Treatment Of Acute Viral Myocarditis Research Articles

Combination of trimetazidine and coenzyme Q10 for the treatment of acute viral myocarditis: a systematic review and meta-analysis.

Coenzyme Q10 (CoQ10) is considered to be beneficial for patients with acute viral myocarditis (AVM). In addition, trimetazidine may be also beneficial to patients with AVM by promoting cardiac energy metabolism. This systematic review and meta-analysis examined the efficacy and safety of combining trimetazidine and CoQ10 with respect to CoQ10 alone in patients suffering from AVM. PubMed, Embase, the Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched for relevant randomized controlled trials (RCTs). An analysis of random effects was employed to combine the results. Sixteen RCTs that included 1,364 patients with AVM contributed to the meta-analysis. Overall, 687 patients received the combined treatment, while 677 received the CoQ10 alone for a duration of 2-12 weeks (mean: 5.2 weeks). In contrast to monotherapy with CoQ10, combined treatment with trimetazidine and CoQ10 significantly improved overall therapy effectiveness (risk ratio [RR]: 1.19, 95% confidence interval [CI]: 1.13 to 1.24, p < 0.001; I2 = 0%). Differences in study parameters such as the incidence of heart failure upon admission, dosage of CoQ10, or length of treatment did not significantly alter the outcomes (p for all subgroup analyses > 0.05). The combined treatment was associated with improved myocardial enzyme levels and recovery of cardiac systolic function as compared to CoQ10 alone (p all < 0.05). In addition, trimetazidine combined with CoQ10 caused no greater increase in adverse events than CoQ10 alone. Trimetazidine combined with CoQ10 is an effective and safe treatment for AVM.

B-arrestin deletion abrogates the innate immune response in murine CVB3 myocarditis

β-arrestins (βarrs), initially discovered as desensitizers of GPCR signaling, are now known to function as intracellular scaffolds and signaling transducers mediating a wide array of signaling cascades including immune responses to inflammatory stimuli. An important cause of immune cell infiltration and cardiac inflammation are viral pathogens such as enterovirus coxsackievirus B3 (CVB3) induced myocarditis. While viral myocarditis is a leading cause of dilated cardiomyopathy, the precise molecular mechanisms for the acute immune response to CVB3 infection are not well understood. Given the important role for βarrs in the acute immune response, we tested the hypothesis that βarrs are necessary for the activation of the acute immune response and mediate the progression and severity of cardiotropic CVB3-induced myocarditis in mice. Five to 7-week-old mice devoid of βarr1 (βarr1 KO) or βarr2 (βarr2 KO) were infected intraperitoneally with 1x103-1x104 plaque forming units (PFU) of CVB3 per animal. Wild type (WT) C57BL/6 mice infected with CVB3 were used as controls. The survival rate 7 days post infection (dpi) was significantly improved in male βarr1 KOs (80%) and βarr2 KOs (75%) compared to male WT control mice (35%, p=0.013). Female WT, βarr1 KO, and βarr2 KO mice showed similar survival rates 7 dpi., ranging from 70% to 80%. Early mortality among all groups before 5 dpi was associated with high viral titers (~6.0 ± 0.5 log10PFU/mg) in the liver compared to mortality after 5 dpi (~2.4 ± 1.7 log10PFU/mg) as determined by plaque assay. Viral titers in the heart (WT=3.7 ± 0.9 log10PFU/mg, βarr1KO=3.6 ± 1.3 log10PFU/mg, βarr2KO=3.5 ± 1.2log10PFU/mg) were similar among all groups suggesting that βarrs are not involved in viral replication. Morphometric analysis showed similar weight loss (~18%) across all groups at 7 dpi corroborated by viral cardiac PFU. Immunofluorescent staining of the heart with the pan-inflammatory marker, CD45, revealed high immune cell infiltration in infected WT mice (34.2% ± 4.5%), whereas immune cell infiltration was significantly blunted in infected βarr1 KO (6.0% ± 1.1%; p&lt;0.0001) and βarr2 KO (8.5% ± 0.9%; p&lt;0.0001) mice. The degree of immune cell infiltration in hearts of infected WT mice was directly correlated with an increase in heart viral titer, whereas immune cell infiltration remained blunted across a broad range of heart viral titers in both βarr1 and 2 KO mice. The blunted immune response in both βarr KOs compared to WT infected controls was consistent across multiple immune cell markers including CD4 for helper T cells and CD11b for innate immune cells. In conclusion, we demonstrate that βarrs are necessary for immune cell recruitment to the heart in CVB3 myocarditis and deletion of βarrs in male mice may be cardioprotective as indicated by an increase in survival rate. These data suggest that βarrs may serve as potential therapeutic targets in the treatment of acute viral myocarditis. This work was supported by the National Institutes of Health Grants HL056687 (to H.A.R.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical characteristics and outcome of 64 patients with severe COVID-19

