: To study the clinical value of high-dose VitC + immunoglobulin for the treatment of viral myocarditis in children. Methods: Children who were diagnosed with viral myocarditis in the hospital between May 2014 and March 2017 were selected as the research subjects and divided into two groups by random number table, observation group received high-dose VitC+ immunoglobulin combined with conventional symptomatic and supportive treatment and control group received conventional symptomatic and supportive treatment. The serum levels of myocardial injury indexes, myocardial remodeling indexes and inflammatory response indexes were measured before treatment as well as at 1 week and 2 weeks after treatment. Results: 1 week and 2 weeks after treatment, serum CK-MB, cTnI, MDA, BNP, PINP, ICTP, MMP2, MMP9, TGFβ1, TNF-α, ICAM-1, MIP-1α and IL-17 levels of both groups of patients were significantly lower than those before treatment, and serum CK-MB, cTnI, MDA, BNP, PINP, ICTP, MMP2, MMP9, TGFβ1, TNF-α, ICAM-1, MIP-1α and IL-17 levels of observation group were lower than those of control group. Conclusion: High-dose VitC +immunoglobulin can reduce the myocardial damage and inhibit the myocardial remodeling and inflammatory response in children with viral myocarditis.

Correlation of peripheral blood IL-17A gene polymorphism with myocardial injury and MMPs/TIMPs balance in patients with viral myocarditis

Objective:To study the correlation of peripheral blood IL-17A gene polymorphism with myocardial injury and MMPs/TIMPs balance in patients with viral myocarditis.Methods:A total of 80 patients who were diagnosed with viral myocarditis in Dongguan Branch, Yan'an University Affiliated Hospital between September 2014 and September 2017 were selected as the VMC group of the research, and 100 healthy volunteers who received physical examination in Dongguan Branch, Yan'an University Affiliated Hospital during the same period were selected as the control group of the research. The peripheral blood was collected to determine the IL-17A gene rs2275913 locus polymorphism, and serum was collected to determine the contents of myocardial injury and MMPs/TIMPs indexes.Results: The proportion of IL-17A gene GG genotype of VMC group was lower than that of control group and the proportion of GA+AA genotype was higher than that of control group;serum IL-17, CK-MB, cTnI, sFas, MDA, PINP, ICTP, MMP2, MMP9, TIMP1 and TIMP2 contents of VMC group were significantly higher than those of control group, and serum IL-17, CK-MB, cTnI, sFas, MDA, PINP, ICTP, MMP2, MMP9, TIMP1 and TIMP2 contents of patients with GA+AA genotype in VMC group were higher than those of patients with GG genotype.Conclusion: The mutation of the allele G to A in the peripheral blood IL-17A gene rs2275913 locus of patients with viral myocarditis can aggravate myocardial injury and MMPs/TIMPs imbalance.

Development of dilated cardiomyopathy with a long latent period followed by viral fulminant myocarditis:A case report

BACKGROUND The clinical course of acute myocarditis ranges from the occurrence of a few symptoms to the development of fatal fulminant myocarditis.Specifically,fulminant myocarditis causes clinical deterioration very rapidly and aggressively.The long-term prognosis of myocarditis is varied,and it fully recovers without leaving any special complications.However,even after recovery,heart failure may occur and eventually progress to dilated cardiomyopathy(DCM),which causes serious left ventricular dysfunction.In the case of follow-up observation,no clear guidelines have been established.CASE SUMMARY We report the case of a 21-year-old woman who presented with dyspnea.She became hemodynamically unstable and showed sustained fatal arrhythmias with decreased heart function.She was clinically diagnosed with fulminant myocarditis based on her echocardiogram and cardiac magnetic resonance results.After 2 d,she was readmitted to the emergency department under cardiopulmonary resuscitation and received mechanical ventilation and extracorporeal membrane oxygenation.An implantable cardioverter defibrillator was inserted for secondary prevention.She recovered and was discharged.Prior to being hospitalized for sudden cardiac function decline and arrhythmia,she had been well for 7 years without any complications.She was finally diagnosed with dilated cardiomyopathy.CONCLUSION DCM may develop unexpectedly in patients who have been cured of acute fulminant myocarditis and have been stable with a long period of remission.Therefore,they should be carefully and regularly observed clinically throughout long-term follow-up.

