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This article discusses a study conducted on pediatric patients with myocarditis, a condition that ranges from asymptomatic to severe heart failure. The study aimed to evaluate the occurrence and severity of arrhythmias in these patients. The results showed that arrhythmias were common in pediatric myocarditis patients, regardless of age and sex. Patients with arrhythmias had a lower left ventricular ejection fraction and were more likely to experience major cardiac events. The study emphasizes the importance of rhythm monitoring in patients with myocarditis. [Extracted from the article]

Myocarditis is a major cause of severe heart failure in pediatric patients. In some patients, this may lead to the need of mechanical circulatory support (MCS) or heart transplantation. MYKKE is a multicenter prospective registry of pediatric patients with suspected myocarditis. We aimed to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation within the MYKKE registry in order to get a better understanding of this critically ill subgroup. Between September 2013 and October 2022, patients within the MYKKE registry were analyzed. Requirement of MCS including Extracorporeal Membrane Oxygenation (ECMO) and Ventricular Assist Device (VAD), heart transplantation and/or occurrence of death defined a sub-cohort of special interest. A total amount of 649 patients was enrolled by 26 medical centers. Median age was 14.3 years, 67% were male. Thirteen percent within this population (n=84/649) received MCS (3 % ECMO; 6 % VAD; 4 % both, ECMO and VAD). Thirty-nine patients (6 %) needed a heart transplant and 33 patients (5 %) died. The subgroup of MCS, heart transplant and dead patients (17 %, n=108) presented with a young median age of 2 years, 55 % were male. Left ventricular dysfunction at initial admission was represented by a median LVEF of 21 %. Out of 63 patients requiring VAD, 17 could be successfully weaned (27 %) after a median time of 97 days. Thirty-one patients were MCS-bridged to transplantation (37 %, n=31/84). Within our subgroup 79 % of patients (n = 85/108) underwent endomyocardial biopsy and in 64 cases diagnosis of myocarditis was confirmed (28 % acute myocarditis, 64 % chronic/healing myocarditis, 8 % healed), further diagnoses included dilated cardiomyopathy (n=9) or others (n=12). Myocarditis represents a life-threatening condition in pediatric patients. Especially young patients are affected by a severe clinical course, which requires MCS and transplantation due to end-stage heart failure. Different underlying pathomechanisms may contribute in a possibly age-dependent manner as genetic predispositions and/or immunological factors. [ABSTRACT FROM AUTHOR]

Background/Objectives: Risk assessment in pediatric myocarditis is challenging, particularly when left ventricular ejection fraction (LVEF) is preserved. This study aimed to evaluate LV myocardial deformation using speckle-tracking echocardiography (STE)-derived longitudinal +strain (LS) and assessed its diagnostic and prognostic value in children with myocarditis. Methods: Retrospective STE-derived layer-specific LV LS analysis was performed on echocardiograms from patients within the multicenter, prospective registry for pediatric myocarditis "MYKKE". Age- and sex-adjusted logistic regression and ROC analysis identified predictors of cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, atrioventricular blockage III°) and major adverse cardiac events (MACE: need for mechanical circulatory support (MCS), cardiac transplantation, and/or cardiac death). Results: Echocardiograms from 175 patients (median age 15 years, IQR 7.9-16.5 years; 70% male) across 13 centers were included. Cardiac arrhythmias occurred in 36 patients (21%), and MACE in 28 patients (16%). Impaired LV LS strongly correlated with reduced LVEF (r > 0.8). Impaired layer-specific LV LS, reduced LVEF, LV dilatation, and increased BSA-indexed LV mass, were associated with the occurrence of MACE and cardiac arrhythmias. In patients with preserved LVEF, LV LS alone predicted cardiac arrhythmias ( p < 0.001), with optimal cutoff values of -18.0% for endocardial LV LS (sensitivity 0.69, specificity 0.94) and -17.0% for midmyocardial LV LS (sensitivity 0.81, specificity 0.75). Conclusions: In pediatric myocarditis, STE-derived LV LS is not only a valuable tool for assessing systolic myocardial dysfunction and predicting MACE but also identifies patients at risk for cardiac arrhythmias, even in the context of preserved LVEF.

