Acute Viral Myocarditis Research Articles

Arrhythmias and conduction disorders in patients with viral heart disease.

Viral heart disease comprises of two cardiovascular entities being evoked by viral infection: acute viral myocarditis and viral cardiomyopathy. Viral myocarditis may completely resolve leaving no traceable sign or cause ongoing inflammation with subsequent development of hypokinetic dilated/non-dilated cardiomyopathy. The exact epidemiology of viral myocarditis remains unknown due to its sometimes asymptomatic course, but according to the Global Burden of Disease Study 2019, the prevalence of myocarditis in young adults is estimated to range between 6.1 per 100,000 in men and 4.4 per 100,000 in women, with the most common viral etiology. According to the literature viral genome can be found in considerable percentage (up to 67,4%) of endomyocardial biopsy specimens obtained from patients with idiopathic left ventricular dysfunction- suggesting viral etiology of the cardiomyopathy. In this review we would like to enlighten most common types of arrhythmias and conduction disorders as well as their prevalence in patients with viral heart disease. Moreover, our paper depicts probable pathological mechanisms in which viruses induce arrhythmias and cardiac conduction system disease in both, acute viral infection and chronic viral disease. We would also like to highlight unresolved problem of sudden death protection in the course of acute myocarditis.

The influence of endurance exercise training on myocardial fibrosis and arrhythmogenesis in a coxsackievirus B3 myocarditis mouse model

Nonischaemic myocardial fibrosis is associated with cardiac dysfunction, malignant arrhythmias and sudden cardiac death. In the absence of a specific aetiology, its finding as late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging is often attributed to preceding viral myocarditis. Athletes presenting with ventricular arrhythmias often have nonischaemic LGE. Previous studies have demonstrated an adverse effect of exercise on the course of acute viral myocarditis. In this study, we have investigated, for the first time, the impact of endurance training on longer-term outcomes such as myocardial fibrosis and arrhythmogenicity in a murine coxsackievirus B3 (CVB)-induced myocarditis model. Male C57BL/6J mice (n = 72) were randomly assigned to 8 weeks of forced treadmill running (EEX) or no exercise (SED). Myocarditis was induced 2 weeks later by a single intraperitoneal injection with CVB, versus vehicle in the controls (PBS). In a separate study, mice (n = 30) were subjected to pretraining for 13 weeks (preEEX), without continuation of exercise during myocarditis. Overall, continuation of exercise resulted in a milder clinical course of viral disease, with less weight loss and better preserved running capacity. CVB-EEX and preEEX-CVB mice tended to have a lower mortality rate. At sacrifice (i.e. 6 weeks after inoculation), the majority of virus was cleared from the heart. Histological assessment demonstrated prominent myocardial inflammatory infiltration and cardiomyocyte loss in both CVB groups. Inflammatory lesions in the CVB-EEX group contained higher numbers of pro-inflammatory cells (iNOS-reactive macrophages and CD8+ T lymphocytes) compared to these in CVB-SED. Treadmill running during myocarditis increased interstitial fibrosis [82.4% (CVB-EEX) vs. 56.3% (CVB-SED); P = 0.049]. Additionally, perivascular and/or interstitial fibrosis with extensive distribution was more likely to occur with exercise [64.7% and 64.7% (CVB-EEX) vs. 50% and 31.3% (CVB-SED); P = 0.048]. There was a numerical, but not significant, increase in the number of scars per cross-section (1.9 vs. 1.2; P = 0.195), with similar scar distribution and histological appearance in CVB-EEX and CVB-SED. In vivo electrophysiology studies did not induce sustained monomorphic ventricular tachycardia, only nonsustained (usually polymorphic) runs. Their cumulative beat count and duration paralleled the increased fibrosis between CVB-EEX and CVB-SED, but the difference was not significant (P = 0.084 for each). Interestingly, in mice that were subjected to pretraining only without continuation of exercise during myocarditis, no differences between pretrained and sedentary mice were observed at sacrifice (i.e. 6 weeks after inoculation and training cessation) with regard to myocardial inflammation, fibrosis, and ventricular arrhythmogenicity. In conclusion, endurance exercise during viral myocarditis modulates the inflammatory process with more pro-inflammatory cells and enhances perivascular and interstitial fibrosis development. The impact on ventricular arrhythmogenesis requires further exploration.