Objective: To investigate the causes of death in patients with severe COVID-19. Methods: A retrospective analysis was performed on 64 patients with severe COVID-19 admitted to Wuhan Pulmonary Hospital from January 12, 2020 to February 28, 2020. There were 36 males and 28 females, aging from 44 to 85 years[median 68 (62, 72)]. Fifty-two patients (81%) had underlying comorbidities. The patients were divided into the death group (n=40) and the survival group (n=24) according to the treatment outcomes. In the death group, 24 were male, and 16 were female, aging from 49 to 85 years [median 69 (62, 72)], with 31 cases (78%) complicated with underlying diseases. In the survival group, there were 12 males and 12 females, aging from 44 to 82 years[median 66 (61,73)], with 21 cases (88%) with comorbidities. Clinical data of the two groups were collected and compared, including general information, laboratory examinations, imaging features and treatments. For normally distributed data, independent group t test was used; otherwise, Mann Whitney test was used to compare the variables. χ(2) test and Fisher exact test was used when analyzing categorical variables. Results: The median of creatine kinase isozyme (CK-MB) in the death group was 19.0 (17.0,23.0) U/L, which was higher than that in the survival group 16.5 (13.5,19.6) U/L. The median level of cTnI in the death group was 0.03 (0.03, 0.07) μg/L, which was significantly higher than that in the survival group (0.02, 0.03) μg/L, with a statistically significant difference between the two groups (P=0.007). The concentration of myoglobin in the death group was 79.5 (28.7, 189.0) μg/L, which was higher than 33.1 (25.7, 54.5) μg/L in the survival group. The level of D-dimer in the death group was 2.0 (0.6, 5.2) mg/L, which was higher than 0.7 (0.4, 2.0) mg/L in the survival group. The LDH level of the death group was 465.0 (337.5,606.5) U/L, which was higher than that of the survibal group, 341.0 (284.0,430.0) U/L, the difference being statistically significant (P=0.006). The concentration of alanine aminotransferase in the death group was 40.0 (30.0, 48.0) U/L, which was higher than 32.5 (24.0, 40.8) U/L in the survival group, and the difference was statistically significant (P=0.047).Abnormal ECG was found in 16 cases (62%) in the death group, which was significantly higher than that in the survival group (29%), the difference being statistically significant (P=0.024) .The main causes of death were severe pneumonia with acute respiratory distress syndrome (ARDS, n=20), acute heart failure(n=9), atrial fibrillation(n=3) and multiple organ dysfunction syndrome (MODS, n=3). Conclusions: ARDS caused by severe pneumonia and acute heart failure and atrial fibrillation caused by acute viral myocarditis were the main causes of death in severe COVID-19 patients. Early prevention of myocardial injury and treatment of acute viral myocarditis complicated with disease progression may provide insights into treatment and reduction of mortality in patients with severe COVID-19.

Clinical effects of tanshinone ⅡA sodium sulfonate combined with trimetazidine and levocarnitine in the treatment of AVMC and its effects on serum TNF‑α, IL‑18 and IL‑35

Clinical effects of tanshinone IIA sodium sulfonate combined with trimetazidine and levocarnitine in the treatment of acute viral myocarditis (AVMC) were investigated. Eighty-six patients with AVMC treated in Dongying City People's Hospital from August 2016 to July 2017 were selected and randomly divided into control group (n=43) and observation group (n=43). Patients in control group were treated with tanshinone IIA sodium sulfonate, while those in observation group were treated with trimetazidine and levocarnitine. The curative effect and improvement in clinical symptoms were compared between the two groups of patients, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of heart-type fatty acid-binding protein (H-FABP), creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) in patients after treatment. Besides, the changes in levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-18 and IL-35 were detected via ELISA. The total effective rate of treatment in observation group was significantly higher than that in control group (p<0.05). The improvement in clinical symptoms in observation group was significantly superior to that in control group (p<0.05). After treatment, levels of H-FABP, CK-MB and cTnI in observation group were obviously lower than those in control group (p<0.05). At 3, 5 and 7 days after treatment, the levels of TNF-α and IL-18 in both groups of patients were decreased compared with those before treatment, but the level of IL-35 was increased compared with that before treatment, and changes in observation group were more significant than those in control group (p<0.05). Tanshinone IIA sodium sulfonate combined with trimetazidine and levocarnitine has definite curative effects in the treatment of patients with AVMC, which can alleviate myocardial injury with higher safety, and effectively mitigate the inflammatory response in patients, so it is of great clinical significance.

