Multifactorial Activation of NLRP3 Inflammasome: Relevance for a Precision Approach to Atherosclerotic Cardiovascular Risk and Disease

Chronic low-grade inflammation, through the specific activation of the NACHT leucine-rich repeat- and PYD-containing (NLRP)3 inflammasome-interleukin (IL)-1\u3b2 pathway, is an important contributor to the development of atherosclerotic cardiovascular disease (ASCVD), being triggered by intracellular cholesterol accumulation within cells. Within this pathological context, this complex pathway is activated by a number of factors, such as unhealthy nutrition, altered gut and oral microbiota, and elevated cholesterol itself. Moreover, evidence from autoinflammatory diseases, like psoriasis and others, which are also associated with higher cardiovascular disease (CVD) risk, suggests that variants of NLRP3 pathway-related genes (like NLRP3 itself, caspase recruitment domain-containing protein (CARD)8, caspase-1 and IL-1\u3b2) may carry gain-of-function mutations leading, in some individuals, to a constitutive pro-inflammatory pattern. Indeed, some reports have recently associated the presence of specific single nucleotide polymorphisms (SNPs) on such genes with greater ASCVD prevalence. Based on these observations, a potential effective strategy in this context may be the identification of carriers of these NLRP3-related SNPs, to generate a genomic score, potentially useful for a better CVD risk prediction, and, possibly, for personalized therapeutic approaches targeted to the NLRP3-IL-1\u3b2 pathway. View Full-Tex

The Interplay of Lipids, Lipoproteins, and Immunity in Atherosclerosis

Purpose of Review: Atherosclerosis is an inflammatory disorder of the arterial wall, in which several players contribute to the onset and progression of the disease. Besides the well-established role of lipids, specifically cholesterol, and immune cell activation, new insights on the molecular mechanisms underlying the atherogenic process have emerged. Recent Findings: Meta-inflammation, a condition of low-grade immune response caused by metabolic dysregulation, immunological memory of innate immune cells (referred to as “trained immunity”), cholesterol homeostasis in dendritic cells, and immunometabolism, i.e., the interplay between immunological and metabolic processes, have all emerged as new actors during atherogenesis. These observations reinforced the interest in directly targeting inflammation to reduce cardiovascular disease. Summary: The novel acquisitions in pathophysiology of atherosclerosis reinforce the tight link between lipids, inflammation, and immune response, and support the benefit of targeting LDL-C as well as inflammation to decrease the CVD burden. How this will translate into the clinic will depend on the balance between costs (monoclonal antibodies either to PCSK9 or to IL-1ß), side effects (increased incidence of death due to infections for anti-IL-1ß antibody), and the benefits for patients at high CVD risk

'Diet and lifestyle' in the management of dyslipidaemia and prevention of CVD - Understanding the level of knowledge and interest of European Atherosclerosis Society members.

Abstract To better understand the level of knowledge and interest in 'diet and lifestyle' for cholesterol management and CVD prevention, European Atherosclerosis Society (EAS) members were invited to take part in an online survey. In total, 269 EAS members participated of which 64 (24%) were students/postdocs, 102 (38%) researchers involved with CVD-related research and 103 (38%) doctors and clinicians who directly interact with patients. All (99%) of the participants either agreed or strongly agreed that 'diet and lifestyle' have a role to play in cholesterol management, with 80% indicating that 'diet and lifestyle' is very or extremely important. Of the clinicians, 75% indicated that their patients voluntarily ask for 'diet and lifestyle' advice and over 80% said they continuously provide 'diet and lifestyle advice' to their patients. Of the surveyed clinicians, 91% feel sufficiently educated and confident to provide expert advice and over 90% recommend medication, diet change, frequent exercise and smoking cessation to their patients. In view of more specific dietary advice, clinicians reportedly recommend a 'Mediterranean diet', and advise to avoid high-fat foods, and to increase intake of high-fibre foods. Interestingly, smoking cessation and alcohol avoidance were mentioned less frequently. In view of educational needs, over half of the surveyed EAS members use the internet and 'guidelines' to learn about 'diet and lifestyle' in relation to cholesterol and CVD risk management. Clinicians tend to use 'guidelines' more often, while students/postdocs tend to use the internet significantly more than clinicians and CVD researchers. Regarding unmet needs for educational tools addressing specifically 'diet and lifestyle', clinicians feel that patient-oriented leaflets and pocket guidelines would be most beneficial materials to introduce, while students/postdocs would prefer an app. In summary, the role of 'diet and lifestyle' as a cornerstone of cholesterol management and CVD risk prevention seems well recognised amongst EAS members surveyed

