Viral Myocarditis—From Pathophysiology to Treatment

The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options.Peer Reviewe

Interferon-β Suppresses Transcriptionally Active Parvovirus B19 Infection in Viral Cardiomyopathy: A Subgroup Analysis of the BICC-Trial

Human parvovirus B19 (B19V) is the predominant virus currently detected in endomyocardial biopsies (EMBs). Recent findings indicate that, specifically, transcriptionally active B19V with detectable viral RNA is of prognostic relevance in inflammatory viral cardiomyopathy. We aimed to evaluate B19V replicative status (viral RNA) and beneficial effects in a sub-collective of the prospective randomized placebo-controlled phase II multi-center BICC-Trial (Betaferon In Chronic Viral Cardiomyopathy) after interferon beta-1b (IFN-β) treatment. EMBs of n = 64 patients with B19V mono-infected tissue were retrospectively analyzed. Viral RNA could be detected in n = 18/64 (28.1%) of B19V DNA positive samples (mean age 51.7 years, 12 male), of whom n = 13 had been treated with IFN-ß. Five patients had received placebo. PCR analysis confirmed in follow-up that EMBs significantly reduced viral RNA loads in n = 11/13 (84.6%) of IFN-ß treated patients (p = 0.001), independently from the IFN-ß dose, in contrast to the placebo group, where viral RNA load was not affected or even increased. Consequently, a significant improvement of left ventricular ejection fraction (LVEF) after treatment with IFN-ß was observed (LVEF mean baseline 51.6 ± 14.1% vs. follow-up 61.0 ± 17.5%, p = 0.03). In contrast, in the placebo group, worsening of LVEF was evaluated in n = 4/5 (80.0%) of patients. We could show for the first-time the beneficial effects from treatment with IFN-ß, suppressing B19V viral RNA and improving the hemodynamic course. Our results need further verification in a larger prospective randomized controlled trial.Peer Reviewe

A general framework for consistent estimation of charge transport properties via random walks in random environments

A general framework is proposed for the study of the charge transport properties of materials via random walks in random environments (RWRE). The material of interest is modeled by a random environment, and the charge carrier is modeled by a random walker. The framework combines a model for the fast generation of random environments that realistically mimic materials morphology with an algorithm for efficient estimation of key properties of the resulting random walk. The model of the environment makes use of tools from spatial statistics and the theory of random geometric graphs. More precisely, the disordered medium is represented by a random spatial graph with directed edge weights, where the edge weights represent the transition rates of a Markov jump process (MJP) modeling the motion of the random walker. This MJP is a multiscale stochastic process. In the long term, it explores all vertices of the random graph model. In the short term, however, it becomes trapped in small subsets of the state space and makes many transitions in these small regions. This behavior makes efficient estimation of velocity by Monte Carlo simulations a challenging task. Therefore, we use aggregate Monte Carlo (AMC), introduced in [T. Brereton et al., Methodol. Comput. Appl. Probab., 16 (2014), pp. 465-484], for estimating the velocity of a random walker as it passes through a realization of the random environment. In this paper, we prove the strong consistency of the AMC velocity estimator and use this result to conduct a detailed case study, in which we describe the motion of holes in an amorphous mesophase of an organic semiconductor, dicyanovinyl-substituted oligothiophene (DCV4T). In particular, we analyze the effect of system size (i.e., number of molecules) on the velocity of single charge carriers

Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice

AbstractCaloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events

MicroRNAs as novel biomarkers and potential therapeutic options for inflammatory cardiomyopathy

Abstract Aims Inflammation of the heart is a complex biological and pathophysiological response of the immune system to a variety of injuries leading to tissue damage and heart failure. MicroRNAs (miRNAs) emerge as pivotal players in the development of numerous diseases, suggesting their potential utility as biomarkers for inflammation and as viable candidates for therapeutic interventions. The primary aim of this investigation was to pinpoint and assess particular miRNAs in individuals afflicted by virus‐negative inflammatory dilated cardiomyopathy (DCMi). Methods and results The study involved the analysis of 152 serum samples sourced from patients diagnosed with unexplained heart failure through endomyocardial biopsy. Among these samples, 38 belonged to DCMi patients, 24 to DCM patients, 44 to patients displaying inflammation alongside diverse viral infections, and 46 to patients solely affected by viral infections without concurrent inflammation. Additionally, serum samples from 10 healthy donors were included. The expression levels of 754 distinct miRNAs were evaluated using TaqMan OpenArray. MiR‐1, miR‐23, miR‐142‐5p, miR‐155, miR‐193, and miR‐195 exhibited exclusive down‐regulation solely in DCMi patients (P < 0.005). These miRNAs enabled effective differentiation between individuals with inflammation unlinked to viruses (DCMi) and all other participant groups (P < 0.005), boasting a specificity surpassing 86%. Conclusions The identification of specific miRNAs offers a novel diagnostic perspective for recognizing intramyocardial inflammation within virus‐negative DCMi patients. Furthermore, these miRNAs hold promise as potential candidates for tailored therapeutic strategies in the context of virus‐negative DCMi

