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.

Foot-and-mouth disease-associated myocarditis is age dependent in suckling calves.

Myocarditis is considered a fatal form of foot-and-mouth disease (FMD) in suckling calves. In the present study, a total of 17 calves under 4 months of age and suspected clinically for FMD were examined for clinical lesions, respiratory rate, heart rate, and heart rhythm. Lesion samples, saliva, nasal swabs, and whole blood were collected from suspected calves and subjected to Sandwich ELISA and reverse transcription multiplex polymerase chain reaction (RT-mPCR) for detection and serotyping of FMD virus (FMDV). The samples were found to be positive for FMDV serotype "O". Myocarditis was suspected in 6 calves based on tachypnoea, tachycardia, and gallop rhythm. Serum aspartate aminotransferase (AST), creatinine kinase myocardial band (CK-MB) and lactate dehydrogenase (LDH), and cardiac troponins (cTnI) were measured. Mean serum AST, cTn-I and LDH were significantly higher (P < 0.001) in < 2 months old FMD-infected calves showing clinical signs suggestive of myocarditis (264.833 ± 4.16; 11.650 ± 0.34 and 1213.33 ± 29.06) than those without myocarditis (< 2 months old: 110.00 ± 0.00, 0.06 ± 0.00, 1050.00 ± 0.00; > 2 months < 4 months: 83.00 ± 3.00, 0.05 ± 0.02, 1159.00 ± 27.63) and healthy control groups (< 2 months old: 67.50 ± 3.10, 0.047 ± 0.01, 1120.00 ± 31.62; > 2 months < 4 months: 72.83 ± 2.09, 0.47 ± 0.00, 1160.00 ± 18.44). However, mean serum CK-MB did not differ significantly amongst the groups. Four calves under 2 months old died and a necropsy revealed the presence of a pathognomic gross lesion of the myocardial form of FMD known as "tigroid heart". Histopathology confirmed myocarditis. This study also reports the relevance of clinical and histopathological findings and biochemical markers in diagnosing FMD-related myocarditis in suckling calves.

Baricitinib protects ICIs-related myocarditis by targeting JAK1/STAT3 to regulate Macrophage polarization.

PURPOSE: The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis. METHODS: To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis. RESULTS: Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings. CONCLUSION: Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related 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.

Rho kinase inhibitor Y-27632 downregulates IL-1ß expression in mice with experimental autoimmune myocarditis.

Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1ß expression in the myocardial tissue of EAM mice. Notably, IL-1ß expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1ß expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

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.

Sacubitril/Valsartan inhibits M1 type macrophages polarization in acute myocarditis by targeting C-type natriuretic peptide.

Studies have shown that Sacubitril/valsartan (Sac/Val) can reduce myocardial inflammation in myocarditis mice, in addition to its the recommended treatment of heart failure. However, the underlying mechanisms of Sac/Val in myocarditis remain unclear. C-type natriuretic peptide (CNP), one of the targeting natriuretic peptides of Sac/Val, was recently reported to exert cardio-protective and anti-inflammatory effects in cardiovascular systems. Here, we focused on circulating levels of CNP in patients with acute myocarditis (AMC) and whether Sac/Val modulates inflammation by targeting CNP in experimental autoimmune myocarditis (EAM) mice as well as LPS-induced RAW 264.7 cells and bone marrow derived macrophages (BMDMs) models. Circulating CNP levels were higher in AMC patients compared to healthy controls, and these levels positively correlated with the elevated inflammatory cytokines IL-6 and monocyte count. In EAM mice, Sac/Val alleviated myocardial inflammation while augmenting circulating CNP levels rather than BNP and ANP, accompanied by reduction in intracardial M1 macrophage infiltration and expression of inflammatory cytokines IL-1ß, TNF-α, and IL-6. Furthermore, Sac/Val inhibited CNP degradation and directly blunted M1 macrophage polarization in LPS-induced RAW 264.7 cells and BMDMs. Mechanistically, the effects might be mediated by the NPR-C/cAMP/JNK/c-Jun signaling pathway apart from NPR-B/cGMP/NF-κB pathway. In conclusion, Sac/Val exerts a protective effect in myocarditis by increasing CNP concentration and inhibiting M1 macrophages polarization.

An Autopsy Case of Fulminant Myocarditis with Massive Left Ventricular Calcification.

Myocardial calcification in myocarditis is rare and may be linked to poor outcomes. We herein report a case of fulminant myocarditis with massive myocardial calcification and its pathological outcomes at autopsy. A 49-year-old man experienced chest pain and was diagnosed with acute myocarditis. His cardiac function did not recover despite mechanical circulatory support in combination with V-A extracorporeal membrane oxygenation and IMPELLA CP®. He eventually developed sepsis and gastrointestinal bleeding and died on day 27. Diffuse myocardial calcification was observed on computed tomography at autopsy. The pathological autopsy depicted that calcification filled every myocardial cell in the left ventricle.

