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The goal in cardiovascular prevention is the reduction of morbidity and mortality through the promotion of healthy lifestyles in the general population. The management of modifiable risk factors with pharmacological and non-pharmacological interventions, based on the individual risk is the first strategy suggested by the current guidelines. Several epidemiological studies have clearly shown the direct correlation between high levels of low-density lipoprotein cholesterol (LDL-C) and incidence of cardiovascular diseases. On the other hand, numerous randomized clinical studies have reported a huge benefit in terms of major cardiovascular events achievable by the reduction of LDL-C, thus supporting the notion that “the lower is better”. Among the lipid-lowering strategies, statins are the drugs of choice in cardiovascular prevention, at both primary and secondary level. To achieve the ambitious targets suggested by the current guidelines, other lipid-lowering therapies are currently available in addition to statins, such as ezetimibe the inhibitors of the PCSK9. Pharmacological research has recently led to the development of a new drug, the bempedoic acid, which further enrich the available therapies. This drug also acts on the biosynthesis of cholesterol but at upstream level than statins. From the biochemical point of view, it has the potential to be considered before the statin with consequent titration of statins to achieve the desirable LDL-C target. In the present review, the biochemical and pharmacological characteristics of bempedoic acid are discussed. An overview of the clinical data that support its use in the management of the cardiovascular patient and its allocation in the lipid-lowering scenario will be also provided.

Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.

Introduction: Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered: This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion: Data from the clinical trials in the ORION program demonstrated efficacy and safety of inclisiran in patients with dyslipidemia. Adverse events were similar in the inclisiran and placebo groups in the clinical trials, although injection-site reactions were more frequent with inclisiran than with placebo. Although the combination of efficacy and safety makes inclisiran a good option for the treatment of dyslipidemia compared to other PCSK9 targeting therapeutic strategies, however, further studies should exclude the possibility that inclisiran, through lower-affinity interactions, may influence other mRNAs in the physiological milieu.

Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability.Chow diet-fed atherosclerosis-prone ApoeWe show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs.Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

Nitric oxide (NO) is a powerful mediator with biological activities such as vasodilation and prevention of vascular smooth muscle cell proliferation as well as functional regulation of cardiac cells. Thus, impaired production or reduced bioavailability of NO predisposes to the onset of different cardiovascular (CV) diseases. Alterations in the redox balance associated with excitation–contraction coupling have been identified in heart failure (HF), thus contributing to contractile abnormalities and arrhythmias. For its ability to influence cell proliferation and angiogenesis, NO may be considered a therapeutic option for the management of several CV diseases. Several clinical studies and trials investigated therapeutic NO strategies for systemic hypertension, atherosclerosis, and/or prevention of in stent restenosis, coronary heart disease (CHD), pulmonary arterial hypertension (PAH), and HF, although with mixed results in long-term treatment and effective dose administered in selected groups of patients. Tadalafil, sildenafil, and cinaguat were evaluated for the treatment of PAH, whereas vericiguat was investigated in the treatment of HF patients with reduced ejection fraction. Furthermore, supplementation with hydrogen sulfide, tetrahydrobiopterin, and nitrite/nitrate has shown beneficial effects at the vascular level.

Significance: Atherosclerotic cardiovascular diseases (ACVDs) continue to be a primary cause of mortality worldwide in adults aged 35-70 years, occurring more often in countries with lower economic development, and they constitute an ever-growing global burden that has a considerable socioeconomic impact on society. The ACVDs encompass diverse pathologies such as coronary artery disease and heart failure (HF), among others. Recent Advances: It is known that oxidative stress plays a relevant role in ACVDs and some of its effects are mediated by lipid oxidation. In particular, lipid peroxidation (LPO) is a process under which oxidants such as reactive oxygen species attack unsaturated lipids, generating a wide array of oxidation products. These molecules can interact with circulating lipoproteins, to diffuse inside the cell and even to cross biological membranes, modifying target nucleophilic sites within biomolecules such as DNA, lipids, and proteins, and resulting in a plethora of biological effects. Critical Issues: This review summarizes the evidence of the effect of LPO in the development and progression of atherosclerosis-based diseases, HF, and other cardiovascular diseases, highlighting the role of protein adduct formation. Moreover, potential therapeutic strategies targeted at lipoxidation in ACVDs are also discussed. Future Directions: The identification of valid biomarkers for the detection of lipoxidation products and adducts may provide insights into the improvement of the cardiovascular risk stratification of patients and the development of therapeutic strategies against the oxidative effects that can then be applied within a clinical setting.