Brain metabolism during cardiopulmonary resuscitation assessed with microdialysis

Abstract Background and Purpose: Microdialysis is an established tool to analyse tissue biochemistry, but the value of this technique to monitor cardiopulmonary resuscitation (CPR) effects on cerebral metabolism is unknown. The purpose of this study was to assess the effects of active-compression-decompression (ACD) CPR in combination with an inspiratory threshold valve (ITV) (0/ experimental CPR) vs. standard CPR on cerebral metabolism measured with microdialysis. Methods: Fourteen domestic pigs were surfaced-cooled to a body core temperature of 26 8C and ventricular fibrillation was induced, followed by 10 min of untreated cardiac arrest; and subsequently, standard (n 0/7) CPR vs. experimental (n0/7) CPR. After 8 min of CPR, all animals received 0.4 U/kg vasopressin IV, and CPR was maintained for an additional 10 min in each group; defibrillation was attempted after a total of 28 min of cardiac arrest, including 18 min of CPR. Results: In the standard CPR group, microdialysis measurements showed a 13-fold increase of the lactate Á/pyruvate ratio from 7.29/1.3 to 95.59/15.4 until the end of CPR (P B/0.01), followed by a further increase up to 1389/32 during the postresuscitation period. The experimental group developed a sixfold increase of the lactate Á/ pyruvate ratio from 7.19/2.0 to 51.19/8.7 (P B/0.05), and a continuous decrease after vasopressin. In the standard resuscitated group, but not during experimental CPR, a significant increase of cerebral glucose levels from 0.69/0.1 to 2.69/0.5 mM was measured (P B/0.01). Conclusion: Using the technique of microdialysis we were able to measure changes of brain biochemistry during and after the very special situation of hypothermic cardiopulmonary arrest. Experimental CPR improved the lactate Á/ pyruvate ratio, and glucose metabolism. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiopulmonary resuscitation; Active compression decompression; Metabolism; Brain ischaemia; Catheter Resumo Contexto : A microdiálise é um método de análise da bioquímica tecidular aceite, mas o valor desta técnica para monitorizar os efeitos da reanimação cardio-pulmonar (CPR) no metabolismo cerebral é desconhecido. O objectivo deste estudo foi avaliar os efeitos da CPR por compressão-descompressão activa (ACD) em combinação com uma válvula de nível inspirató rio (ITV), CPR experimental vs CPR standard, no metabolismo cerebral avaliado com microdiálise. Métodos : Arrefeceram-se catorze porcos domésticos até uma temperatura corporal central de 26 8C induziu-se fibrilhação ventricular, seguida de 10 min de paragem cardíaca não tratada; subsequentemente, foi realizada CPR standard (n 0/7) vs. CPR experimental (n 0/7). Depois de 8 min de CPR, todos os animais receberam 0.4 U/Kg de vasopressina IV e a CPR foi mantida por mais 10 min em cada grupo; foi tentada desfibrilhação apó s um total de 28 min de paragem cardíaca, incluindo 18 min de CPR. Resultados : No grupo de CPR standard, as mediçõ es por microdiálise mostraram um aumento de 13 vezes da razão lactato-piruvato de 7.29/1.3 para 95.59/15.4, até ao final da CPR (P B/ 0.01), seguido de uma aumento adicional até 1389/32 no período pó s-reanimação. O grupo experimental desenvolveu um aumento de 6 vezes da razão lactato-piruvato, de 7.19/2.0 para 51.19/8.7 (P B/0.05), e um aumento contínuo após vasopressina. reanimação standard, mas não durante a CPR experimental, foi medido um aumento significativo dos níveis de glicose cerebral, de 0.69/0.1 para 2.6 v 0.5 mM (P B/0.01). Conclusões : Através da técnica da microdiálise foi possível medirmos alteraçõ es na bioquímica cerebral durante e apó s a situação muito especial de paragem cardiopulmonar por hipotermia. A CPR experimental aumentou a razão lactato-piruvato e o metabolismo da glicose.

GLP-1–oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice

AIMS/HYPOTHESIS: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)–oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1–oestrogen during beta cell failure under glucolipotoxic conditions. METHODS: Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1–oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1–oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. RESULTS: In contrast to GLP-1, GLP-1–oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1–oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1–oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. CONCLUSIONS/INTERPRETATION: GLP-1–oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone