Effect of a PCSK9 Inhibitor and a Statin on Cholesterol Efflux Capacity: a Limitation of Current Cholesterol-Lowering Treatments?

Background: Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100 containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins which could impact on cholesterol efflux capacity (CEC). Methods: We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420mg every 2 weeks) and atorvastatin (80mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol was measured. Results: Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect P<0.01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (P>0.05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r =0.339, P<0.01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r =0.487, P<0.05). Conclusions: In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100 containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy

Molecular epidemiology of meticillin-resistant Staphylococcus aureus in Italian cystic fibrosis patients: A national overview

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HDL-mediated cholesterol efflux and plasma loading capacities are altered in subjects with metabolically-but not genetically driven non-alcoholic fatty liver disease (NAFLD)

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (-18.6%; p < 0.001) as well as that mediated by cholesterol transporters (-25.3% ABCA1; -16.3% ABCG1; -14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically-vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically-vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (−18.6%; p < 0.001) as well as that mediated by cholesterol transporters (−25.3% ABCA1; −16.3% ABCG1; −14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired

Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease

Background: Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. Objective: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4. Methods: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased A beta(42) and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. Results: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE epsilon 4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454). Conclusion: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD

Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs

Background: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. Sources of material: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. Abstract of findings: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. Conclusion: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk

Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions

The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions

FORECASTING THE SUCCESS OF HYPERLOOP TECHNOLOGY ON ITALIAN ROUTES: A BROAD FEASIBILITY STUDY

Large Infrastructure Projects, also referred as Large Engineering Projects (or LEPs), are always controversial due to the fact that standard cost-benefit analysis and other economic evaluations are often negative due to their high implementation cost and their high level of risk related the uncertainty and innovation they bring with them. Anyway, in the last decades, the investment on LEPs in increasing all over the world (Flyvjierg, B., 2014), and the construction of LEPs is still considered a basic leverage to increase the wealth of nations. The topic is particularly relevant at EU level. In fact the decision-making process on which infrastructure (LEP) should be funded and which not by the public sector has been criticized by new “sovranist” political parties. For example, studies both in favor and against the funding of the same infrastructure have been published by different academics, even belonging to the same institution (Ponti, M. et al., 2019) (Cantarella G.E., et al., 2019). In the last few months there is a lot of discussion in Italy about the feasibility of an Hyperloop, that is a “Hyperloop is a sealed tube or system of tubes through which a pod may travel free of air resistance or friction conveying people or objects at high speed while being very efficient, thereby drastically reducing travel times over medium-range distances” (Opgenoord, Max M.J., 2019). In particular, six possible route have been drafted, e.g. Milan-Rome, Milan Cadorna Station-Milan Malpensa Airport, Verona-Trieste and others. The Authors want to evaluate the economic feasibility of that revolutionary transpiration mode, applying a broad approach, according both the indications of the European Commission's Guide to Cost-Benefit Analysis of Investment Projects (2014), including both ordinary costs and benefits, and evaluation also the innovation benefits that such transportation mode, if implemented, will bring: evaluating such a transportation mode as, for example, an ordinary high speed train mode, won’t be correct, because implementing it will cause innovation in several technologic fields and in the transportation sector as a whole, and these benefits must be encompassed in the analysis. In addition, the authors will evaluate other success criteria such as the one indicated by Atkinson, R. (1999), i.e. “stakeholder benefits against which projects can be assessed”. Including the approach by Turner and Zolin (2012) of taking into account multiple perspectives by multiple stakeholders over multiple time frames: In Large Engineering Projects “How different stakeholders perceive success can change with time, and so the project manager needs leading performance indicators that go beyond the traditional triple constraint to forecast how key stakeholders will perceive success months or even years later” (Turner and Zolin, 2012). This research has the aim of carrying out a preliminary technical-economic feasibility study of a potential Hyperloop line connecting the cities of Rome and Milan, chosen as they are poles of attraction and generators of transportation demand. The main objective is not to analyze the validity of the technology used as to assess the feasibility and sustainability of such a project. The first section briefly describes the history and technology, the main characteristics and limitations of these vehicles. The second section presents a transportation study of the potential demand through surveys that will make it possible to identify users' preferences, assessing the transportation demand and the willingness to pay of potential users. In the third and fourth sections a financial and economic analysis is performed, presenting assumptions and limitations that this research necessarily has, due to the lack of information on several areas. In the last section before conclusions, some consideration is made about the possible social impact on potential stakeholders involvement, presenting also preliminary feedback from interviews to industrial stakeholder that are considering their involvement in a hyperloop venture in Italy. In the last section, the Authors make a balance of their findings and outline the further development of the research on this topic

Persone, Pianeta, Profitto: la sostenibilità "3P" come chiave di volta nel successo dei megaprogetti