Background: Since the onset of widespread COVID-19 vaccination, increased incidence of COVID-19 vaccine-associated myocarditis (VA-myocarditis) has been noted, particularly in male adolescents., Methods: Patients <18 years with suspected myocarditis following COVID-19 vaccination within 21 days were enrolled in the PedMYCVAC cohort, a substudy within the prospective multicenter registry for pediatric myocarditis "MYKKE." Clinical data at initial admission, 3- and 9-months follow-up were monitored and compared to pediatric patients with confirmed non-vaccine-associated myocarditis (NVA-myocarditis) adjusting for various baseline characteristics., Results: From July 2021 to December 2022, 56 patients with VA-myocarditis across 15 centers were enrolled (median age 16.3 years, 91% male). Initially, 11 patients (20%) had mildly reduced left ventricular ejection fraction (LVEF; 45%-54%). No incidents of severe heart failure, transplantation or death were observed. Of 49 patients at 3-months follow-up (median (IQR) 94 (63-118) days), residual symptoms were registered in 14 patients (29%), most commonly atypical intermittent chest pain and fatigue. Diagnostic abnormalities remained in 23 patients (47%). Of 21 patients at 9-months follow-up (259 (218-319) days), all were free of symptoms and diagnostic abnormalities remained in 9 patients (43%). These residuals were mostly residual late gadolinium enhancement in magnetic resonance imaging. Patients with NVA-myocarditis (n=108) more often had symptoms of heart failure (P = .003), arrhythmias (P = .031), left ventricular dilatation (P = .045), lower LVEF (P < .001) and major cardiac adverse events (P = .102)., Conclusions: Course of COVID-19 vaccine-associated myocarditis in pediatric patients seems to be mild and differs from non-vaccine-associated myocarditis. Due to a considerable number of residual symptoms and diagnostic abnormalities at follow-up, further studies are needed to define its long-term implications., Competing Interests: Disclosures None reported., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Toscana virus is a major cause of arboviral disease in humans in the Mediterranean basin during summer. However, early virus-host cell interactions and entry mechanisms remain poorly characterized. Investigating iPSC-derived human neurons and cell lines, we found that virus binding to the cell surface was specific, and 50% of bound virions were endocytosed within 10 min. Virions entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomal compartments. Penetration required intact late endosomes and occurred within 30 min following internalization. Virus entry relied on vacuolar acidification, with an optimal pH for viral membrane fusion at pH 5.5. The pH threshold increased to 5.8 with longer pre-exposure of virions to the slightly acidic pH in early endosomes. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold. Overall, our study establishes Toscana virus as a late-penetrating virus and reveals an atypical use of vacuolar acidity by this virus to enter host cells., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Koch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Cold-inducible RNA-binding protein (CIRBP) has been shown to be involved not only in cooling-induced cellular protection but also as a mediator of sterile inflammation, a critical mechanism of the innate immune response in ischemia/reperfusion (I/R) injury. The role of microglia and its activation in cerebral I/R injury warrants further investigation as both detrimental and regenerative properties have been described. Therefore, we investigated the effects of cooling, specifically viability, activation, and release of damage associated molecular patterns (DAMPs) on oxygen glucose deprivation/reperfusion- (OGD/R-) induced injury in murine BV-2 microglial cells., Methods: Murine BV-2 microglial cells were exposed to 2 to 6 h OGD (0.2% O 2 in glucose- and serum-free medium) followed by up to 19 h of reperfusion, simulated by restoration of oxygen (21% O 2 ) and nutrients. Cells were maintained at either normothermia (37°C) or cooled to 33.5°C, 1 h after experimental start. Cultured supernatants were harvested after exposure to OGD for analysis of DAMP secretions, including high-mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), and CIRBP, and cytotoxicity was assessed by lactate dehydrogenase releases after exposure to OGD and reperfusion. Intracellular cold-shock proteins CIRBP and RNA-binding motif 3 (RBM3) as well as caspases 9, 8, and 3 were also analyzed via Western blot analysis. Furthermore, inducible nitric oxide synthase (iNOS), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor- α (TNF- α ), interleukin-6 (IL-6), interleukin-1 β (IL-1 β ), interleukin-1 α (IL-1 α ), monocyte chemotactic protein 1 (MCP-1), transforming growth factor β (TGF β ), CIRBP, and RBM3 gene expressions were assessed via reverse transcription polymerase chain reaction, and TNF- α , IL-6, and IL-1 β releases into the cultured supernatants were assessed via enzyme-linked immunosorbent assays (ELISA)., Results: Prolonged exposure to OGD resulted in increased BV-2 necrotic cell death, which was attenuated by cooling. Cooling also significantly induced cold-shock proteins CIRBP and RBM3 gene expressions, with CIRBP expression more rapidly regulated than RBM3 and translatable to significantly increased protein expression. DAMPs including HMGB-1, HSP70, and CIRBP could be detected in cultured supernatants after 6 h of OGD with CIRBP release being significantly attenuated by cooling. Exposure to OGD suppressed cytokine gene expressions of IL-1 β , TNF- α , MCP-1, and TGF β independently of temperature management, whereas cooling led to a significant increase in IL-1 α gene expression after 6 h of OGD. In the reperfusion phase, TNF- α and MCP-1 gene expressions were increased, and cooling was associated with significantly lower TGF β gene expression. Interestingly, cooled Normoxia groups had significant upregulations of microglial activation marker, Iba1, IL-1 β , and TNF- α gene expressions., Conclusion: BV-2 microglial cells undergo necrotic cell death resulting in DAMP release due to OGD/R-induced injury. Cooling conveyed neuroprotection in OGD/R-injury as observable in increased cell viability as well as induced gene expressions of cold shock proteins. As cooling alone resulted in both upregulation of microglial activation, expression of proinflammatory cytokines, and cold shock protein transcript and protein expression, temperature management might have ambiguous effects in sterile inflammation. However, cooling resulted in a significant decrease of extracellular CIRBP, which has recently been characterized as a novel DAMP and a potent initiator and mediator of inflammation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Jana Lücht et al.)

Introduction: Hypothermia attenuates cerebral ischemia-induced neuronal cell death associated with neuroinflammation. The calcineurin inhibitor cyclosporin A (CsA) has been shown to be neuroprotective by minimizing activation of inflammatory pathways. Therefore, we investigated whether the combination of hypothermia and treatment with CsA has neuroprotective effects in an oxygen-glucose deprivation/reperfusion (OGD/R) injury model in neuronal and BV-2 microglia monocultures, as well as in an organotypic hippocampal slice culture (OHSC)., Methods: Murine primary neurons, BV-2 microglia, and OHSC were pretreated with CsA and exposed to 1 h OGD (0.2% O 2 ) followed by reperfusion at normothermia (37°C) or hypothermia (33.5°C). Cytotoxicity was measured by lactate dehydrogenase and glutamate releases. Damage-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1), heat shock protein 70 (Hsp70), and cold-inducible RNA-binding protein (CIRBP) were detected in cultured supernatant by western blot analysis. Interleukin-6 (IL-6), Interleukin-1α and -1β (IL-1α/IL1-β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP1), inducible nitric oxide synthase (iNOS), glia activation factors ionized calcium-binding adapter molecule 1 (Iba1), and transforming growth factor β1 (TGF-β1) gene expressions were analyzed by RT-qPCR., Results: Exposure to OGD plus 10 μM CsA was sufficient to induce necrotic cell death and subsequent release of DAMPs in neurons but not BV-2 microglia. Moreover, OGD/R-induced secondary injury was also observed only in the neurons, which was not attenuated by cooling and no increased toxicity by CsA was observed. BV-2 microglia were not sensitive to OGD/R-induced injury but were susceptible to CsA-induced toxicity in a dose dependent manner, which was minimized by hypothermia. CsA attenuated IL-1β and Iba1 expressions in BV-2 microglia exposed to OGD/R. Hypothermia reduced IL-1β and iNOS expressions but induced TNF-α and Iba1 expressions in the microglia. However, these observations did not translate to the ex vivo OHCS model, as general high expressions of most cytokines investigated were observed., Conclusion: Treatment with CsA has neurotoxic effects on primary neurons exposed to OGD but could inhibit BV-2 microglia activation. However, CsA and hypothermia treatment after ischemia/reperfusion injury results in cytotoxic neuroinflammation in the complex ex vivo OHSC.