Genome-wide association study of BNT162b2 vaccine-related myocarditis identifies potential predisposing functional areas in Hong Kong adolescents.

Vaccine-related myocarditis associated with the BNT162b2 vaccine is a rare complication, with a higher risk observed in male adolescents. However, the contribution of genetic factors to this condition remains uncertain. In this study, we conducted a comprehensive genetic association analysis in a cohort of 43 Hong Kong Chinese adolescents who were diagnosed with myocarditis shortly after receiving the BNT162b2 mRNA COVID-19 vaccine. A comparison of whole-genome sequencing data was performed between the confirmed myocarditis cases and a control group of 481 healthy individuals. To narrow down potential genomic regions of interest, we employed a novel clustering approach called ClusterAnalyzer, which prioritised 2,182 genomic regions overlapping with 1,499 genes for further investigation. Our pathway analysis revealed significant enrichment of these genes in functions related to cardiac conduction, ion channel activity, plasma membrane adhesion, and axonogenesis. These findings suggest a potential genetic predisposition in these specific functional areas that may contribute to the observed side effect of the vaccine. Nevertheless, further validation through larger-scale studies is imperative to confirm these findings. Given the increasing prominence of mRNA vaccines as a promising strategy for disease prevention and treatment, understanding the genetic factors associated with vaccine-related myocarditis assumes paramount importance. Our study provides valuable insights that significantly advance our understanding in this regard and serve as a valuable foundation for future research endeavours in this field.

Cardiomyopathy in First-Degree Relatives of Patients Presenting With Acute Myocarditis: Prevalence and Prognostic Significance.

BACKGROUND: Acute myocarditis has been genetically linked to dilated cardiomyopathy (DCM), but the clinical significance remains uncertain. We investigated the prevalence and long-term prognosis of DCM and heart failure (HF) among unselected patients hospitalized with acute myocarditis and their first-degree relatives compared with an age- and sex-matched cohort. METHODS: This was an observational study utilizing the Danish nationwide registries, where all patients with a first-time myocarditis diagnosis from 1995 to 2018 were identified and matched (on birth year and sex) with 10 controls from the general population. RESULTS: Totally 3176 patients with acute myocarditis and 31 760 controls were included (median age, 49.8 [Q1-Q3, 32.5-70.2] years; 35.6% female). At baseline, patients with myocarditis had a higher prevalence of DCM (7 [0.2%] versus 8 [0.0%]) and HF (336 [10.6%] versus 695 [2.2%]) than controls; P<0.0001 for both. Patients with myocarditis more often had siblings with DCM (12 [0.4%] versus 17 [0.05%]) or HF (36 [1.1%] versus 89 [0.3%]); P<0.0001, odds ratios 7.09 (3.38-14.85) and 2.92 (1.25-6.80), respectively, whereas parental DCM and HF did not differ among patients with myocarditis and controls. Patients with myocarditis had greater 20-year incidence of DCM, HF, and all-cause mortality (0.5% [0.3%-0.9%], 15% [13%-17%], and 47% [44%-50%]) compared with controls (0.06% [0.03%-0.11%], 6.8% [6.4%-7.3%], and 34% [33%-35%]; P<0.0001). Having a first-degree relative with DCM or HF was associated with increased long-term mortality among the patients with myocarditis (hazard ratio, 1.40 [1.11-1.77]) but not among the controls (hazard ratio, 0.90 [0.81-1.01]; Pdifference=0.0008). CONCLUSIONS: Acute myocarditis aggregates with DCM within families, where it carries a worsened prognosis. A differential association between parents and siblings (with sibling preponderance) could suggest that additional environmental factors are important for myocarditis development even in predisposed individuals.

Major Group-B Enterovirus populations deleted in the noncoding 5' region of genomic RNA modulate activation of the type I interferon pathway in cardiomyocytes and induce myocarditis.