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.

The natural history of CVB3 myocarditis in C57BL/6J mice: an extended in-depth characterization

Background and aimsViral infections are the leading cause of myocarditis. Besides acute cardiac complications, late-stage sequelae such as myocardial fibrosis may develop, importantly impacting the prognosis. Coxsackievirus B3 (CVB)-induced myocarditis in mice is the most commonly used translational model to study viral myocarditis and has provided the majority of our current understanding of the disease pathophysiology. Nevertheless, the late stages of disease, encompassing fibrogenesis and arrhythmogenesis, have been underappreciated in viral myocarditis research to date. The present study investigated the natural history of CVB-induced myocarditis in C57BL/6J mice, expanding the focus beyond the acute phase of disease. In addition, we studied the impact of sex and inoculation dose on the disease course. Methods and resultsC57BL/6J mice (12 weeks old; n=154) received a single intraperitoneal injection with CVB to induce viral myocarditis, or vehicle (PBS) as control. Male mice (n=92) were injected with 5 × 105 (regular dose) (RD) or 5 × 106 (high dose) (HD) plaque-forming units of CVB, whereas female mice received the RD only. Animals were sacrificed 1, 2, 4, 8, and 11 weeks after CVB or PBS injection. Virally inoculated mice developed viral disease with a temporary decline in general condition and weight loss, which was less pronounced in female animals (P<.001). In male CVB mice, premature mortality occurred between days 8 and 23 after inoculation (RD: 21%, HD: 20%), whereas all female animals survived. Over the course of disease, cardiac inflammation progressively subsided, with faster resolution in female mice. There were no substantial group differences in the composition of the inflammatory cell infiltrates: predominance of cytotoxic T cells at day 7 and 14, and a switch from arginase1-reactive macrophages to iNOS-reactive macrophages from day 7 to 14 were the main findings. There was concomitant development and maturation of different patterns of myocardial fibrosis, with enhanced fibrogenesis in male mice. Virus was almost completely cleared from the heart by day 14. Serum biomarkers of cardiac damage and cardiac expression of remodeling genes were temporarily elevated during the acute phase of disease. Cardiac CTGF gene upregulation was less prolonged in female CVB animals. In vivo electrophysiology studies at weeks 8 and 11 demonstrated that under baseline conditions (i.e. in the absence of proarrhythmogenic drugs), ventricular arrhythmias could only be induced in CVB animals. The cumulative arrhythmia burden throughout the entire stimulation protocol was not significantly different between CVB and control groups. ConclusionCVB inoculation in C57BL/6J mice represents a model of acute self-limiting viral myocarditis, with progression to different patterns of myocardial fibrosis. Sex, but not inoculation dose, seems to modulate the course of disease.

Retraction Note to: A New Mixed-Ligand Ni(II) Complex: Crystal Structure, Protective and Anti-Inflammatory Activities of its Nanoparticles on Acute Viral Myocarditis by Reducing the Release of Inflammatory Cytokines TNF-α and IL-1β

Retraction Note to: A New Mixed-Ligand Ni(II) Complex: Crystal Structure, Protective and Anti-Inflammatory Activities of its Nanoparticles on Acute Viral Myocarditis by Reducing the Release of Inflammatory Cytokines TNF-α and IL-1β

MG53 protects against Coxsackievirus B3-induced acute viral myocarditis in mice by inhibiting NLRP3 inflammasome-mediated pyroptosis via the NF-κB signaling pathway