The change of paradigm determined by the introduction of cardiac computed tomography (CCT) in the field of cardiovascular medicine has allowed new evidence to emerge. These evidences point towards a major role, probably the most important one in terms of prognostic impact, in the detection, characterization and quantification of atherosclerosis as the main driver and endpoint for the management of coronary artery disease (CAD). Extensive literature has been published in the last decade with large numbers and patients’ populations, investigating several aspects and correlations between atherosclerotic plaque features and risk factors; also, the relationship between plaque features, both with qualitative and quantitative approaches, and cardiovascular events has been investigated. More recent studies have also pointed out the relationship between the knowledge and classification of sub-clinical atherosclerosis and the induced modification of medical therapy (both aggressiveness and compliance) that is most likely able to increase the effect of anti-atherosclerotic drugs, hence significantly improving prognosis. Non-invasive assessment of CAD by means of CCT is becoming the primary tool for management and also the most important parameter for the comprehension of natural history of CAD and how the therapies we adopt are affecting plaque burden as a whole. In this review we will address the modern concepts of CAD driven understanding and management of cardiovascular disease.

Non-invasive depiction of coronary arteries has been a great challenge for imaging specialists since the introduction of computed tomography (CT). Technological development together with improvements in spatial, temporal, and contrast resolution, progressively allowed implementation of the current clinical role of the CT assessment of coronary arteries. Several technological evolutions including hardware and software solutions of CT scanners have been developed to improve spatial and temporal resolution. The main challenges of cardiac computed tomography (CCT) are currently plaque characterization, functional assessment of stenosis and radiation dose reduction. In this review, we will discuss current standards and future improvements in CCT.

Background The 2018 European Society of Cardiology/European Society of Hypertension arterial hypertension guidelines do not recommend routine carotid ultrasound as a tool to identify hypertension‐mediated organ damage, unless clinically indicated. However, carotid plaque (CP) is a strong correlate of increased arterial stiffness, which influences blood pressure (BP) control over time. Thus, we assessed whether evidence of CP at first visit could predict BP control during follow‐up. Methods and Results From the CSN (Campania Salute Network) Registry, 6684 patients with hypertension had complete carotid ultrasound examination and were categorized by the presence of CP at baseline. Optimal BP control was defined as average BP P P P P Conclusions Presence of CP in treated patients with hypertension is associated with suboptimal BP control during follow‐up, independently of worse metabolic profile and presence of left ventricular hypertrophy.

BackgroundPatients with SLE have an endothelial dysfunction (ED), which is considered the earliest marker of cardiovascular (CV) disease. Endothelial cell activation induced by proinflammatory cytokines is defined by the endothelial expression of cell-surface adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. The aim of this study was to investigate whether serum endothelial adhesion molecule levels are influenced by blood hydroxychloroquine (HCQ) levels in SLE.MethodsConsecutive patients with SLE taking a stable dose of HCQ were investigated. At study entry and 6 months later HCQ blood levels were quantified by tandem mass spectrometry. Serum levels of P-selectin, E-selectin, ICAM-1 and VCAM-1 were also measured using a Luminex 200 instrument. Comparison of endothelial soluble adhesion molecules in groups with different HCQ blood levels was performed by t-test.Results83 patients with SLE were enrolled. Correlation were demonstrated between mean blood HCQ concentrations and endothelial soluble adhesion molecules (E-selectin, ICAM-1 and VCAM-1). Moreover, serum levels of ICAM-1 and VCAM-1 were significantly lower in the patients with SLE with HCQ blood levels >500 ng/mL (83.67±52.8 ng/mL vs 158.81±125.1 ng/mL and 8.9±2.2 ng/mL vs 10.4±2.3 ng/mL). Serum levels of E-selectin were nearly significantly lower in the patients with SLE with HCQ blood levels >500 ng/mL (64.7±30.2 ng/mL vs 71.6±42.2 ng/mL, p=0.06). No significant difference in concentration of P-selectin was detected.ConclusionsIn the present study, there was a trend towards higher adhesion molecules levels with lower HCQ blood levels in patients with SLE. Further longitudinal studies will determine whether changes in endothelial biomarkers reflect decreased clinical CV events.

