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A large body of evidence has shown that modulation of the nuclear receptors peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), the proprotein convertase subtilisin/kexin type 9 (PCSK9) and inflammatory processes by natural compounds has hypolipidemic and anti-atherosclerotic effects. These beneficial outcomes are certainly related to the crucial function of these targets in maintaining cholesterol homeostasis and regulating systemic inflammation. Currently, the therapeutic scenario for cardiovascular diseases (CVD) offers a plethora of widely validated and functional pharmacological treatments to improve the health status of patients. However, patients are increasingly sceptical of pharmacological treatments which are often associated with moderate to severe side effects. The aim of our review is to provide a collection of the most recent scientific evidence on the most common phytochemicals, used for centuries in the Mediterranean diet and traditional chinese medicine that act on these key regulators of cholesterol homeostasis and systemic inflammation, which could constitute important tools for CVD management.

Objective Excess cholesterol loading on arterial macrophages is linked to foam cell formation, atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). However, the effect of changes in cholesterol loading on coronary plaque trajectory and the impact of RA therapies on this relationship are unknown. We investigated the association between variations in cholesterol loading capacity (CLC) over time and atherosclerosis progression.Methods In a prospective observational cohort study, coronary CT angiography evaluated atherosclerosis (non-calcified, partially calcified or fully calcified plaques and coronary artery calcium (CAC) score) in 100 patients with RA without cardiovascular disease at baseline and 6.9±0.4 years later. The presence of ≥5 plaques and lesions rendering >50% stenosis was considered an extensive and obstructive disease, respectively. Serum CLC was measured on human THP-1 monocyte-derived macrophages with a fluorometric assay.Results Mean CLC change (follow-up CLC−baseline CLC) was 1.54 (SD 3.69) μg cholesterol/mg protein. In models adjusting for atherosclerotic cardiovascular disease risk score, baseline plaque and other relevant covariates, CLC change (per SD unit increase) is associated with a higher likelihood of progression of non-calcified (OR 2.55, 95% CI 1.22 to 5.35), fully calcified plaque (OR 3.10, 95% CI 1.67 to 5.76), CAC (OR 1.80, 95% CI 1.18 to 2.74) and new extensive or obstructive disease (OR 2.43, 95% CI 1.11 to 5.34). Exposure to prednisone unfavourably influenced, while biologics and statins favourably affected the relationship between CLC change and atherosclerosis progression (all p-for-interactions ≤0.048).Conclusion CLC change is associated with atherosclerosis progression in a dose-dependent manner, including lipid-rich non-calcified plaques and extensive or obstructive disease that yield the greatest cardiovascular risk.

Abstract Objective The purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients. Methods The study enrolled 70 AD patients and 74 cognitively normal controls comparable for age and sex. Lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF. Results AD patients have normal plasma lipids but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in the plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls but the content of small discoidal preβ-HDL particles was significantly reduced. In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients’ plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aβ1-42 CSF content. Conclusion Taken together our data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aβ1-42).

Objectives: Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). Methods: Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. Results: ABCA1-CEC negatively correlated with ABCG1-CEC (r = −0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20–3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65–1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61–0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23–0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18–3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and

Objectives: High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events. Methods: Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol. Results: Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction ≤ 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027). Conclusion: ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

Objectives Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA).Methods Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum.Results CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users.Conclusion CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.

BackgroundThe etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities.MethodsWe measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively.ResultsWe found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (−16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA.ConclusionsWe demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (−41.6%, p < 0.0001 and −56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (−6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.