Effects of Shenmai Injection(参麦注射液)Combined with Meglumine Adenosine Cyclophosphate Injection on Cardiac Function and Peripheral Serum Levels of TNF-α,TGF-β1 and IFN-γ in Patients with Viral Myocarditis

Objective: To explore effects of Shenmai Injection(参麦注射液) combined with Meglumine Adenosine Cyclophosphate Injection on cardiac function and peripheral serum levels of tumor necrosis factor-α(TNF-α), transforming growth factor-β1(TGF-β1) and interferon-γ(IFN-γ) in patients with viral myocarditis.Methods: A total of 70 patients with viral myocarditis admitted in Cardiovascular Medicine Department of our hospital from June 2016 to June 2018 were selected and divided into a control group(treated with Meglumine Adenosine Cyclophosphate Injection) and an observation group(additionally treated with Shenmai Injection(参麦注射液) on the treatment basis of the control group) according to random number method, with 35 cases in each group.Before and after the treatment, cardiac functional indexes like cardiac index(CI), left ventricular ejection fraction(LVEF) and left ventricular shortening fraction(FS), serum levels of TNF-α, TGF-β1 and IFN-γ, clinical efficacy and adverse reactions occurred in the 2 groups were recorded and compared.Results: Therapeutic effective rate in the observation group was 88.57%, higher than 68.57% in the control group(P < 0.05).After the treatment, cardiac functional indexes like CI, LVEF and FS were higher than those in the control group(P < 0.05).After the treatment, the serum expression levels of TNF-α and TGF-β1 were lower than those in the control group(P < 0.05), while the serum expression level of IFN-γ was higher than that in the control group(P < 0.05).There was no statistically significant difference in the adverse reaction rates between the 2 groups(P > 0.05).Conclusion: The treatment of patients with viral myocarditis by Shenmai Injection(参麦注射液) combined with Meglumine Adenosine Cyclophosphate Injection is more effective, reducing inflammation and restoring cardiac function.

Study on the protective effect of adenosine cyclophosphate combined with vitamin C antiviral therapy on myocardial injury in children with viral myocarditis

Objective:TTo study the protective effect of adenosine cyclophosphate combined with vitamin C antiviral therapy on myocardial injury in children with viral myocarditis.Methods: 88 cases of children with viral myocarditis treated in Ningde Hospital of Traditional Chinese Medicine of Fujian University of Traditional Chinese Medicine between June 2014 and September 2016 were selected and randomly divided into the intervention group and the control group who received adenosine cyclophosphate combined with vitamin C antiviral therapy and conventional therapy respectively. Serum levels of myocardial injury indexes, antioxidant indexes and collagen metabolism indexes were determined.Results:1 week and 2 weeks after treatment, serum LDH, CK, CK-MB, ET-1, Ang-II, PICP and PINP contents of both groups were significantly lower than those before treatment while SOD, GSH-Px, CAT and HO-1 contents were significantly higher than those before treatment and serum LDH, CK, CK-MB, ET-1, Ang-II, PICP and PINP contents of intervention group were significantly lower than those of control group while SOD, GSH-Px, CAT and HO-1 contents were significantly higher than those of control group.Conclusion: Adenosine cyclophosphate combined with vitamin C therapy for viral myocarditis can reduce myocardial injury and improve collagen metabolism.

Experience in Treating Viral Myocarditis with Master Lei's Huoxue Decoction

Modem medical treatment of viral myocarditis by suppressing viral replication and improving cardiomyocyte metabolism has a good effect on the acute infectious period of viral myocarditis,but the curative rate is poor,especially the sequelae of viral myocarditis,which often lingers for years to decades.The use of traditional Chinese medicine can achieve a certain curative effect by promoting the positive and dispelling evil spirits as well as balancing yin and yang.After long-term observation,it is found to have clear eff ect on improving myocardial injury caused by viral myocarditis.

Comparison study of Mongolian milkvetch root and Indigowood treating murine viral myocarditis

Objective To investigate perfect therapeutic measure of Chinese traditional herbs through observing curative effect of single dose traditional Chinese medicine on murine viral myocarditis(VMC).Method Balb/C mice were inoculated intraperitoneally with diluted solution of coxsackievirus B3(CVB3) , and then were divided into three groups randomly: infected control group, Mongolian milkvetch root treated group; Indigowood treated group. The mice were put to death and their hearts were examined on day 3,5,7,10,14,21 post inoculated, and were stained with hemotoxylin and eosin(HE) to observe myocardial lesions and to estimate myocardial histopathological scores, simultaneously to separate virus from myocardium. In addition, we observed myocardial ultrastructure by electron microscopy on 7th day post inoculated. Result Compared with infected control group, myocardial histopathological scores of both Mongolian milkvetch root treated group from 5th day to 21st day post inoculated and Indigowood treated group on 5th day and 7th day post inoculated showed significant decrease(P< 0.05).Conclusion Mongolian milkvetch root could protect myocardial cells.