Background and aims: Data from animals suggest that immunoglobulins G (IgG) play a mechanistic role in atherosclerosis and diabetes through endothelial dysfunction and insulin resistance. Patients with common variable immunodeficiency (CVID), who have low circulating levels of IgG and are treated with intravenous polyclonal IgG (IVIgG), may provide an ideal model to clarify whether circulating IgG modulate endothelial function and affect insulin sensitivity in humans. Methods and results: We studied 24 patients with CVID and 17 matched healthy controls (HC). Endothelial function was evaluated as flow mediated dilation (FMD) of the brachial artery at baseline and 1, 7, 14, and 21 days after IVIgG infusion in the CVID patients. We measured also plasma glucose, insulin, and calculated the HOMA-IR index. We also investigated the role of human IgG on the production of Nitric Oxide (NO) in vitro in Human Coronary Artery Endothelial Cells (HCAEC). Compared to HC, FMD of CVID patients was significantly impaired at baseline (9.4 ± 0.9 and 7.6 ± 0.6% respectively, p < 0.05) but rose above normal levels 1 and 7 days after IVIgG infusion to return at baseline at 14 and 21 days. Serum insulin concentration and HOMA-IR index dropped by 50% in CVID patients after IVIgG (p < 0.002 vs. baseline). In vitro IgG stimulated NO production in HCAEC. Conclusions: Reduced IgG levels are associated with endothelial dysfunction and IVIgG stimulates endothelial function directly while improving insulin sensitivity. The current findings may suggest an anti-atherogenic role of human IgG.

Objectives: Metabolic syndrome (MetS) is usually associated in general population with systemic inflammation and higher cardiovascular risk, but data about the effect of statins in patients with HIV infection and MetS are lacking to date. Methods: Prospective cohort study of treated HIV-infected patients, aged from 40 to 60 years, with or without MetS, who started rosuvastatin (10 mg daily), and were followed-up for 12 months. The primary endpoint was change in serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The secondary endpoint was change in the carotid intima-media thickness (IMT). Results: One hundred and twenty-five patients were enrolled: 61 with MetS (MetS group) and 64 without MetS (control group). After 12 months, rosuvastatin produced a significant decrease in mean serum levels of hsCRP (-0.28 mg/dL; p = .037), IL-6 (-2.1 pg/mL; p = .018) and TNF-α (-6.3 pg/mL; p = .004) in patients with MetS. On the contrary, in controls rosuvastatin did not lead to a significant change in mean levels of all biomarkers. After 12 months, the mean IMT increase at the carotid bifurcation was significantly lower in the MetS group than in the control group at the carotid bifurcation (0.017 vs. 0.031 mm; p = .037) and in all other anatomical sites. Conclusion: Our findings suggest that rosuvastatin is effective in reducing serum inflammation markers and slowing atherosclerosis progression rate in HIV-infected patients on cART and with MetS, while its effects on serum biomarkers and IMT increase seem to be negligible in those without MetS.

Epidemiological studies have documented a high incidence of diabetes in hypertensive patients.Insulin resistance is defined as a less than expected biologic response to a given concentration of the hormone and plays a pivotal role in the pathogenesis of diabetes. However, over the last decades, it became evident that insulin resistance is not merely a metabolic abnormality, but is a complex and multifaceted syndrome that can also affect blood pressure homeostasis. The dysregulation of neuro-humoral and neuro-immune systems is involved in the pathophysiology of both insulin resistance and hypertension. These mechanisms induce a chronic low grade of inflammation that interferes with insulin signalling transduction. Molecular abnormalities associated with insulin resistance include the defects of insulin receptor structure, number, binding affinity, and/or signalling capacity. For instance, hyperglycaemia impairs insulin signalling through the generation of reactive oxygen species, which abrogate insulin-induced tyrosine autophosphorylation of the insulin receptor. Additional mechanisms have been described as responsible for the inhibition of insulin signalling, including proteasome-mediated degradation of insulin receptor substrate 1/2, phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation of both insulin receptor and insulin receptor substrates. Insulin resistance plays a key role also in the pathogenesis and progression of hypertension-induced target organ damage, like left ventricular hypertrophy, atherosclerosis and chronic kidney disease. Altogether these abnormalities significantly contribute to the increase the risk of developing type 2 diabetes.