Major 5'-terminally deleted (5'TD) RNA forms of group-B coxsackievirus (CVB-5'TD) has been associated with myocarditis in both mice and humans. Although it is known that interferon-ß (IFN-ß) signaling is critical for an efficient innate immune response against CVB-induced myocarditis, the link between CVB-5'TD RNA forms and type I IFN signaling in cardiomyocytes remains to be explored. In a mouse model of CVB3/28-induced myocarditis, major early-emerging forms of CVB-5'TD RNA have been characterized as replicative viral populations that impair IFN-ß production in the heart. Synthetic CVB3/28 RNA forms mimicking each of these major 5'TD virus populations were transfected in mice and have been shown to modulate innate immune responses in the heart and to induce myocarditis in mice. Remarkably, transfection of synthetic viral RNA with deletions in the secondary structures of the 5'-terminal CVB3 RNA domain I, modifying stem-loops "b", "c" or "d", were found to impair IFN-ß production in human cardiomyocytes. In addition, the activation of innate immune response by Poly(I:C), was found to restore IFN-ß production and to reduce the burden of CVB-5'TD RNA-forms in cardiac tissues, thereby reducing the mortality rate of infected mice. Overall, our results indicate that major early-emerging CVB3 populations deleted in the domain I of genomic RNA, in the 5' noncoding region, modulate the activation of the type I IFN pathway in cardiomyocytes and induce myocarditis in mice. These findings shed new light on the role of replicative CVB-5'TD RNA forms as key pathophysiological factors in CVB-induced human myocarditis.

Viral myocarditis in combination with genetic cardiomyopathy as a cause of sudden death. An autopsy series.

Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in combination, are the most frequent, but underestimated, causes of SCD. Molecular autopsy is essential for prevention. Several studies have shown an association between genetic cardiomyopathies and viral myocarditis, which is probably underestimated due to insufficient post-mortem investigations. We report on four autopsy cases illustrating the pathogenesis of these combined pathologies. In two cases, a genetic hypertrophic cardiomyopathy was diagnosed in combination with Herpes Virus Type 6 (HHV6) and/or Parvovirus-B19 (PVB19) in the heart. In the third case, autopsy revealed a dilated cardiomyopathy and virological analyses revealed acute myocarditis caused by three viruses: PVB19, HHV6 and Epstein-Barr virus. Genetic analyses revealed a mutation in the gene coding for desmin. The fourth case illustrated a channelopathy and a PVB19/HHV6 coinfection. Our four cases illustrate the highly probable deleterious role of cardiotropic viruses in the occurrence of SCD in subjects with genetic cardiomyopathies. We discuss the pathogenetic link between viral myocarditis and genetic cardiomyopathy. Molecular autopsy is essential in prevention of these SCD, and a close collaboration between cardiologists, pathologists, microbiologists and geneticians is mandatory.

RNA m5C methylation modification: a potential therapeutic target for SARS-CoV-2-associated myocarditis.

The Corona Virus Disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has quickly spread worldwide and resulted in significant morbidity and mortality. Although most infections are mild, some patients can also develop severe and fatal myocarditis. In eukaryotic RNAs, 5-methylcytosine (m5C) is a common kind of post-transcriptional modification, which is involved in regulating various biological processes (such as RNA export, translation, and stability maintenance). With the rapid development of m5C modification detection technology, studies related to viral m5C modification are ever-increasing. These studies have revealed that m5C modification plays an important role in various stages of viral replication, including transcription and translation. According to recent studies, m5C methylation modification can regulate SARS-CoV-2 infection by modulating innate immune signaling pathways. However, the specific role of m5C modification in SARS-CoV-2-induced myocarditis remains unclear. Therefore, this review aims to provide insights into the molecular mechanisms of m5C methylation in SARS-CoV-2 infection. Moreover, the regulatory role of NSUN2 in viral infection and host innate immune response was also highlighted. This review may provide new directions for developing therapeutic strategies for SARS-CoV-2-associated myocarditis.

NASCI case of the month: desmoplakin cardiomyopathy masquerading as acute myocarditis.

We present a case of a young patient with chest pain. Labs and cardiac imaging were suspicious for acute myocarditis. Genetic testing revealed a diagnosis of desmoplakin cardiomyopathy. Desmoplakin cardiomyopathy may be considered in patients with recurrent acute myocarditis or a family history of cardiac disease to avoid the potential for misdiagnosis.

Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. OBJECTIVES: The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis. METHODS: For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children). CONCLUSIONS: Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.

