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Abstract Background Increased levels of pro-inflammatory proteins in plasma can be detected in older individuals and associate with the so called chronic low-grade inflammation, which contributes to a faster progression of aged-related cardiovascular (CV) diseases, including frailty, neurodegeneration, gastro-intestinal diseases and disorders reflected by alterations in the composition of gut microbiota. However, successful genetic programme of long-living individuals alters the trajectory of the ageing process, by promoting an efficient immune response that can counterbalance deleterious effects of inflammation and the CV complications. This is the case of BPIFB4 gene in which, homozygosity for a four single-nucleotide polymorphism (SNP) haplotype, the Longevity-Associated Variant (LAV) correlates with prolonged health span and reduced risk of CV complications and inflammation. The relation between LAV-BPIFB4 and inflammation has been proven in different experimental models, here we hypothesized that also human homozygous carriers of LAV-BPIFB4 gene may experience a lower inflammatory burden as detected by plasma proteomics that could explain their favourable CV risk trajectory over time. Moreover, we explored the therapeutic effects of LAV-BPIFB4 in inflammatory disease and monolayer model of intestinal barrier. Results We used high-throughput proteomic approach to explore the profiles of circulating proteins from 591 baseline participants selected from the PLIC cohort according to the BPIFB4 genotype to identify the signatures and differences of BPIFB4 genotypes useful for health and disease management. The observational analysis identified a panel of differentially expressed circulating proteins between the homozygous LAV-BPIFB4 carriers and the other alternative BPIFB4 genotypes highlighting in the latter ones a higher grade of immune-inflammatory markers. Moreover, in vitro studies performed on intestinal epithelial organs from inflammatory bowel disease (IBD) patients and monolayer model of intestinal barrier demonstrated the benefit of LAV-BPIFB4 treatment. Conclusions Homozygosity for LAV-BPIFB4 results in the attenuation of inflammation in PLIC cohort and IBD patients providing preliminary evidences for its therapeutic use in inflammatory disorders that need to be further characterized and confirmed by independent studies.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and morbidity worldwide. Low-density lipoprotein cholesterol (LDL-C) is one of the most important causal factors for ASCVD. Based on the evidence of the clinical benefits of lowering LDL-C, the current 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines provide guidance for optimal management of people with dyslipidaemia. These guidelines include new and revised concepts, with a general tightening of LDL-C goals to be achieved, especially for patients at high and very high cardiovascular risk, based on the results of clinical trials of the recently approved drugs for the treatment of hypercholesterolaemia. However, some issues are still open for discussion. Among others, the concept of lifetime exposure to elevated LDL-C levels will probably drive the pharmacological approach and future guidelines. In addition, other factors such as non-HDL-C, apolipoprotein B, and lipoprotein(a) are becoming increasingly important in determining cardiovascular risk. Finally, there is the question of whether combination therapy should be used as the first step to maximise the effectiveness of the pharmacological approach, avoiding the stepwise approach, which is likely to have a detrimental effect on adherence. Given the ever-changing landscape and the availability of new drugs targeting other important lipids, future guidelines will need to consider all these issues.

Background HDL is endowed with several metabolic, vascular, and immunoinflammatory protective functions. Among them, a key property is to promote reverse cholesterol transport from cells back to the liver. The aim of this study was to estimate the association of scavenger receptor class B type I (SR-BI)- and ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux (the two major routes for cholesterol efflux to HDL) with the presence, extent, and severity of coronary artery disease (CAD), vascular wall remodelling processes, coronary plaque characteristics, and the incidence of myocardial infarction in the different subgroups of patients from the CAPIRE study.Methods Patients (n = 525) from the CAPIRE study were divided into two groups: low-risk factors (RF), with 0–1 RF (n = 263), and multiple-RF, with ≥2 RFs; within each group, subjects were classified as no-CAD or CAD based on the segment involvement score (SIS) evaluated by coronary computed tomography angiography (SIS = 0 and SIS > 5, respectively). SR-BI- and ABCA1-mediated cholesterol efflux were measured using the plasma of all patients.Results SR-BI-mediated cholesterol efflux was significantly reduced in patients with CAD in both the low-RF and multiple-RF groups, whereas ABCA1-mediated cholesterol efflux was similar among all groups. In CAD patients, multivariable analysis showed that SR-BI-mediated cholesterol efflux