Pyroptosis, a novel programmed cell death mediated by NOD-like receptor protein 3 (NLRP3) inflammasome, is a critical pathogenic process in acute viral myocarditis (AVMC). Mitsugumin 53 (MG53) is predominantly expressed in myocardial tissues and has been reported to exert cardioprotective effects through multiple pathways. Herein, we aimed to investigate the biological function of MG53 in AVMC and its underlying regulatory mechanism in pyroptosis. BALB/c mice and HL-1 cells were infected with Coxsackievirus B3 (CVB3) to establish animal and cellular models of AVMC. As inflammation progressed in the myocardium, we found a progressive decrease in myocardial MG53 expression, accompanied by a significant enhancement of cardiomyocyte pyroptosis. MG53 overexpression significantly alleviated myocardial inflammation, apoptosis, fibrosis, and mitochondrial damage, thereby improving cardiac dysfunction in AVMC mice. Moreover, MG53 overexpression inhibited NLRP3 inflammasome-mediated pyroptosis, reduced pro-inflammatory cytokines (IL-1β/18) release, and suppressed NF-κB signaling pathway activation both in vivo and in vitro. Conversely, MG53 knockdown reduced cell viability, facilitated cell pyroptosis, and increased pro-inflammatory cytokines release in CVB3-infected HL-1 cells by promoting NF-κB activation. These effects were partially reversed by applying the NF-κB inhibitor BAY 11–7082. In conclusion, our results suggest that MG53 acts as a negative regulator of NLRP3 inflammasome-mediated pyroptosis in CVB3-induced AVMC, partially by inhibiting the NF-κB signaling pathway. MG53 is a promising candidate for clinical applications in AVMC treatment.

Acute myocarditis: an overview of pathogenesis, diagnosis and management.

Acute myocarditis encompasses a diverse presentation of inflammatory cardiomyopathies with infectious and non-infectious triggers. The clinical presentation is heterogeneous, from subtle symptoms like mild chest pain to life-threatening fulminant heart failure requiring urgent advanced hemodynamic support. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, diagnostic approach, management strategies, and directions for future research in acute myocarditis. The pathogenesis of myocarditis involves interplay between the inciting factors and the subsequent host immune response. Infectious causes, especially cardiotropic viruses, are the most frequently identified precipitants. However, autoimmune processes independent of microbial triggers, as well as toxic myocardial injury from drugs, chemicals or metabolic derangements also contribute to the development of myocarditis through diverse mechanisms. Furthermore, medications like immune checkpoint inhibitor therapies are increasingly recognized as causes of myocarditis. Elucidating the nuances of viral, autoimmune, hypersensitivity, and toxic subtypes of myocarditis is key to guiding appropriate therapy. The heterogeneous clinical presentation coupled with non-specific symptoms creates diagnostic challenges. A multifaceted approach is required, incorporating clinical evaluation, electrocardiography, biomarkers, imaging studies, and endomyocardial biopsy. Cardiovascular magnetic resonance imaging has become pivotal for non-invasive assessment of myocardial inflammation and fibrosis. However, biopsy remains the gold standard for histological classification and definitively establishing the underlying etiology. Management relies on supportive care, while disease-specific therapies are limited. Although some patients recover well with conservative measures, severe or fulminant myocarditis necessitates aggressive interventions such as mechanical circulatory support devices and transplantation. While immunosuppression is beneficial in certain histological subtypes, clear evidence supporting antiviral or immunomodulatory therapies for the majority of acute viral myocarditis cases remains insufficient. Substantial knowledge gaps persist regarding validated diagnostic biomarkers, optimal imaging surveillance strategies, evidence-based medical therapies, and risk stratification schema. A deeper understanding of the immunopathological mechanisms, rigorous clinical trials of targeted therapies, and longitudinal outcome studies are imperative to advance management and improve the prognosis across the myocarditis spectrum.

Parkin plays a crucial role in acute viral myocarditis by regulating mitophagy activity.

Rationale: Parkin (an E3 ubiquitin protein ligase) is an important regulator of mitophagy. However, the role of Parkin in viral myocarditis (VMC) remains unclear. Methods: Coxsackievirus B3 (CVB3) infection was induced in mice to create VMC. Cardiac function and inflammatory response were evaluated by echocardiography, histological assessment, and molecular analyses. AAV9 (adeno-associated virus 9), transmission electron microscopy (TEM) and western blotting were used to investigate the mechanisms by which Parkin regulates mitophagy and cardiac inflammation. Results: Our data indicated that Parkin- and BNIP3 (BCL2 interacting protein 3 like)-mediated mitophagy was activated in VMC mice and neonatal rat cardiac myocytes (NRCMs) infected with CVB3, which blocked autophagic flux by inhibiting autophagosome-lysosome fusion. Parkin silencing aggravated mortality and accelerated the development of cardiac dysfunction in CVB3-treated mice. While silencing of Parkin did not significantly increase inflammatory response through activating NF-κB pathway and production of inflammatory cytokines post-VMC, the mitophagy activity were reduced, which stimulated the accumulation of damaged mitochondria. Moreover, Parkin silencing exacerbated VMC-induced apoptosis. We consistently found that Parkin knockdown disrupted mitophagy activity and inflammatory response in NRCMs. Conclusion: This study elucidated the important role of Parkin in maintaining cardiac function and inflammatory response by regulating mitophagy activity and the NF-κB pathway during acute VMC. Although the functional impact of mitophagy remains unclear, our findings suggest that Parkin silencing may accelerate VMC development.

Transcriptional and functional analysis of plasma exosomal microRNAs in acute viral myocarditis

AimTo assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). Materials & methodsPeripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. ResultsP < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to β-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. ConclusionsHsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC.

GPR15-mediated T cell recruitment during acute viral myocarditis facilitated virus elimination and improved outcome

Viral myocarditis is characterized by infiltration of mononuclear cells essential for virus elimination. GPR15 has been identified as a homing receptor for regulatory T cells in inflammatory intestine diseases, but its role in inflammatory heart diseases is still elusive. Here we show that GPR15 deficiency impairs coxsackievirus B3 elimination, leading to adverse cardiac remodeling and dysfunction. Delayed recruitment of regulatory T cells in GPR15-deficient mice was accompanied by prolonged persistence of cytotoxic and regulatory T cells. In addition, RNA sequencing revealed prolonged inflammatory response and altered chemotaxis in knockout mice. In line, we identified GPR15 and its ligand GPR15L as an important chemokine receptor–ligand pair for the recruitment of regulatory and cytotoxic T cells. In summary, the insufficient virus elimination might be caused by a delayed recruitment of T cells as well as delayed interferon-γ expression, resulting in a prolonged inflammatory response and an adverse outcome in GPR15-deficient mice.

CD4+TEM cells drive the progression from acute myocarditis to dilated cardiomyopathy in CVB3-induced BALB/c mice

Acute viral myocarditis can progress to chronic myocarditis leading to dilated cardiomyopathy (DCM). Persistent CD4+ T-cell-mediated autoimmunity triggered by infection plays a critical role in this progression. Increasing evidence demonstrates that effector memory CD4+T (CD4+TEM) cells, a subset of memory CD4+ T cells, are crucial pathogenic mediators of many autoimmune diseases. However, the role of CD4+TEM cells during the progression from acute viral myocarditis to DCM remains unknown. In this study, we observed an increase in CD4+TEM cells both in the periphery and the heart, and memory CD4+ T cells were the predominant sources of IL-17A and IFN-γ among inflamed heart-infiltrating CD4+ T cells during the progression from acute myocarditis to chronic myocarditis and DCM in CVB3-induced BALB/c mice. Moreover, splenic CD4+TEM cells sorted from DCM mice induced by CVB3 were found to respond to cardiac self-antigens ex vivo. Additionally, adoptive transfer experiments substantiated their pathogenic impact, inducing sustained myocardial inflammation, tissue fibrosis, cardiac injury, and impairment of cardiac systolic function in vivo. Our findings illustrate that long-lived CD4+TEM cells are important contributors to the progression from acute viral myocarditis into DCM.

Modulation of myocardial inflammation, fibrosis development and ventricular arrhythmogenicity by endurance exercise in murine coxsackievirus B3 myocarditis