Efficacy of Yanhuning injection in the treatment of acute viral myocarditis with Xiedu Qinxin syndrome

Objective To investigate the effect of Yanhuning injection antiviral therapy in the treatment of acute viral myocarditis patients with Xiedu Qinxin syndrome. Methods From May 2016 to August 2017, 84 acute viral myocarditis patients with Xiedu Qinxin syndrome in the Integrated Traditional Chinese and Western Medicine Hospital of Wenzhou were enrolled in this study.According to the digital table, they were randomly divided into observation group and the control group, with 42 cases in each group.The control group received conventional antiviral therapy, and the observation group was given Yanhuning injection.The heart type free fatty acid binding protein(H-FABP), serum troponin I (cTnI), macrophage migration inhibitory factor(MIF) and interleukin 4(IL-4) were measured before and after treatment for 4 weeks.The clinical symptoms score and the effective rate were compared between the two groups at the same time. Results The serum levels of cTnI, H-FABP, MIF and IL-4 of the two groups after treatment were lower than those before treatment(all P<0.05), which of the observation group after treatment were significantly lower than those of the control group (t=3.012, P=0.039; t=2.835, P=0.040; t=3.534, P=0.032; t=3.323, P=0.033). The effective rate of the observation group was significantly higher than that of the control group (90.48% vs.80.95%, χ2=3.432, P=0.038). The scores of palpitations, sore throat, upsetting the chest tightness of the observation group after treatment were significantly lower than those of the control group (t=3.045, P=0.038; t=2.946, P=0.039; t=3.467, P=0.031; t=3.358, P=0.032). Conclusion Yanhuning injection antiviral therapy in the treatment of acute viral myocarditis patients with Xiedu Qinxin syndrome can significantly improve the efficacy of patients. Key words: Myocarditis; Yanhuning injection; Fatty acid binding proteins; Troponin I (cTnI); Macrophage migration inhibitory factor (MIF); Interleukin-4

Ulinastatin Protects against CVB3-Induced Acute Viral Myocarditis through Nrf2 Activation.

Inflammation and oxidative stress are implicated in the pathogenesis of acute viral myocarditis (AVM). Ulinastantin (UTI), an inhibitor of serine protease widely used in treatment of pancreatitis and various inflammatory disorders, displays cardioprotective properties in experimental animals. Although the specific mechanism through which UTI regulates cardiac function is not well explored, evidence suggests that UTI might activate nuclear factor E2-related factor 2 (Nrf2) signaling. In this study, we investigated the role of Nrf2 in mediating UTI's cardioprotection in a mouse model of AVM. We found that UTI is an activator of Nrf2 signaling. It markedly increased Nrf2 nuclear translocation, Nrf2 transcription capacity, and the downstream protein expression. In addition, UTI possessed strong protective functions in coxsackievirus B3 (CVB3)-induced AVM. UTI treatment effectively reduced the cardiac damage, decreased the expression of inflammatory cytokines, and balanced oxidative stress via improving the activity of anti-oxidant and detoxifying enzymes. Even more impressively, UTI achieved its cardioprotective activities in an Nrf2-dependent manner. Taken together, our study has identified a novel pathway through which UTI exerts its cardioprotective functions and provides a molecular basis for UTI potential applications in the treatment of AVM and other inflammatory disorders.

Necroptosis may be a novel mechanism for cardiomyocyte death in acute myocarditis.

In this study, we investigated the roles of RIP1/RIP3 mediated cardiomyocyte necroptosis in CVB3-induced acute myocarditis. Serum concentrations of creatinine kinase (CK), CK-MB, and cardiac troponin I were detected using a Hitachi Automatic Biochemical Analyzer in a mouse model of acute VMC. Histological changes in cardiac tissue were observed by light microscope and expression levels of RIP1/RIP3 in the cardiac tissue were detected via Western blot and immunohistochemistry. The data showed that RIP1/RIP3 was highly expressed in cardiomyocytes in the acute VMC mouse model and that the necroptosis pathway specific blocker, Nec-1, dramatically reduced the myocardial damage by downregulating the expression of RIP1/RIP3. These findings provide evidence that necroptosis plays a significant role in cardiomyocyte death and it is a major pathway for cell death in acute VMC. Blocking the necroptosis pathway may serve as a new therapeutic option for the treatment of acute viral myocarditis.

