Measures of high-density lipoprotein function in men and women with severe aortic stenosis

Background: Calcification of the aortic valve is a common heart valve disorder, in some cases leading to clinically impactful severe aortic stenosis (AS). Sex-specific differences in aortic valve calcification (ACV) exist, with women having a lower burden of calcification than men as measured by computed tomography; however, the pathophysiological mechanism that leads to these differences remains unclear. Methods: Using cultured human Tamm-Horsfall protein 1 (THP-1) macrophages and human aortic valve interstitial cells, the effects of high-density lipoprotein (HDL) particles isolated from the plasma of men and women with severe AS were studied for cholesterol efflux capacity (CEC). Results: HDL-CEC was assessed in 46 patients with severe AS, n = 30 men, n = 16 women. ATP-Binding Cassette A1 (ABCA1)-mediated HDL-CEC was measured from human cultured THP-1 macrophages to plasma HDL samples. Women with severe AS had more ABCA1-mediated HDL-CEC, as compared to men (8.50 ± 3.90% cpm vs. 6.80 ± 1.50% cpm, P = 0.04). HDL pre-β1 and α-particles were higher in women than in men by spectral density, (pre-β1 HDL, 20298.29 ± 1076.15 vs. 15,661.74 ± 789.00, P = 0.002, and α-HDL, 63006.35 ± 756.81 vs. 50,447.00 ± 546.52, P =0.03). Lecithin-cholesterol acyltransferase conversion of free cholesterol into cholesteryl esters was higher in women than men (16.44 ± 9.11%/h vs. 12.00 ± 8.07%/h, P = 0.03). Conclusions: Sex-specific changes in various parameters of HDL-CEC were found in patients with severe AS. Sex-based modifications in HDL functionality by HDL-CEC might account for the reduced burden of calcification in women vs. men with severe AS. Therefore, future studies should target sex-related pathways in AS to help to improve understanding and treatment of AS

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

A unique protease-sensitive high density lipoprotein particle containing the apolipoprotein A-I(Milano) dimer effectively promotes ATP-binding Cassette A1-mediated cell cholesterol efflux

Carriers of the apolipoprotein A-I-Milano (A-I-M) variant present with severe reductions of plasma HDL levels, not associated with premature coronary heart disease (CHD). Sera from 14 A-I-M. carriers and matched controls were compared for their ability to promote ABCA1-driven cholesterol efflux from J774 macrophages and human fibroblasts. When both cell types are stimulated to express ABCA1, the efflux of cholesterol through this pathway is greater with A-I-M than control sera (3.4 +/- 1.0% versus 2.3 +/- 1.0% in macrophages; 5.2 +/- 2.4% versus 1.9 +/- 0.1% in fibroblasts). A-I-M and control sera are instead equally effective in removing cholesterol from unstimulated cells and from fibroblasts not expressing ABCA1. The A-I-M sera contain normal amounts of apoA-I-containing pre beta-HDL and varying concentrations of a unique small HDL particle containing a single molecule of the A-I-M, dimer; chymase treatment of serum degrades both particles and abolishes ABCA1-mediated cholesterol efflux. The serum content of chymase-sensitive HDL correlates strongly and significantly with ABCA1-mediated cholesterol efflux (r = 0.542, p = 0.004). The enhanced capacity of A-I-M serum for ABCA1 cholesterol efflux is thus explained by the combined occurrence in serum of normal amounts of apoA-I-containing pre beta-HDL, together with a unique protease-sensitive, small HDL particle containing the A-I-M dimer, both effective in removing cell cholesterol via ABCA1

Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (28% and 44.8%, respectively) and of medium-sized HDL (10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (25.5, 41.1 and 30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.\u2014Zimetti, F., S. De Vuono, M. Gomaraschi, M. P. Adorni, E. Favari, N. Ronda, M. A. Ricci, F. Veglia, L. Calabresi, and G. Lupattelli. Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction

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

A Business Case to make sustainability work in project management

Sustainability in the triple bottom line (TBL), also referred as 3P framework (People, Planet, Profit) is becoming a key driver for business strategy in the 21st century (Elkington, 1999). The question “How can we develop prosperity without compromising the life of future generations?” is today generally recognized worldwide as a basic need for setting strategic goals of organizations (Tharp, 2012). In scientific literature, sustainability is a fair new topic (Aarseth et al, 2016). What is missing today is the deployment of these strategic goals related to sustainability into the operational activities of organization (Brook, 2014). The discipline that can help organizations achieve their strategic goals is project management: in fact, in order to survive and prosper in a global environment that is continuously evolving, organizations must endlessly develop changes in their way of doing business, and project management is a key skill capable to execute these changes in a structured manner (Silvius et al., 2012). Currently, no Project Management frameworks (PMI and IPMA above all) include sustainability knowledge areas or specific processes (VV.AA., 2017; Macelino- Sabada, 2015). Moreover, no specific input nor output in project management frameworks considers sustainability in the 3P approach, but only some (rare) specific points referring to one of the three pillars can be found (Silvius et al., 2012). A project manager, alone, can’t succeed in including sustainability goals in his/her project, if these goals are competing with goals set by the project sponsor and/or PMO in the project charter (Martens, 2017). In order to influence the way project management is carried out, and to include sustainability into project goals, decisions must be made during the business analysis phase (i.e. the phase during which decision on what project solution is the best to solve the problem addressed is taken), analysed and included into the business case, approved through a formal Go/NoGo decision, so that project managers are fully empowered to develop projects in a controlled manner (Gimenez, 2012; Carvalho, 2017). In fact, no organization would leave the discretionary power to make decisions related to sustainability to individual project managers (Martens, 2016). Indeed, sustainability decisions cause expenses that cannot be justified simply from the project’s point of view, because sustainability has long-term goals, whereas project goals are generally shortterm oriented (Silvius et al., 2012). Decisions on sustainability must be made at a strategic level and, then, cascaded to professionals managing the tactic level, otherwise not even the best project managers have the power to implement sustainability principles (Sanchez, 2015). For example, in civil (mega)projects, sustainability rating systems, such as LEED for buildings or Envision for infrastructures, can be applied. These frameworks cause direct cost of resources to carry them on all along the project duration, and indirect cost for extra-design required and for non-standard solutions to address sustainability goals (Chandratilake 2013; Oluwalaiye, 2019): these direct and indirect extracosts cannot be decided in the project phase, but must be decided before the decision of developing the project is taken. This approach is potentially in conflict with the definition of project management: “The application of knowledge, skills, tools and techniques to project activities to meet the project requirement” (VV.AA., 2017). In fact, if project requirements only include project goals and requirements needed for the project’s specific purpose, probably sustainability has no chance to be present in project management. Instead, project requirements must include points that consider the organization’s long term strategy: in this way, sustainability can be seen as sustainable for business purposes (Oakland, 2015). For this reason, this paper identifies principles for developing a business case for a (mega)project including sustainability, in order to evaluate the implications of incorporating a 3P framework in the way projects are selected. It is the Author’s opinion that, as long as the cost for sustainability implementation has not been clearly included into project budget, sustainability will still resemble one of the “good intentions”, without a concrete possibility to be implemented through projects. In the following section of this paper, the Author will list strategies to implement sustainability in projects within a 3P framework, classified within distinct business sectors, and provide hints for evaluating direct and indirect costs and benefits, to work as an input for a business case and an economic evaluation of the project (Banihashemi, 2017; Beske, 2014; Chong, 2017; Clinning, 2017; Shah, 2018; Terrapon-Pfaff, 2014; Xue, 2018). Sustainability goals are economically sustainable if considered in the organizational framework (long-term). If the short-term focus is maintained, sustainability goals cannot be supported because violating the economic sustainability. The preliminary topics to be considered by this research are: Direct cost savings due (mainly) to environmental sustainability, such as reducing the use of material and energy during project development; Increase in the market share of the performing organization due to the increasing demand of sustainable products worldwide Reduction of risks occurrency and impact by implementing sustainable practices Increase in the organization’s share value and received investments due to implementation of sustainable practices Personnel turn over reduction, and attractiveness for qualified professional, in implementing sustainability principles Better decision-making process due to the resolution of ethical dilemmas Increasing the performing organization’s brand value In the following steps, the research will develop in detail the balancing of costs for sustainability and benefits both in the short term and in the long term of implementing it