Abstract Aims Nonischaemic myocardial fibrosis is associated with progressive deterioration of myocardial function and forms the substrate for arrhythmias in atria and ventricles. In the absence of a specific aetiology, its origin is commonly attributed to preceding viral myocarditis. Athletes presenting with ventricular arrhythmias often demonstrate nonischaemic fibrosis on magnetic resonance imaging. Previous translational studies have shown an adverse effect of exercise on the course of acute viral myocarditis. Nevertheless, the effect on myocardial fibrosis development, a frequent and important consequence of viral myocarditis, has not yet been investigated. In the present study, we evaluate for the first time the impact of endurance exercise on longer-term myocardial inflammation, myocardial fibrosis and arrhythmogenicity using a murine viral myocarditis model. Methods and results Male C57BL/6J mice (11 weeks of age, n=72) were randomly assigned to 8 weeks of treadmill running (EEX) or without exercise (SED). Two weeks into the study (training or control), animals were injected intraperitoneally with either coxsackievirus B3 to induce acute viral myocarditis (CVB) or vehicle (PBS). Exercising myocarditis mice showed lower mortality (11% vs. 27%), albeit without statistical significance (P=0.23). At sacrifice (i.e. 6 weeks after inoculation), prominent myocardial inflammatory infiltration and cardiomyocyte loss was observed in both CVB groups, without difference on semiquantitative histological scoring. Nevertheless, the infiltrating cells in the CVB-EEX group were more often proinflammatory in nature (predominantly iNOS-reactive macrophages and positive CD8+/CD4+ ratio) compared to these in CVB-SED (predominantly arginase-1-reactive macrophages and higher CD4+/CD8+ ratio). In addition, the EEX group showed more haemosiderin-laden macrophages and spindled fibroblasts as signs of organisation. At that time, the majority of virus was cleared from the heart. Treadmill running during myocarditis enhanced development of interstitial fibrosis (with limited or extensive distribution)(82.4% in CVB-EEX vs. 56.3% in CVB-SED; P=0.049) and perivascular and/or interstitial fibrosis with extensive distribution (64.7% &amp; 64.7% in CVB-EEX vs. 50% &amp; 31.3% in CVB-SED; P=0.048). The highest scar counts were observed in CVB-EEX, but the mean count (1.9 vs. 1.2; P=0.19) did not significantly differ between the myocarditis groups. In CVB-EEX, the lesions contained denser and more organised collagen bundles. In vivo electrophysiology studies showed similar ventricular arrhythmia inducibility (P&amp;gt;0.20) and arrhythmia burden (P=0.49) in the myocarditis groups, although the longest arrhythmias and highest cumulative burden occurred in CVB-EEX. Conclusion Endurance exercise training during viral myocarditis modulates the longer-term inflammatory process and promotes perivascular and interstitial fibrosis development, potentially enhancing ventricular arrhythmogenicity.

The lncRNA MEG3/miRNA-21/P38MAPK axis inhibits coxsackievirus 3 replication in acute viral myocarditis

Evidence is emerging on the roles of long noncoding RNAs (lncRNAs) as regulatory factors in a variety of viral infection processes, but the mechanisms underlying their functions in coxsackievirus group B type3 (CVB3)-induced acute viral myocarditis have not been explicitly delineated. We previously demonstrated that CVB3 infection decreases miRNA-21 expression; however, lncRNAs that regulate the miRNA-21-dependent CVB3 disease process have yet to be identified. To evaluate lncRNAs upstream of miRNA-21, differentially expressed lncRNAs in CVB3-infected mouse hearts were identified by microarray analysis and lncRNA/miRNA-21 interactions were predicted bioinformatically. MEG3 was identified as a candidate miRNA-21-interacting lncRNA upregulated in CVB3-infected mouse hearts. MEG3 expression was verified to be upregulated in HeLa cells 48 h post CVB3 infection and to act as a competitive endogenous RNA of miRNA-21. MEG3 knockdown resulted in the upregulation of miRNA-21, which inhibited CVB3 replication by attenuating P38-MAPK signaling in vitro and in vivo. Knockdown of MEG3 expression before CVB3 infection inhibited viral replication in mouse hearts and alleviated cardiac injury, which improved survival. Furthermore, the knockdown of CREB5, which was predicted bioinformatically to function upstream of MEG3, was demonstrated to decrease MEG3 expression and CVB3 viral replication. This study identifies the function of the lncRNA MEG3/miRNA-21/P38 MAPK axis in the process of CVB3 replication, for which CREB5 could serve as an upstream modulator.