Mapping the interplay of immunoproteasome and autophagy in different heart failure phenotypes.

Proper protein degradation is required for cellular protein homeostasis and organ function. Particularly, in post-mitotic cells, such as cardiomyocytes, unbalanced proteolysis due to inflammatory stimuli and oxidative stress contributes to organ dysfunction. To ensure appropriate protein turnover, eukaryotic cells exert two main degradation systems, the ubiquitin-proteasome-system and the autophagy-lysosome-pathway. It has been shown that proteasome activity affects the development of cardiac dysfunction differently, depending on the type of heart failure. Studies analyzing the inducible subtype of the proteasome, the immunoproteasome (i20S), demonstrated that the i20S plays a double role in diseased hearts. While i20S subunits are increased in cardiac hypertrophy, atrial fibrillation and partly in myocarditis, the opposite applies to diabetic cardiomyopathy and ischemia/reperfusion injury. In addition, the i20S appears to play a role in autophagy modulation depending on heart failure phenotype. This review summarizes the current literature on the i20S in different heart failure phenotypes, emphasizing the two faces of i20S in injured hearts. A selection of established i20S inhibitors is introduced and signaling pathways linking the i20S to autophagy are highlighted. Mapping the interplay of the i20S and autophagy in different types of heart failure offers potential approaches for developing treatment strategies against heart failure.

miR-29b-3p regulates cardiomyocytes pyroptosis in CVB3-induced myocarditis through targeting DNMT3A.

BACKGROUND: Viral myocarditis (VMC) is a disease resulting from viral infection, which manifests as inflammation of myocardial cells. Until now, the treatment of VMC is still a great challenge for clinicians. Increasing studies indicate the participation of miR-29b-3p in various diseases. According to the transcriptome sequencing analysis, miR-29b-3p was markedly upregulated in the viral myocarditis model. The purpose of this study was to investigate the role of miR-29b-3p in the progression of VMC. METHODS: We used CVB3 to induce primary cardiomyocytes and mice to establish a model of viral myocarditis. The purity of primary cardiomyocytes was identified by immunofluorescence. The cardiac function of mice was detected by Vevo770 imaging system. The area of inflammatory infiltration in heart tissue was shown by hematoxylin and eosin (H&E) staining. The expression of miR-29b-3p and DNMT3A was detected by quantitative real time polymerase chain reaction (qRT-PCR). The expression of a series of pyroptosis-related proteins was detected by western blot. The role of miR-29b-3p/DNMT3A in CVB3-induced pyroptosis of cardiomyocytes was studied in this research. RESULTS: Our data showed that the expression of miR-29b-3p was upregulated in CVB3-induced cardiomyocytes and heart tissues in mice. To explore the function of miR-29b-3p in CVB3-induced VMC, we conducted in vivo experiments by knocking down the expression of miR-29b-3p using antagomir. We then assessed the effects on mice body weight, histopathology changes, myocardial function, and cell pyroptosis in heart tissues. Additionally, we performed gain/loss-of-function experiments in vitro to measure the levels of pyroptosis in primary cardiomyocytes. Through bioinformatic analysis, we identified DNA methyltransferases 3A (DNMT3A) as a potential target gene of miR-29b-3p. Furthermore, we found that the expression of DNMT3A can be modulated by miR-29b-3p during CVB3 infection. CONCLUSIONS: Our results demonstrate a correlation between the expression of DNMT3A and CVB3-induced pyroptosis in cardiomyocytes. These findings unveil a previously unidentified mechanism by which CVB3 induces cardiac injury through the regulation of miR-29b-3p/DNMT3A-mediated pyroptosis.

Fulminant myocarditis induced by SARS-CoV-2 infection without severe lung involvement: insights into COVID-19 pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often leads to pulmonary complications. Cardiovascular sequelae, including myocarditis and heart failure, have also been reported. Here, the study presents two fulminant myocarditis cases infected by SARS-CoV-2 exhibiting remarkable elevation of cardiac biomarkers without significant pulmonary injury, as determined by imaging examinations. Immunohistochemical staining reveals the viral antigen within cardiomyocytes, indicating that SARS-CoV-2 could directly infect the myocardium. The full viral genomes from respiratory, anal, and myocardial specimens are obtained via next-generation sequencing. Phylogenetic analyses of the whole genome and spike gene indicate that viruses in the myocardium/pericardial effusion and anal swabs are closely related and cluster together yet diverge from those in the respiratory samples. In addition, unique mutations are found in the anal/myocardial strains compared to the respiratory strains, suggesting tissue-specific virus mutation and adaptation. These findings indicate genetically distinct SARS-CoV-2 variants have infiltrated and disseminated within myocardial tissues, independent of pulmonary injury, and point to different infection routes between the myocardium and respiratory tract, with myocardial infections potentially arising from intestinal infection. These findings highlight the potential for systemic SARS-CoV-2 infection and the importance of a thorough multi-organ assessment in patients for a comprehensive understanding of the pathogenesis of COVID-19.

Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Blood transcriptome analysis uncovered COVID-19-myocarditis crosstalk.

BACKGROUND: The condition of COVID-19-related myocarditis has emerged as a prominent contributor to COVID-19 mortality. As the epidemic persists, its incidence continues to rise. Despite ongoing efforts, the elucidation of COVID-19-related myocarditis underlying molecular mechanisms still requires further investigation. METHODS: Hub genes for COVID-19-related myocarditis were screened by integrating gene expression profile analysis via differential expression in COVID-19 (GSE196822) and myocarditis (GSE148153 and GSE147517). After verification with independent datasets (GSE211979, GSE167028, GSE178491 and GSE215865), the hub genes were studied using a range of systems-biology approaches, such as ceRNA, TF-mRNA networks and PPI networks, as well as gene ontology, pathway enrichment, immune infiltration analysis and drug target identification. RESULTS: TBKBP1 and ERGIC1 were identified as COVID-19-related myocarditis hub genes via integrated bioinformatics analysis. In addition, receiver operating characteristic curves constructed based on the expression levels of TBKBP1 and ERGIC1 could effectively distinguish healthy control individuals from patients with COVID-19. Functional enrichment analysis suggested several enriched biological pathways related to inflammation and immune response. Immune cell changes correlated with TBKBP1 and ERGIC1 levels in patients with COVID-19 or patients with COVID-19 and myocarditis. Tamibarotene, methotrexate and theophylline were identified as a potential drug targeting TBKBP1 and ERGIC1. CONCLUSION: TBKBP1 and ERGIC1 were identified as crucial genes in the development of COVID-19-related myocarditis and have demonstrated a strong association with innate antiviral immunity. The present work may be helpful for further investigation of the molecular mechanisms and new therapeutic drug targets correlated with myocarditis in COVID-19.

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

AIM: To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). MATERIALS & METHODS: Peripheral 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. RESULTS: P < 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 ß-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. CONCLUSIONS: Hsa-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.

Role of genetics in inflammatory cardiomyopathy.

Traditional cardiomyopathy paradigms segregate inflammatory etiologies from those caused by genetic variants. An identified or presumed trigger is implicated in acute myocarditis or chronic inflammatory cardiomyopathy but growing evidence suggests a significant proportion of patients have an underlying cardiomyopathy-associated genetic variant often even when a clear inflammatory trigger is identified. Recognizing a possible genetic contribution to inflammatory cardiomyopathy may have major downstream implications for both the patient and family. The presenting features of myocarditis (i.e. chest pain, arrhythmia, and/or heart failure) may provide insight into diagnostic considerations. One example is isolated cardiac sarcoidosis, a distinct inflammatory cardiomyopathy that carries diagnostic challenges and clinical overlap; genetic testing has increasingly reclassified cases of isolated cardiac sarcoidosis as genetic cardiomyopathy, notably altering management. On the other side, inflammatory presentations of genetic cardiomyopathies are likewise underappreciated and a growing area of investigation. Inflammation plays an important role in the pathogenesis of several familial cardiomyopathies, especially arrhythmogenic phenotypes. Given these clinical scenarios, and the implications on clinical decision making such as initiation of immunosuppression, sudden cardiac death prevention, and family screening, it is important to recognize when genetics may be playing a role.

HLA binding-groove motifs are associated with myocarditis induction after Pfizer-BioNTech BNT162b2 vaccination.

BACKGROUND AND AIMS: We found a higher incidence of myocarditis in young males who had received at least two Pfizer-BioNTech BNT162b2 vaccinations. The human leukocyte antigens (HLA) are known to play an important role in infectious and autoinflammatory diseases. We hypothesized that certain HLA alleles might be associated with vaccination-induced myocarditis. METHODS: HLA typing was performed using next-generation sequencing technology with the Illumina Iseq100 platform. HLA class I and II loci were genotyped in 29 patients with post-vaccination myocarditis and compared with HLA data from 300 healthy controls. RESULTS: We demonstrate that the DRB1*14:01, DRB1*15:03 alleles and the motifs in HLA-A - Leu62 and Gln63, which are part of binding pocket B and HLA-DR Tyr47, His60, Arg70 and Glu74, which are part of binding pockets P4, P7 and P9, were significantly associated with disease susceptibility. CONCLUSIONS: Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves may affect the presentation of peptides derived from the Pfizer-BioNTech BNT162b2 vaccination to T cells and induce an inflammatory process that results in myocarditis.

Identification of the communal pathogenesis and immune landscape between viral myocarditis and dilated cardiomyopathy.

AIMS: Studies have confirmed that viral myocarditis (VMC) is one of the risk factors for dilated cardiomyopathy (DCM). The molecular mechanisms underlying the progression from VMC to DCM remain unclear and require further investigation. METHODS AND RESULTS: The mRNA microarray datasets GSE57338 (DCM) and GSE1145 (VMC) were obtained from the Gene Expression Omnibus database. The candidate key genes were further screened using weighted correlation network analysis (WGCNA), protein-protein interaction and external dataset validation, and the correlation between the candidate key genes and immune cells and the signalling pathways of the candidate key genes were observed by enrichment analysis and immune infiltration analysis. The expression of key genes was validated in the external dataset GSE35182. The crosstalk genes between DCM and VMC were mainly enriched in 'transcriptional misregulation in cancer', 'FoxO signalling pathway', 'AGE-RAGE signalling pathway in diabetic complications', 'thyroid hormone signalling pathway', 'AMPK signalling pathway', and other signalling pathways. The immune infiltration analysis indicated that VMC was mainly associated with resting dendritic cells and M0 macrophages, while DCM was mainly associated with monocytes, M0 macrophages, CD8+ T cells, resting CD4 memory T cells, naive CD4+ T cells, and resting mast cells. In DCM-related dataset GSE57338 and VMC-related dataset GSE1145, a total of 18 candidate key genes were differentially expressed. BLC6, FOXO1, and UBE2M were identified as the key genes that lead to the progression from VMC to DCM by GSE35182. CONCLUSIONS: Three key genes (BLC6, FOXO1, and UBE2M) were identified and provided new insights into the diagnosis and treatment of VMC with DCM.

Identification and functional analysis of circulating small extracellular vesicle lncRNA signatures in children with fulminant myocarditis.

Fulminant myocarditis (FM) is the most serious type of myocarditis. However, the molecular mechanism underlying the pathogenesis of FM has not been fully elucidated. Small extracellular vesicles (sEVs) play important roles in many diseases, but any potential role in paediatric FM has not been reported. Here, the differential signatures of lncRNAs in plasma sEVs were studied in FM children and healthy children using transcriptome sequencing followed by functional analysis. Then immune-related lncRNAs were screened to study their role in immune mechanisms, the levels and clinical relevance of core immune-related lncRNAs were verified by qRT-PCR in a large sample size. Sixty-eight lncRNAs had increased levels of plasma sEVs in children with FM and 11 had decreased levels. Functional analysis showed that the sEVs-lncRNAs with different levels were mainly related to immunity, apoptosis and protein efflux. Seventeen core immune-related sEVs-lncRNAs were screened, functional enrichment analysis showed that these lncRNAs were closely related to immune activation, immune cell migration and cytokine pathway signal transduction. The results of the study show that sEVs-lncRNAs may play an important role in the pathogenesis of fulminant myocarditis in children, especially in the mechanism of immune regulation.