Handheld bedside ultrasound in the diagnosis of myocarditis

Myocarditis is a disease process that every emergency physician fears missing.Its severity can be mild to life-threatening,and many cases are likely undetected because they are subclinical with nonspecifi c signs.[1]Subtle cardiac signs may be overshadowed by systemic symptoms of the underlying infectious process.Fever,myalgias,lethargy,symptoms commonly associated with viral syndrome,can mask the life-threatening myocarditis that may be present.In fact,in the United States Myocarditis Treatment Trial,almost 90%of patients reported symptoms consistent with a viral prodrome.[2]Ammirati et al[3]reported that 27%of patients with myocarditis had either reduced left ventricular ejection fraction,ventricular arrhythmias,or low cardiac output.Here,we present a case report,in which handheld point-of-care ultrasound was utilized at the bedside to aid in the critical diagnosis of myocarditis.With the additional information provided through this imaging modality,this patient was able to be transferred to the appropriate tertiary care facility in an expeditious manner and receive possible defi nitive treatment.

Role of T Cells in Viral and Immune-mediated Myocarditis

Myocarditis is characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function with a heterogeneous etiology. Both viral- and myosin-induced myocarditis experimental models are used to mimic myocarditis in humans. Here, coxsackie virus B3-induced and non-virus-induced myocarditis models and data obtained in clinical studies were reviewed. Experimental murine myocarditis following immunization with α-myosin together with complete Freund adjuvant represents the classical immune-mediated model. T helper 1 (Th1) and Th2 pathways and important cytokines are involved in the autoimmunity of myocarditis, and the dynamic balance between Th17 and regulatory T cell seems to have an important role in the process of myocarditis. The purpose of this review is to summarize the existing understanding of the immunological mechanisms underlying myocarditis and exploring gaps in knowledge in both animal and human studies, since these mechanistic insights are a critical requirement for the development of novel therapeutic and vaccination strategies.

COVID-19 and cardiac complications:Myocarditis and multisystem inflammatory syndrome in children

Coronavirus is an important pathogen causing disease in humans and animals.At the end of 2019,an investigation into an increase in pneumonia cases in Wuhan,Hubei Province,China,found that the cause was a new coronavirus.This disease,which spread rapidly across China and caused an outbreak worldwide,resulted in a pandemic.Although this virus has previously been referred to as 2019-nCoV,which causes coronavirus disease 2019(COVID-19),later it was named severe acute respiratory syndrome coronavirus 2.Children were usually asymptomatic and rarely severely affected.In April 2020,reports from the United Kingdom indicated that children may have Kawasaki disease or a clinical condition similar to toxic shock syndrome.This clinical picture was later defined as multisystem inflammatory syndrome in children.Since then,similarly affected children as well as cases with other cardiac complications have been reported in other parts of the world.In this review,we aimed to evaluate COVID-19 in terms of cardiac involvement by reviewing the literature.

Cardioembolic Stroke as a Sequela of General Ventricular Hypokinesia Secondary to Acute Myocarditis in a 16-Year-Old Male

Paediatric cardiac disease is an established cause of ischemic stroke in the neonatal and infantile groups. These diseases may be congenital or acquired. However, clinical myocarditis is in itself, relatively uncommon in older children. The most common pathogen is Coxsackie virus B. The offending agent instigates an immune response, which causes myocardial oedema with eventual systolic and diastolic dysfunction. Cardioembolic stroke can occur secondary to an intra-mural thrombus in a dysfunctional atrium or ventricle. We describe the case of an adolescent male with acute myocarditis complicated by a thromboembolic stroke. After initial management of acute pulmonary oedema and heart failure with restricted ejection fraction (HFrEF), the child developed seizure-like symptoms on the 10th day of hospitalization, prompting urgent neuro-radio diagnosis, which revealed acute infarcts in the cerebellum and frontal lobe of the cerebrum. We believe this case to be of clinical relevance because;1) The diagnosis of an acute stroke in children is often delayed due to the atypical clinical presentation and often the absence of traditional stroke-like symptoms, and 2) There is a lack of sufficient high-quality evidence regarding the predictors and the immediate management of stroke in paediatric heart disease, as well as inadequate data on prevalence and incidence in paediatric cardioembolic strokes.