Acute lymphocytic myocarditis presenting as complete heart block in an adult: a case report

BackgroundComplete heart block (CHB) as a first presentation of acute viral myocarditis is a rare occurrence associated with increased morbidity and mortality. In such cases, an endomyocardial biopsy is recommended to make a clear histological diagnosis aiding to differentiate from other possible conditions such as sarcoiditic myocarditis, giant cell myocarditis, and eosinophilic myocarditis. Insertion of a permanent pacemaker may be considered on a case-to-case basis.Case presentationA previously healthy 21-year-old female presented to the emergency department after having suffered two episodes of syncope on a background of a few days’ history of myalgias, chills, and rigors. Electrocardiogram showed high-grade Mobitz II block with intermittent periods of CHB. A bedside echocardiogram upon admission demonstrated normal biventricular systolic function. Given the patient’s unstable haemodynamic status and lack of obvious reversible causes for the CHB, a permanent dual-chamber pacemaker was inserted urgently. Initial blood investigations indicated an ongoing inflammatory process highlighting the possibility of myocarditis as a cause of the CHB. Therefore, a troponin level was taken and was noted to be elevated confirming the suspicion of myocarditis. The left ventricular ejection fraction (LVEF) decreased over the following days to approximately 20%, clinically resulting in pulmonary oedema and acute shortness of breath. The patient required aggressive intravenous diuresis and anti-heart failure medication. An endomyocardial biopsy (EMB) confirmed the diagnosis of lymphocytic myocarditis. The patient’s condition improved secondary to an improvement in LVEF and resolution of the heart block. A cardiac magnetic resonance (CMR) imaging performed 6 weeks from admission reported an improved LVEF of 51% with no late gadolinium enhancement (LGE). Based on the reassuring CMR findings and the resolution of CHB on follow-up pacemaker checks, it was deemed safe to explant the pacemaker.ConclusionsAcute myocarditis may be complicated with high-degree AV block and cardiogenic shock necessitating close observation in a critical care unit. A permanent pacemaker may provide atrio-ventricular synchrony which helps stabilise the patient’s condition and protect from a prolonged period of heart block. Early myocardial fibrosis on EMB and degree of LGE on CMR are indicators of persistent atrioventricular block. Guideline-directed treatment of heart failure is essential.

Ruxolitinib ameliorated coxsackievirus B3-induced acute viral myocarditis by suppressing the JAK-STAT pathway

BackgroundAccumulating evidences have demonstrated that overwhelming inflammation occurs in the process of Coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVM). No specific therapy is available. More than an effective Janus-associated kinase (JAK) inhibiter, ruxolitinib exerts a critical role in the inflammatory diseases. In this study, we investigated the potential effect of ruxolitinib on CVB3-induced acute viral myocarditis. MethodIn vivo, BALB/c mice were intraperitoneally injected of CVB3, treated of a successive gavage of ruxolitinib for seven days, and subjected to a series of analysis. In vitro, primary bone marrow-derived macrophages (BMDMs) and cardiac fibroblasts were isolated, cultured, treated, harvested and finally detected. ResultsIn vivo, acute viral myocarditis was successfully induced by the injection of CVB3 characterized by impaired cardiac function, predominant infiltration of inflammatory cells, necroptosis of myocardium, great increase of cardiac troponin I (cTnI) and cytokine levels, replication of CVB3, and excessive activation of JAK-STAT pathways. Oral administration of ruxolitinib suppressed the activation of JAK-STAT pathway in a dosage-dependent way, lessened the infiltration of inflammatory cells and necroptosis of myocardium, reduced the levels of cTnI and cytokines, and finally alleviated CVB3-induced cardiac dysfunction, with the reduced production of type I interferon and no promising effect on the replication of CVB3. In vitro, the treatment of ruxolitinib inhibited the activation of JAK-STAT pathway and increase of multiple cytokines mRNA levels in BMDMs and had no protective effect against CVB3 replication in cardiac fibroblasts. ConclusionsOur study suggested that ruxolitinib ameliorated CVB3-induced AVM by inhibiting the activation of JAK-STAT pathway, infiltration of inflammatory cells and necroptosis of myocardium, which may provide a novel strategy for AVM therapy.