Summary: Background: The impact of the stepwise implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) treatment algorithm on low-density lipoprotein cholesterol (LDL-C) goal attainment was simulated in patients from the DA VINCI study. Methods: Monte Carlo simulation was used to evaluate treatment optimisation scenarios, based on a patient's risk category: statin intensification (step 1), addition of ezetimibe (step 2), and addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (step 3). Residual cardiovascular risk and predicted relative and absolute risk reduction (RRR and ARR) in cardiovascular events were assessed. Findings: In DA VINCI, 2482 patients did not achieve their 2019 ESC/EAS LDL-C goals and were included in the simulation. In patients without atherosclerotic cardiovascular disease (ASCVD) (n = 962), 27.0% (n = 259) and 57.0% (n = 548) are likely to achieve their LDL-C goals at step 1 and step 2, respectively. Of those at very high risk without ASCVD (n = 74), 88.1% (n = 65) are likely to achieve their LDL-C goals at step 3. In patients with ASCVD (n = 1520), 12.0% (n = 183), 42.1% (n = 641) and 93.2% (n = 1416) are likely to achieve their LDL-C goals at steps 1, 2 and 3, respectively. In patients with and without ASCVD, treatment optimisation may result in mean simulated RRR of 24.0% and 17.7%, respectively, and ARR of 8.1% and 2.6%, respectively. Interpretation: Most patients at high cardiovascular risk are unlikely to achieve LDL-C goals through statin optimisation and ezetimibe, and will require a PCSK9 inhibitor, leading to greater reduction in cardiovascular risk. Funding: Amgen.

Summary: Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M−) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk‐increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M− and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M− also had lower mean levels of pretreatment low‐density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M− and FH/M+ groups

Background: Major guidelines recommend the initiation of a beta-blocker therapy after an acute myocardial infarction (AMI). We aimed to map the treatment pathway of beta-blockers for AMI survivors during the first wave of COVID-19 pandemic in Italy and to investigate predictors for treatment non-initiation.Methods: Healthcare utilization databases of Lombardy Region were investigated. Subjects aged ≥18 years who were hospitalised with AMI in the period February-March-April of 2018, 2019, and 2020 were included, and followed for 30 days from the discharge date, to investigate whether they presented a first prescription of beta-blockers. A multivariate logistic model was performed to evaluate the effect of several covariates on the probability of not receiving a post-AMI beta-blocker therapy.Results: The cohorts comprised 2259, 2383, and 1932 individuals who were hospitalised with AMI in the 3-month period in 2018, 2019, and 2020, respectively. Overall in 2020, about 58–60% of individuals with AMI received a prescription of beta-blockers within 1 month after the discharge. A continuous decreasing trend over time was observed. Men were 30% more likely to start the treatment than women, increasing age was associated with significant increasing probability of not receiving a post-infarction beta-blocker therapy, while having received an antihypertensive or lipid-lowering treatment, or having been hospitalized for heart failure prior to the AMI hospitalization reduced the likelihood of not being treated with beta-blockers.Conclusion: The initiation of beta-blocker treatment after AMI remains an under-prescribed practice, that does not seem to have been further affected by the first wave of the COVID-19 pandemic.

Background and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (

Objective: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population. Methods: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks. Results: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of −19.66% (95% CI: −29.48% to −9.84%; P < .001) and −12.28% (95% CI: −22.12% to −2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD −5.20%; 95% CI: −15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported. Conclusions: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