The Maximal Pore Size of Hydrophobic Microporous Membranes Does Not Fully Characterize the Resistance to Plasma Breakthrough of Membrane Devices for Extracorporeal Blood Oxygenation

open4Extracorporeal membrane oxygenation (ECMO) in blood-outside devices equipped with hydrophobic membranes has become routine treatment of respiratory or cardiac failure. In spite of membrane hydrophobicity, significant amounts of plasma water may form in the gas compartment during treatment, an event termed plasma water breakthrough. When this occurs, plasma water occludes some gas pathways and ultimately cripples the oxygenator gas exchange capacity requiring its substitution. This causes patient hemodilution and increases the activation of the patient's immune system. On these grounds, the resistance to plasma water breakthrough is regarded as an important feature of ECMO devices. Many possible events may explain the occurrence of plasma breakthrough. In spite of this, the resistance to plasma breakthrough of ECMO devices is commercially characterized only with respect to the membrane maximal pore size, evaluated by the bubble pressure method or by SEM analysis of membrane surfaces. The discrepancy between the complexity of the events causing plasma breakthrough in ECMO devices (hence determining their resistance to plasma breakthrough), and that claimed commercially has caused legal suits on the occasion of the purchase of large stocks of ECMO devices by large hospitals or regional institutions. The main aim of this study was to identify some factors that contribute to determining the resistance to plasma breakthrough of ECMO devices, as a means to minimize litigations triggered by an improper definition of the requirements of a clinically efficient ECMO device. The results obtained show that: membrane resistance to breakthrough should be related to the size of the pores inside the membrane wall rather than at its surface; membranes with similar nominal maximal pore size may exhibit pores with significantly different size distribution; membrane pore size distribution rather than the maximal pore size determines membrane resistance to breakthrough; the presence of surfactants in the patient's blood (e.g., lipids, alcohol, etc.) may significantly modify the intrinsic membrane resistance to breakthrough, more so the higher the surfactant concentration. We conclude that the requirements of ECMO devices in terms of resistance to plasma breakthrough ought to account for all these factors and not rely only on membrane maximal pore size.openFragomeni Gionata, Terzini Mara, Comite Antonio, Catapano GerardoFragomeni, Gionata; Terzini, Mara; Comite, Antonio; Catapano, Gerard

The current landscape of imaging recommendations in cardiovascular clinical guidelines: toward an imaging-guided precision medicine

The purpose of this article is to provide an overview on the role of CT scan and MRI according to selected guidelines by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA). ESC and ACC/AHA guidelines were systematically reviewed for recommendations to CT and MRI use in specific cardiovascular (CV) clinical categories. All recommendations were collected in a dataset, including the class of recommendation, the level of evidence (LOE), the specific imaging technique, the clinical purpose of the recommendation and the recommending Society. Among the 43 included guidelines (ESC: n = 18, ACC/AHA: n = 25), 26 (60.4%) contained recommendations for CT scan or MRI (146 recommendations: 62 for CT and 84 for MRI). Class of recommendation IIa (32.9%) was the most represented, followed by I (28.1%), IIb (24%) and III (11.9%). MRI recommendations more frequently being of higher class (I: 36.9%, IIa: 29.8%, IIb: 21.4%, III: 11.9%) as compared to CT (I: 16.1%, IIa: 37.1%, IIb: 27.4%, III: 19.4%). Most of recommendation (55.5%) were based on expert opinion (LOE C). The use of cardiac CT and cardiac MR in the risk assessment, diagnosis, therapeutic and procedural planning is in continuous development, driven by an increasing need to evolve toward an imaging-guided precision medicine, combined with cost-effectiveness and healthcare sustainability. These developments must be accompanied by an increased availability of high-performance scanners in healthcare facilities and should emphasize the need of increasing the number of radiologists fully trained in cardiac imaging