Abstract P1049: The Impact Of Endurance Exercise On Longer-term Myocardial Fibrosis Development And Ventricular Arrhythmogenicity In Murine Coxsackievirus B3 Myocarditis

Aims: Diagnostic work-up of athletes often reveals nonischaemic myocardial fibrosis, which is associated with cardiac dysfunction and malignant arrhythmias. Its isolated finding on magnetic resonance imaging is commonly attributed to preceding viral myocarditis. Previous murine studies have shown a negative effect of exercise early in the course of viral myocarditis. In this study, we investigate, for the first time, the impact of endurance exercise on myocardial fibrosis development and arrhythmogenicity in a murine viral myocarditis model. Methods &amp; Results: Eleven-week-old male C57BL/6J mice (n=72) were randomised to 8 weeks of treadmill running (EEX) or without exercise (SED). After 2 weeks, animals received a single injection with either coxsackievirus B3 to induce acute viral myocarditis (CVB) or vehicle as control (PBS). Exercise resulted in a milder clinical disease course, with less weight loss and better preserved running capacity. In addition, mortality was lower in exercising myocarditis mice (11 vs. 27%), however without statistical significance (P=0.23). Exercise during myocarditis increased the occurrence of interstitial fibrosis (limited or extensive distribution) at sacrifice ( i.e. 6 weeks after inoculation)(82.4% in CVB-EEX vs. 56.3% in CVB-SED; P=0.049). Additionally, exercise enhanced development of perivascular and/or interstitial fibrosis with extensive distribution (64.7% &amp; 64.7% in CVB-EEX vs. 50% &amp; 31.3% in CVB-SED; P=0.048). CVB-EEX animals demonstrated more myocardial scars on average, albeit not significantly (1.9 vs. 1.2; P=0.19), with similar scar distribution. Despite manifest fibrotic remodelling, collagen and fibrogenetic genes were not upregulated in the myocarditis groups at the time of sacrifice. In vivo right ventricular programmed electrical stimulation showed comparable ventricular arrhythmia inducibility in the myocarditis groups (P&gt;0.20). The longest arrhythmias and highest cumulative arrhythmia burden occurred in CVB-EEX, however, without reaching statistical significance when compared to CVB-SED (P=0.49). Conclusion: Endurance exercise during viral myocarditis enhances perivascular and interstitial fibrosis development, which may promote ventricular arrhythmogenicity.

Molecular Characteristics of Enterovirus B83 Strain Isolated from a Patient with Acute Viral Myocarditis and Global Transmission Dynamics.

This study determined the global genetic diversity and transmission dynamics of enterovirus B83 (EV-B83) and proposed future disease surveillance directions. Blood samples were collected from a patient with viral myocarditis, and viral isolation was performed. The complete genome sequence of the viral isolate was obtained using Sanger sequencing. A dataset of 15 sequences (from three continents) that had sufficient time signals for Bayesian phylogenetic analysis was set up, and the genetic diversity and transmission dynamics of global EV-B83 were analyzed using bioinformatics methods, including evolutionary dynamics, recombination event analysis, and phylogeographic analysis. Here, we report the complete genome sequence of an EV-B83 strain (S17/YN/CHN/2004) isolated from a patient with acute viral myocarditis in Yunnan Province, China. All 15 EV-B83 strains clustered together in a phylogenetic tree, confirming the classification of these isolates as a single EV type, and the predicted time for the most recent common ancestor appeared in 1998. Recombinant signals were detected in the 5'-untranslated region and 2A-3D coding regions of the S17 genome. The phylogeographic analysis revealed multiple intercontinental transmission routes of EV-B83. This study indicates that EV-B83 is globally distributed. Our findings add to the publicly available EV-B83 genomic sequence data and deepen our understanding of EV-B83 epidemiology.

Impact of Hypocalcemia on the Prognosis of Patients with Acute Myocarditis.