IL-22-producing Th22 cells play a protective role in CVB3-induced chronic myocarditis and dilated cardiomyopathy by inhibiting myocardial fibrosis.

BackgroundA new subset of T helper (Th) cells, named IL-22-producing Th22 cells, was identified recently. Th22 cells have been implicated in immunity and inflammation. However, the role of these cells in the progression from acute viral myocarditis (AVMC) to dilated cardiomyopathy (DCM) and myocardial fibrosis remains unknown.MethodsBALB/c mice were repeatedly i.p. infected with Coxsackie virus B3 (CVB3) to establish models of AVMC, chronic myocarditis and DCM. On week 2, 12 and 24 post initial injection, the percentage of splenic Th22 cells, the levels of plasma IL-22, cardiac IL-22 receptor (IL-22R) expression, and indicators of myocardial fibrosis were measured. Further, mice with AVMC and chronic myocarditis were treated with an anti-IL-22 neutralizing antibody (Ab). The collagen volume fraction (CVF), the percentage of splenic Th22 cells, plasma IL-22 levels, cardiac IL-22R expression and indicators of myocardial fibrosis were then monitored.ResultsCompared to control mice at the same time points, AVMC, chronic myocarditis and DCM mice have higher percentage of splenic Th22 cells, higher plasma IL-22 levels, increased cardiac IL-22R, as well as increased collagen typeI-A1 (COL1-A1), collagen type III-A1 (COL3-A1) and matrix metalloproteinase-9 (MMP9) expression. However, the expression of tissue inhibitor of metalloproteinase-1(TIMP-1) was decreased. Treatment of AVMC and chronic myocarditis mice with an anti-IL-22 Ab decreased the survival rate and exacerbated myocardial fibrosis. The percentage of splenic Th22 cells, plasma IL-22 levels and cardiac IL-22R expression also decreased in anti-IL-22 Ab treatment group as compared to IgG and PBS treated groups of AVMC and chronic myocarditis mice. Moreover, increased expression of COL1-A1, COL3-A1, MMP9 but decreased expression of TIMP-1 were observed in anti-IL-22 Ab mouse group.ConclusionsTh22 cells play an important role in the pathogenesis of CVB3-induced mouse chronic myocarditis and DCM. IL-22 is a myocardium-protective cytokine by inhibiting myocardial fibrosis. Therefore, Th 22 cells may be considered as potential therapeutic targets for DCM.

Antiviral Activity of Coxsackievirus B3 3C Protease Inhibitor in Experimental Murine Myocarditis

We investigated the efficacy of a 3C protease inhibitor (3CPI) in a murine coxsackievirus B3 (CVB3) myocarditis model. CVB3 is a primary cause of viral myocarditis. The CVB3 genome encodes a single polyprotein that undergoes a series of proteolytic events to produce several viral proteins. Most of this proteolysis is catalyzed by the 3C protease (3CP). By way of a micro-osmotic pump, each mouse received 50 mM 3CPI in 100 μL of 100% dimethyl sulfoxide (DMSO) during a 72-hour period. On the day of pump implantation, mice (n = 40) were infected intraperitoneally with 10(6) plaque-forming units of CVB3. For the infected controls (n = 50), the pump was filled with 100% DMSO without 3CPI. The 3-week survival rate of 3CPI-treated mice was significantly higher than that of controls (90% vs 22%; P < .01). Myocardial inflammation, viral titers, and viral RNA levels were also reduced significantly in the 3CPI-treated group compared with these measures in the controls. The protein-based drug 3CPI inhibited the activity of 3CP of CVB3, significantly inhibited viral proliferation, and attenuated myocardial inflammations, subsequent fibrosis, and CVB3-induced mortality in vivo. Thus, this CVB3 3CPI has the potential to be a novel therapeutic agent for the treatment of acute viral myocarditis during the viremic phase.

Virus receptor trap neutralizes coxsackievirus in experimental murine viral myocarditis

The coxsackie and adenovirus receptor (CAR) and the decay-accelerating factor (DAF) are receptors for coxsackievirus B3 (CVB3), which is known as the major cause of human viral myocarditis. We investigated the potential for therapeutic use of soluble virus receptor fusion proteins. We designed and generated a novel virus receptor trap (hCAR-hDAF:Fc) consisting of both CVB3 receptors and the Fc portion of human IgG1 and evaluated its antiviral effects in experimental CVB3 myocarditis. Among four soluble virus receptor fusion proteins (hCAR:Fc, hDAF:Fc, hCAR-hDAF:Fc and hDAF-hCAR:Fc), hCAR:Fc and hCAR-hDAF:Fc in the supernatant of transfected cells neutralized echovirus, adenovirus, and various serotypes of CVB in a dose-dependent manner. Both soluble viral receptor proteins bound to the VP0 and VP1 capsid proteins of CVB3. The in vivo efficacy of viral receptor proteins was evaluated by intramuscular injection of plasmid (hCAR:Fc or hCAR-hDAF:Fc) followed by electroporation in a murine model of CVB3 myocarditis. Serum levels of the virus receptor proteins increased relative to baseline values from day 3 and peaked on day 14 at 12.9-fold for hCAR:Fc and 7.1-fold for hCAR-hDAF:Fc. The 3-week survival rate was significantly higher in hCAR-hDAF:Fc-treated mice (61%) than in hCAR:Fc-treated mice (29%) and in controls (15%; p<0.05). Myocardial inflammation, fibrosis, and myocardial virus titers were all significantly reduced in the hCAR:Fc and hCAR-hDAF:Fc groups compared to the controls. Our soluble virus receptor trap, hCAR-hDAF:Fc, attenuated viral infection, myocardial inflammation, and fibrosis, resulting in higher survival rates in mice with coxsackieviral myocarditis. Furthermore, it consists exclusively of human components, and we demonstrated that this soluble virus receptor trap may be used as a potential candidate for a novel therapeutic agent for the treatment of acute viral myocarditis during the viremic phase.

Ventricular assist device use for the treatment of acute viral myocarditis

Ventricular assist device use for the treatment of acute viral myocarditis

Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis

OBJECTIVESThis study examines the efficacy of FTY720 (FTY), a new immunosuppressor, in the treatment of acute viral myocarditis in a murine model.BACKGROUNDImmunosuppressive agents have no proven therapeutic efficacy in experimental or clinical myocarditis.METHODSEncephalomyocarditis virus was inoculated i.p. in DBA/2 mice on day 0. Postinoculation treatment consisted of FTY 10 mg/kg/day p.o. (FTY group), or cyclosporine A (CsA) 40 mg/kg/day p.o. (CsA group) or distilled water p.o. only (control group). Survival until day 14, as well as cardiac histopathology, virus concentrations, cytokines (interleukin [IL]-2, IL-12, interferon [IFN]-gamma and tumor necrosis factor [TNF]-alpha) and nitric oxide (NO) on day 5 were examined.RESULTSIn the control and CsA groups, all mice died within 10 and 7 days, respectively. However, in the FTY group, 27% of the animals survived up to day 14. Compared with the control group, 1) histological scores were significantly lower in the FTY group but unchanged in the CsA group; 2) virus concentration was significantly higher in the CsA group but not in the FTY group; 3) expressions of IL-2, IL-12 and IFN-gamma in the heart were suppressed in both the FTY and CsA groups, though suppression was weaker in the FTY group; 4) TNF-alpha and NO were significantly increased in the CsA group but not in the FTY group.CONCLUSIONSFTY720 had a significant therapeutic effect in acute experimental myocarditis without inducing excessive virus replication. This report is the first to describe a beneficial effect by an immunosuppressive agent in the treatment of acute viral myocarditis.

A study on combination therapy of western and traditional Chinese medicine of acute viral myocarditis

To investigate the combination therapy of Western and traditional Chinese medicine on treatment of acute viral myocarditis, 48 patients were randomly divided into 2 groups. The 1st group consisted of 30 patients, receiving the combination therapy of Western and traditional Chinese medicine, including Astragalus membranaceus, taurine, coenzyme Q10 and antiarrhythmics, while the 2nd group consisted of 18 patients, receiving the conventional therapy, including glucose-insulin-potassium (GIK), coenzyme Q10 and also antiarrhythmics. The efficacy of combination therapy of western and traditional Chinese medicine was better than that of conventional therapy in improving the clinical manifestation, negative converting positive EVsRNA in peripheral leukocytes and controlling the premature beats. The combination therapy of western and traditional Chinese medicine was an effective method in treating acute viral myocarditis.

Temporary mechanical support with the BVS 5000 assist device during treatment of acute viral myocarditis

Temporary mechanical support with the BVS 5000 assist device during treatment of acute viral myocarditis