Aspirin is the most commonly used medication worldwide. Beside its well-known anti-inflammatory effects, a role has emerged in the prevention of cardiovascular events. However, a significant benefit has been demonstrated in secondary cardiovascular prevention only, while there is limited evidence supporting a role in primary prevention. This discrepancy might depend on the that so far, the high-risk populations that will achieve the greatest benefits yet experiencing minimal harmful side effects have not been identified. Patients with autoimmune systemic rheumatic diseases have an increased risk of cardiovascular complications compared with the general population, which makes aspirin of potential value in these subjects. Moving from general aspects of aspirin pharmacology and specific issues in general population, the aim of this study is to review the evidence about the role of low-dose aspirin in primary cardiovascular prevention in autoimmune systemic rheumatic diseases.

Objectives The persistent positivity of aPLs, either isolated or associated with thrombotic and/or obstetric events (APS), has been associated with the increase of intima-media thickness (IMT) and carotid plaques. Despite the fact that aPLs can promote both thrombotic and obstetric complications, some pathogenic differences have been documented between the two entities. This study aimed to evaluate whether the atherosclerotic risk differs between subjects with obstetric and thrombotic APS. Methods A total of 167 APS women (36 obstetric and 131 thrombotic) were compared with 250 aPLs negative controls. IMT of the common carotid artery (CCA) and of the bulb and the prevalence of carotid plaques were assessed. Results CCA- and bulb-IMT were significantly higher in women with thrombotic APS, while being similar between the obstetric APS and the controls [CCA-IMT: mean (s.d.) 0.97 (0.49), 0.78 (0.22) and 0.81 (0.12) mm for the thrombotic, obstetric and control groups, respectively, P < 0.001 between thrombotic and controls, P = 0.002 between thrombotic and obstetric; bulb-IMT: mean (s.d.) 1.38 (0.79), 0.96 (0.27) and 0.96 (0.51) mm for the thrombotic, obstetric and control groups, P < 0.001]. Women with thrombotic APS had significantly increased risk of presenting carotid plaques. This risk was significantly lower in obstetric APS. Conclusion Unlike thrombotic APS, obstetric APS is not associated with an increase of markers of subclinical atherosclerosis. If confirmed on wider populations, these results could suggest different pathogenetic role of aPLs in promoting atherosclerosis in vascular and obstetric APS, and raise questions on the risk–benefit profile of thromboprophylaxis in obstetric APS outside pregnancy periods.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, ankle-brachial index, pulse wave velocity, and coronary artery calcium. the Prospective Studies of Atherosclerosis (Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. in summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. the consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences. (c) 2020 S. Karger AG, Basel, Austrian Science Fund (FWF)Austrian Science Fund (FWF) [P 32488]; Dr.-Johannes-and-Hertha-Tuba Foundation, This work was funded by the Austrian Science Fund (FWF) (P 32488) and the Dr.-Johannes-and-Hertha-Tuba Foundation. Funders of individual studies contributing to the present analysis arelisted onthe Proof-ATHERO webpage(https://clinicalepi.i-med.ac.at/research/proof-athero/studies/).

Atherosclerosis is responsible for large cardiovascular mortality in many countries globally. It has been shown over the last decades that the reduction of atherosclerotic progression is a critical factor for preventing future cardiovascular events. Low-density lipoproteins (LDL) have been successfully targeted, and their reduction is one of the key preventing measures in patients with atherosclerotic disease. LDL particles are pivotal for the formation and progression of atherosclerotic plaques; yet, they are quite heterogeneous, and smaller, denser LDL species are the most atherogenic. These particles have greater arterial entry and retention, higher susceptibility to oxidation, as well as reduced affinity for the LDL receptor. Increased proportion of small, dense LDL particles is an integral part of the atherogenic lipoprotein phenotype, the most common form of dyslipidemia associated with insulin resistance. Recent data suggest that both genetic and epigenetic factors might induce expression of this specific lipid pattern. In addition, a typical finding of increased small, dense LDL particles was confirmed in different categories of patients with elevated cardiovascular risk. Small, dense LDL is an independent risk factor for cardiovascular diseases, which emphasizes the clinical importance of both the quality and the quantity of LDL. An effective management of atherosclerotic disease should take into account the presence of small, dense LDL in order to prevent cardiovascular complications.