Acute viral myocarditis is a serious complication of viral infectious diseases, including coronavirus disease 2019 (COVID-19). To better understand the pathogenesis of acute viral myocarditis, we retrospectively analyzed the incidence and prognostic significance of hypocalcemia among patients with acute myocarditis, most of whom were considered to have acute viral myocarditis. We retrospectively reviewed the demographic and clinical data of patients with clinically confirmed acute myocarditis treated in our hospital over a 13-year period from 2006 to 2019, including laboratory results, cardiac imaging findings, and clinical outcomes. These data were compared between lower, middle, and higher calcium groups depending on the minimum calcium level measured during hospitalization. Among the 288 patients with acute myocarditis included, the hypocalcemia group (lower calcium group) had poorer clinical and laboratory results, received more medications and device support, and experienced poorer outcomes, including heart failure, arrhythmias, and death. Specifically, the left ventricular ejection fraction was significantly lower, and the length of hospital stay was significantly longer in the hypocalcemia group than in the other two groups. Furthermore, the incidence rates of atrioventricular block, ventricular tachycardia/ventricular fibrillation, cardiogenic shock, and mortality were significantly higher in the hypocalcemia group. Multivariate Cox regression analysis identified hypocalcemia as an independent risk factor for 30-day mortality in patients with acute myocarditis. In conclusion, the clinical evidence provided by the present study indicates that hypocalcemia is a risk factor for poorer outcomes in patients with acute myocarditis that should be considered carefully in the diagnosis and treatment of these patients.

Alterations of the gut microbiome and metabolic profile in CVB3-induced mice acute viral myocarditis

BackgroundAcute viral myocarditis (AVMC) is an inflammatory disease of the myocardium. Evidence indicates that dysbiosis of gut microbiome and related metabolites intimately associated with cardiovascular diseases through the gut-heart axis.MethodsWe built mouse models of AVMC, then applied 16 S rDNA gene sequencing and UPLC-MS/MS metabolomics to explore variations of gut microbiome and disturbances of cardiac metabolic profiles.ResultsCompared with Control group, analysis of gut microbiota showed lower diversity in AVMC, decreased relative abundance of genera mainly belonging to the phyla Bacteroidetes, and increased of phyla Proteobacteria. Metabolomics analysis showed disturbances of cardiac metabolomics, including 62 increased and 84 decreased metabolites, and mainly assigned to lipid, amino acid, carbohydrate and nucleotide metabolism. The steroid hormone biosynthesis, cortisol synthesis and secretion pathway were particularly enriched in AVMC. Among them, such as estrone 3-sulfate, desoxycortone positively correlated with disturbed gut microbiome.ConclusionIn summary, both the structure of the gut microbiome community and the cardiac metabolome were significantly changed in AVMC. Our findings suggest that gut microbiome may participate in the development of AVMC, the mechanism may be related to its role in dysregulated metabolites such as steroid hormone biosynthesis.

Inhibitor of CD147 Suppresses T Cell Activation and Recruitment in CVB3-Induced Acute Viral Myocarditis.

Viral myocarditis (VMC) is a common disease characterized by cardiac inflammation. AC-73, an inhibitor of CD147, disrupts the dimerization of CD147, which participates in the regulation of inflammation. To explore whether AC-73 could alleviate cardiac inflammation induced by CVB3, mice were injected intraperitoneally with AC-73 on the fourth day post-infection (dpi) and sacrificed on the seventh dpi. Pathological changes in the myocardium, T cell activation or differentiation, and expression of cytokines were analyzed using H&E staining, flow cytometry, fluorescence staining and multiplex immunoassay. The results showed that AC-73 alleviated cardiac pathological injury and downregulated the percentage of CD45+CD3+ T cells in the CVB3-infected mice. The administration of AC-73 reduced the percentage of activated CD4+ and CD8+ T cells (CD69+ and/or CD38+) in the spleen, while the percentage of CD4+ T cell subsets in the spleen was not changed in the CVB3-infected mice. In addition, the infiltration of activated T cells (CD69+) and macrophages (F4/80+) in the myocardium also decreased after the AC-73 treatment. The results also showed that AC-73 inhibited the release of many cytokines and chemokines in the plasma of the CVB3-infected mice. In conclusion, AC-73 mitigated CVB3-induced myocarditis by inhibiting the activation of T cells and the recruitment of immune cells to the heart. Thus, CD147 may be a therapeutic target for virus-induced cardiac inflammation.