The risk of atherosclerotic cardiovascular disease (ASCVD) is strongly related to lifetime exposure to low-density lipoprotein (LDL)-cholesterol in longitudinal studies. Lipid-lowering therapy (using statins, ezetimibe and PCSK9 inhibitors) substantially ameliorates the risk and is associated with long-term reduction in cardiovascular (CV) events. The robust evidence supporting these therapies supports their continued (and expanding) role in risk reduction. In addition to these ‘conventional’ therapeutics, while waiting for other innovative therapies, growing evidence supports the use of a range of ‘nutraceuticals’ (constituents of food prepared as pharmaceutical formulations) including preparations of red yeast rice (RYR), the product of yeast (Monascus purpureus) grown on rice, which is a constituent of food and is used in traditional Chinese medicine. The major active ingredient, monacolin K, is chemically identical to lovastatin. RYR preparations have been demonstrated to be safe and effective in reducing LDL-C, and CV events. However, surprisingly, RYR has received relatively little attention in international guidelines – and conventional drugs with the strongest evidence for event reduction should always be preferred in clinical practice. Nevertheless, the absence of recommendations relating to RYR may preclude the use of a product which may have clinical utility in particular groups of patients (who may anyway self-prescribe this product), what in the consequence might help to reduce population CV risk. This Position Paper of the International Lipid Expert Panel (ILEP) will use the best available evidence to give advice on the use of red-yeast rice in clinical practice.

Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver for the atherosclerotic process and that treatments that low‐density lipoprotein cholesterol lowering by up‐regulation of low‐density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline‐based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.

The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)

Cholesterol homeostasis can modulate immunity via multiple pathways. Here the authors show that apolipoprotein E, an important regulator of cholesterol, produced by myeloid cells can regulate T cell activation by controlling the antigen presentation activity of dendritic cells in both humans and mice.

Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel “omic” approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of “omics” presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these “omics”, are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre.

For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at the lowest levels but also those with high HDL-C levels are at increased risk of cardiovascular (CV) mortality. This “U-shaped” association has further fueled the discussion on the pathophysiological role of HDL in CVD. In fact, genetic studies, Mendelian randomization approaches, and clinical trials have challenged the notion of HDL-C levels being causally linked to CVD protection, independent of the cholesterol content in low-density lipoproteins (LDL-C). These findings have prompted a reconsideration of the biological functions of HDL that can be summarized with the word “HDL functionality”, a term that embraces the many reported biological activities beyond the so-called reverse cholesterol transport, to explain this lack of correlation between HDL levels and CVD. All these aspects are summarized and critically discussed in this review, in an attempt to provide a background scenario for the “HDL story”, a lipoprotein still in search of a role.

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)

Abstract Background For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable. Methods For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated. Results In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables. Conclusions We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies.

Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)-induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1−/− mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1−/− mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1−/− mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3β and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications.

High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.

When stimulated, rat serosal mast cells degranulate and secrete a cytoplasmic neutral protease, chymase. We studied the fragmentation of apolipoprotein (apo) A-I during proteolysis of HDL3 by chymase, and examined how chymase-dependent proteolysis interfered with the binding of eight murine monoclonal antibodies (Mabs) against functional domains of apoA-I. Size exclusion chromatography of HDL3 revealed that proteolysis for up to 24 h did not alter the integrity of the α-migrating HDL, whereas a minor peak containing particles of smaller size with preβ mobility disappeared after as little as 15 min of incubation. At the same time, generation of a large (26 kDa) polypeptide containing the N-terminus of apoA-I was detected. This large fragment and other medium-sized fragments of apoA-I produced after prolonged treatment with chymase were found to be associated with the αHDL; meanwhile, small lipid-free peptides were rapidly produced. Incubation of HDL3 with chymase inhibited binding of Mab A-I-9 (specific for preβ1HDL) most rapidly (within 15 min) of the eight studied Mabs. This rapid loss of binding was paralleled by a similar reduction in the ability of HDL3 to induce high-affinity efflux of cholesterol from macrophage foam cells, indicating that proteolysis had destroyed an epitope that is critical for this function. In sharp contrast, prolonged degradation of HDL3 by chymase failed to reduce the ability of HDL3 to activate LCAT, even though it led to modification of three epitopes in the central region of apoA-I that are involved in lecithin cholesterol acyltransferase (LCAT) activation.This differential sensitivity of the two key functions of HDL3 to the proteolytic action of mast cell chymase is compatible with the notion that, in reverse cholesterol transport, intactness of apoA-I is essential for preβ1HDL to promote the high-affinity efflux of cellular cholesterol, but not for the α-migrating HDL particles to activate LCAT.