Secondo numerose analisi e studi recenti (Miller & Lessard, 2000; Flyvbjerg et al., 2003; Locatelli, 2018), il superamento dei costi, i ritardi nelle tempistiche e le notevoli carenze in termini di risultati attesi rappresentano le principali problematiche nella gestione dei megaprogetti. In tutto il mondo, i megaprogetti affrontano problemi e criticità simili, indipendentemente dalla cultura e dal task environment di riferimento. La "lron Law" dei megaprogetti (Flyvbjerg, 2017) che recita: "Fuori budget, fuori tempo, e al di sotto dei benefici attesi" è universalmente identificata come una delle maggiori sfide per la gestione dei megaprogetti. In effetti, nel corso dell'ultimo secolo, i megaprogetti hanno dimostrato di non riuscire ad ottenere i risultati inizialmente previsti. Quando si tratta di rispettare i vincoli di budget e cronologici, i megaprogetti sono influenzati da diverse variabili e comportamenti, che ne alterano le prestazioni. Le carenze in termini di benefici finali ottenuti sono un'ulteriore prospettiva di scarsa performance, considerando l'impatto che questi sforzi hanno sulle comunità e sugli stakeholder. Dalla revisione della letteratura e dai contributi empirici, è possibile mappare e descrivere alcune linee guida gestionali volte a migliorare le prestazioni dei megaprogetti. (Cantoni et al., 2019) Secondo gli autori, esistono fattori complessi alla base della realizzazione dei Megaproject che devono essere affrontati da prospettive e punti di vista interdisciplinari, per essere affrontati in modo adeguato ed efficace (Favari et al., 2020). In questa ricerca specifica, gli autori indagheranno la possibilità che l'approccio olistico necessario per superare la “Iron Law” dei megaprogetti possa essere identificato nei principi della Sostenibilità 3P. La sostenibilità in un framework 3P (People, Profit, Planet), definita anche Sustainability in Triple Bottom Line, è sempre di più considerata un fattore determinante negli studi di fattibilità dei megaprogetti secondo le istituzioni finanziarie internazionali (IFI). Nei grandi progetti di ingegneria, è possibile utilizzare protocolli per la valutazione dei livelli di sostenibilità che questi realizzano, come, ad esempio, il protocollo Envision dell’Institute for Sustainable Infrastructure, o LEED del Green Building Council, il primo dedicato alle infrastrutture, mentre il secondo agli edifici. Attualmente, in diversi casi, la sostenibilità viene considerata come un argomento di cui parlano solamente top manager e presidenti di aziende e istituzioni senza un nulla di concreto a supporto (Favari, 2020). Questo articolo esplora non solo la sostenibilità come fattore critico di successo nei megaprogetti, ma anche le strategie per una sua implementazione concreta nei grandi progetti di ingegneria, integrando i tre pilastri della sostenibilità (sostenibilità finanziaria, ambientale e sociale) in un unico schema coerente, affinché possa diventare non solo un bel tema da citare nei discorsi di fine anno agli azionisti e agli investitori, ma anche un concreto sostegno per aumentare il livello di resilienza delle organizzazioni che realizzano (mega)progetti, e quindi aumentare notevolmente la probabilità di raggiungimento dei risultati attesi di un grande progetto di ingegneria. In questa ricerca, gli autori esamineranno lo stato dell'arte per l'applicazione della sostenibilità in 3P nei megaprogetti, e concluderanno con un elenco di raccomandazioni per facilitare la resilienza di un megaprogetto che implementa pratiche sostenibili nel corso di tutto il suo ciclo di vita

Sustainability as a turning point for the success of megaprojects. The Italian approach

Since their birth, megaprojects, defined as projects with a budget of more than one billion (USD) (Warrack, 1985), have encountered considerable difficulties in producing the results initially expected: “Over budget, over time, under benefits, over and over again.” as “the Iron Law of Megaprojects” by B. Flyvbjerg states. Some authors highlights that most of Megaprojects have facing problems in producing the expected outcome because of the traditional adoption of the triple constraint as success parameter, which tends to evaluate project’s success on the basis of a delivery that respects costs, time and quality (Silvius, 2017). However, megaprojects usually have an impact that can go well beyond the immediate completion of the project (Turner, 2012). The different stakeholders tend to evaluate the success of a megaproject at different times and considering non-univocal criteria. The literature (Shenhar and Dvir, 2007; Zolin, 2012; Turner, 2014) generally highlights that the project participants (project manager and team) evaluate project success immediately after the delivery phase, while consumers judge success in the months following the end of the project based on how well it achieves its immediate business objectives. In addition, investors and megaprojects’ sponsors are able to assess the project success only after two or three years, evaluating (a) the financial ability to refund the investment and (b) the alignment of the project output with the company strategy goals (Derakhshan, 2019)