Proton and heavy ion acceleration by stochastic fluctuations in the Earth's magnetotail

Abstract. Spacecraft observations show that energetic ions are found in the Earth's magnetotail, with energies ranging from tens of keV to a few hundreds of keV. In this paper we carry out test particle simulations in which protons and other ion species are injected in the Vlasov magnetic field configurations obtained by Catapano et al. (2015). These configurations represent solutions of a generalized Harris model, which well describes the observed profiles in the magnetotail. In addition, three-dimensional time-dependent stochastic electromagnetic perturbations are included in the simulation box, so that the ion acceleration process is studied while varying the equilibrium magnetic field profile and the ion species. We find that proton energies of the order of 100 keV are reached with simulation parameters typical of the Earth's magnetotail. By changing the ion mass and charge, we can study the acceleration of heavy ions such as He+ +  and O+, and it is found that energies of the order of 100–200 keV are reached in a few seconds for He+ + , and about 100 keV for O+

CFD-based methodology for the characterization of the combustion process of a passive pre-chamber gasoline engine

Pre-chamber (PC) ignition systems, enabling Turbulent Jet Ignition (TJI) combustion, represent a promising technology to extend the lean limit of Spark Ignition Internal Combustion Engines. Indeed, the higher ignition energy provided by the turbulent jets contributes to the limitation of combustion duration and variability even in diluted conditions. However, a detailed analysis of the combustion process is needed to maximize the performance of the system. More specifically, the interaction between the chemical and the turbulent scales are key factors in assessing the probabilities of main chamber (MC) ignition, determining the ignition pattern, and characterizing the combustion process. For this reason, the development of reliable numerical models is a crucial factor to pave the way toward a deeper understanding of details concerning TJI combustion. In the present work, a 3D-CFD numerical model was validated against experimental data at 4000 rpm, in stoichiometric and lean (i.e., λ = 1.2) conditions in a single-cylinder gasoline engine equipped with a passive pre-chamber. In both operations, the evolution of the turbulent combustion regimes over the whole combustion process was investigated, highlighting analogies and differences between the selected operative conditions. Additionally, a methodology to characterize the MC ignition and combustion process, able to describe the different phases of the interaction between PC and MC, and assess the thermal, turbulent, and chemical effects of the turbulent jets is presented

The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment.

Metastatic prostate cancer represents a yet unsolved clinical problem due to the high frequency of relapse and treatment resistance. Understanding the pathways that lead to prostate cancer progression is an important task to prevent this deadly disease. The ETS transcription factor ESE3/EHF has an important role in differentiation of human prostate epithelial cells. Loss of ESE3/EHF in prostate epithelial cells determines transformation, epithelial-to-mesenchymal transition (EMT) and acquisition of stem-like properties. In this study we identify IL-6 as a direct target of ESE3/EHF that is activated in prostate epithelial cells upon loss of ESE3/EHF. ESE3/EHF and IL-6 were significantly inversely correlated in prostate tumors. Chromatin immunoprecipitation confirmed binding of ESE3/EHF to a novel ETS binding site in the IL-6 gene promoter. Inhibition of IL-6 reverted transformation and stem-like phenotype in tumorigenic ESE3/EHF knockdown prostate epithelial cell models. Conversely, IL-6 stimulation induced malignant phenotypes, stem-like behavior and STAT3 activation. Increased level of IL-6 was observed in prostatospheres compared with adherent bulk cancer cells and this was associated with stronger activation of STAT3. Human prostate tumors with IL-6 elevation and loss of ESE3/EHF were associated with STAT3 activation and displayed upregulation of genes related to cell adhesion, cancer stem-like and metastatic spread. Pharmacological inhibition of IL-6/STAT3 activation by a JAK inhibitor restrained cancer stem cell growth in vitro and inhibited self-renewal in vivo. This study identifies a novel connection between the transcription factor ESE3/EHF and the IL-6/JAK/STAT3 pathway and suggests that targeting this axis might be preferentially beneficial in tumors with loss of ESE3/EHF