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-1ß/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.

Multisystemic Inflammation Influences Prognosis in Fulminant Lymphocytic Myocarditis.

BACKGROUND: Multisystem inflammatory syndrome (MIS) is a hyperinflammatory shock associated with cardiac dysfunction and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are no reports on using MIS criteria, such as multisystemic inflammation (MSI) in fulminant myocarditis, without SARS-CoV-2 infection. This study investigated the differences in clinical characteristics and course between patients with fulminant lymphocytic myocarditis (FLM) plus MSI and those without MSI.Methods and Results: This multicenter retrospective cohort study included 273 patients with FLM registered in the JROAD-DPC database between April 2014 and March 2017. We evaluated the presence of MSI using criteria modified from previously reported MIS criteria and compared the characteristics and risk of mortality or heart transplantation between FLM patients with MSI and without MSI. Of the 273 patients with FLM, 107 (39%) were diagnosed with MSI. The MSI group was younger (44 vs. 57 years; P<0.0001) and had more females (50% vs. 36%; P=0.0236), a higher incidence of pericardial effusion (58% vs. 40%; P=0.0073), and a lower 90-day mortality rate (19% vs. 33%; P=0.0185) than the non-MSI group. The risk of mortality at 90 days was lower in FLM patients aged <50 years with MSI aged <50 years than in those without MSI (P=0.0463). CONCLUSIONS: These results suggest that MSI may influence the prognosis of FLM, especially in patients aged <50 years.

Macrophage membrane-modified targeted phase-change nanoparticles for multimodal imaging of experimental autoimmune myocarditis.

Myocarditis is an important public health issue due to the high prevalence of sudden death in adolescents and young adults. Nevertheless, the early identification of myocarditis remains a serious problem for clinicians. There is no single non-invasive method to diagnose myocarditis in the currently available clinical guidelines and consensus. Molecular imaging is an effective approach for accurate diagnosis. Poly(lactic acid-glycolic acid) (PLGA) is considered to be the preferred carrier for molecular imaging because of its biosafety and modifiability. Macrophage membrane-modified biomimetic nanoprobes (MM-NPs) possess low immunogenicity and inflammation-directed chemotaxis capabilities and are repeatedly chosen as materials for targeted diagnosis and treatment of inflammatory diseases. In this study, experimental autoimmune myocarditis (EAM) was used as an animal model of inflammation. Previous studies have confirmed that this model is similar to pathological injury caused by acute myocarditis in humans. In multimodal imaging (US/PA/MRI), a phase-change material (PFH) and superparamagnetic iron oxide (SPIO) are used as imaging substances. Early identification of myocardial inflammatory sites was achieved by the tail vein injection of MM/NPs loaded with PFH and SPIO. This probe is expected to be a powerful tool for clinicians to diagnose myocarditis.

CD73/adenosine axis exerts cardioprotection against hypobaric hypoxia-induced metabolic shift and myocarditis in a sex-dependent manner.

BACKGROUND: Clinical and experimental studies have shown that the myocardial inflammatory response during pathological events varies between males and females. However, the cellular and molecular mechanisms of these sex differences remain elusive. CD73/adenosine axis has been linked to anti-inflammatory responses, but its sex-specific cardioprotective role is unclear. The present study aimed to investigate whether the CD73/adenosine axis elicits sex-dependent cardioprotection during metabolic changes and myocarditis induced by hypobaric hypoxia. METHODS: For 7 days, male and female mice received daily injections of the CD73 inhibitor adenosine 5'- (α, ß-methylene) diphosphate (APCP) 10 mg/kg/day while they were kept under normobaric normoxic and hypobaric hypoxic conditions. We evaluated the effects of hypobaric hypoxia on the CD73/adenosine axis, myocardial hypertrophy, and cardiac electrical activity and function. In addition, metabolic homeostasis and immunoregulation were investigated to clarify the sex-dependent cardioprotection of the CD73/adenosine axis. RESULTS: Hypobaric hypoxia-induced cardiac dysfunction and adverse remodeling were more pronounced in male mice. Also, male mice had hyperactivity of the CD73/adenosine axis, which aggravated myocarditis and metabolic shift compared to female mice. In addition, CD73 inhibition triggered prostatic acid phosphatase ectonucleotidase enzymatic activity to sustain adenosine overproduction in male mice but not in female mice. Moreover, dual inhibition prostatic acid phosphatase and CD73 enzymatic activities in male mice moderated adenosine content, alleviating glycolytic shift and proinflammatory response. CONCLUSION: The CD73/adenosine axis confers a sex-dependent cardioprotection. In addition, extracellular adenosine production in the hearts of male mice is influenced by prostatic acid phosphatase and tissue nonspecific alkaline phosphatase.

Clinical presentation of cardiac symptoms following treatment with tumor-infiltrating lymphocytes: diagnostic challenges and lessons learned.

BACKGROUND: Treatment with tumor-infiltrating lymphocytes (TILs) is rapidly evolving for patients with solid tumors. Following metastasectomy, TILs (autologous, intratumoral CD4+ and CD8+ T cells with the potential to recognize tumor-associated antigens) are isolated and non-specifically expanded ex vivo in the presence of interleukin-2 (IL-2). Subsequently, the TILs are adoptively transferred to the patients after a preconditioning non-myeloablative, lymphodepleting chemotherapy regimen, followed by administration of high-dose (HD) IL-2. Here, we provide an overview of known cardiac risks associated with TIL treatment and report on seven patients presenting with cardiac symptoms, all with different clinical course and diagnostic findings during treatment with lymphodepleting chemotherapy, TIL, and HD IL-2, and propose a set of clinical recommendations for diagnosis and management of these symptoms. PATIENTS AND METHODS: This single-center, retrospective study included selected patients who experienced TIL treatment-related cardiac symptoms at the Netherlands Cancer Institute. In addition, 12 patients were included who received TIL in the clinical trial setting without experiencing cardiac symptoms, from whom complete cardiac biomarker follow-up during treatment was available [creatine kinase (CK), CK-myocardial band, troponin T and N-terminal pro-B-type natriuretic peptide]. RESULTS: Within our TIL patient population, seven illustrative cases were chosen from the patients who developed symptoms suspected of severe cardiotoxicity: myocarditis, myocardial infarction, peri-myocarditis, atrial fibrillation, acute dyspnea, and two cases of heart failure. An overview of their clinical course, diagnostics carried out, and management of the symptoms is provided. CONCLUSIONS: In the absence of evidence-based guidelines for the treatment of TIL therapy-associated cardiotoxicity, we provided an overview of literature, case descriptions, and recommendations for diagnosis and management to help physicians in daily practice, as the number of patients qualifying for TIL treatment is rapidly increasing.

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.

Diagnostic challenges and forensic implications in a case of infantile fatal myocarditis.

We present the case of a 23-month-old child who died less than 24 h after the onset of cardiac symptoms, despite being admitted to the hospital 72 h earlier. Autopsy revealed no significant macroscopic changes, and histologic examination revealed focal lymphocytic myocarditis with myocyte disruption, diffuse alveolar damage in the exudative phase, and generalized lymphocytic immune activation in other organs. Ante-mortem and post-mortem microbiological exams did not clearly prove a causative role of infectious agents. The peculiarity of this case was characterized by the contrast between the severe clinical features and the mild cardiac histological findings. This discrepancy, coupled with the suspicion of a viral causative role based on both ante-mortem and post-mortem microbiological examinations, presented significant challenges in reaching an etiological diagnosis. This case also confirms that the diagnosis of myocarditis in children cannot be made solely on the basis of histological cut-offs or microbiological results. Using abductive reasoning, various diagnostic hypotheses were formulated and evaluated to arrive at the final diagnosis of fatal myocarditis of viral or post-viral origin. Data from post-mortem examination are often the only source of information that is available to the experts, especially in cases of sudden infant death syndrome. In such cases, the forensic pathologists should accurately evaluate findings that may appear to indicate a different etiology, and, in the absence of clinical or radiological data, interpret post-mortem data in a logically correct manner. The autopsy is the first essential step to evaluate the cause of death and must be integrated with the results of ante- and post-mortem diagnostic tests in a holistic approach, which is crucial to allow forensic pathologists to provide an appropriate and relevant opinion.

Diagnosis and management of primary heart involvement in systemic sclerosis.

PURPOSE OF REVIEW: In systemic sclerosis (SSc) primary heart involvement (pHI) is frequent, even though often unrecognized due to its occult nature and to the lack of a specific diagnostic algorithm. The purpose of this review is to report the state of the art of the evidence in the current literature, as well as the overall diagnostic modalities and therapeutic strategies for primary heart involvement in SSc. RECENT FINDINGS: SSc-pHI is defined by the presence of cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications; it may be sub-clinical and must be confirmed through diagnostic investigations. Novel electrocardiographic analysis and cardiac magnetic resonance (CMR) with mapping techniques have been recently proposed, showing a great utility in the early identification of SSc-pHI and in the noninvasive characterization of myocardial tissue. Immunosuppressive therapy emerged as fundamental to curb myocardial inflammation, and recent preclinical and clinical data support the role of antifibrotic drugs to treat SSc-pHI. SUMMARY: our review will help clinicians to properly integrate the available diagnostic modalities for the assessment of SSc-pHI. The ultimate goal is to propose a feasible diagnostic algorithm for the early identification of patients with SSc-pHI, and a schematic therapeutic approach to manage SSc-pHI.