Citrus fruits are the main fruits of the Mediterranean diet and have been long recognized for their beneficial effects on human health. Observational studies have shown a significant association between dietary flavonoid intake and reduced risk of cardiovascular and malignant diseases. The beneficial effects of citrus fruits on human health appear to be due to their high content in vitamins, minerals and fibers. In particular, the antioxidant and anti-inflammatory activities have been indicated as some of the mechanisms through which citrus fruits may thwart the development of chronic degenerative diseases such as atherosclerosis and cancer. This review would critically examine the results from numerous experimental and clinical studies carried out in order assess the contribute of citrus flavonoids to the prevention of chronic pathological conditions including atherosclerosis and cancer.

Introduction: The pathophysiology of atherosclerosis and its acute complications, such as the Acute Coronary Syndromes (ACS), is continuously under investigation. Immunity and inflammation seem to play a pivotal role in promoting formation and grow of atherosclerotic plaques. At the same time, plaque rupture followed by both platelets’ activation and coagulation cascade induction lead to intracoronary thrombus formation. Although these phenomena might be considered responsible of about 90% of ACS, in up to 5–10% of acute syndromes, a non-obstructive coronary artery disease (MINOCA) might be documented. This paper gives an overview on atherothrombosis and immuno-inflammation processes involved in ACS pathophysiology, also emphasizing the pathological mechanisms potentially involved in MINOCA. Areas covered: The relationship between immuno-inflammation and atherothrombosis is continuously updated by recent findings. At the same time, pathophysiology of MINOCA still remains a partially unexplored field, stimulating the research of potential links between these two aspects of ACS pathophysiology. Expert opinion: Pathophysiology of ACS has been extensively investigated; however, several gray areas still remain. MINOCA represents one of these areas. At the same time, many aspects of immune-inflammation processes are still unknown. Thus, research should be continued to shed a brighter light on both these sides of “ACS” moon.

Background and aims: Atherosclerosis is widely accepted to be an inflammatory disease driven by lipid accumulation and leukocyte recruitment. More recently, galectins, a family of β-galactoside binding proteins, have been shown to play a role in leukocyte recruitment among other immunomodulatory functions. Galectin (Gal) −9, a tandem repeat type galectin expressed by the endothelium in inflammatory environments, has been proposed to promote leukocyte recruitment. However, the role of Gal-9 in the context of monocyte recruitment remains elusive. Methods and Results: Here, we characterise the immunomodulatory role of Gal-9 in context of atherosclerosis. We show that ApoE−/−Gal-9−/− mice have a significantly reduced aortic plaque burden compared to their ApoE−/− littermate controls after 12 weeks of high fat diet. RNA sequencing data from two independent studies reveal Lgals9 expression in leukocyte clusters isolated from murine atherosclerotic plaques. Additionally, soluble Gal-9 protein induces monocyte activation and a pro-inflammatory phenotype in macrophages. Furthermore, we show that immobilised recombinant Gal-9 acts as capture and adhesion molecule for CD14+ monocytes in a β2-integrin and glycan dependent manner, while adhesion of monocytes to stimulated endothelium is reduced when Gal-9 is knocked down. Gal-9 also facilitates enhanced recruitment of leukocytes from peripheral arterial disease (PAD) patients compared to healthy young and aged controls. We further characterise the endothelium as source of circulating Gal-9, which is increased in plasma of PAD patients compared to healthy controls. Conclusions: These results highlight a pathological role for Gal-9 as promoter of monocyte recruitment and atherosclerotic plaque progression, making it a novel target in the prevention of plaque formation and progression.

Many drugs affect lipid metabolism and have side effects which promote atherosclerosis. The prevalence of cancer-therapy-related cardiovascular (CV) disease is increasing due to development of new drugs and improved survival of patients: cardio-oncology is a new field of interest and research. Moreover, drugs used in transplanted patients frequently have metabolic implications. Increasingly, internists, lipidologists, and angiologists are being consulted by haematologists for side effects on metabolism (especially lipid metabolism) and arterial circulation caused by drugs used in haematology. The purpose of this article is to review the main drugs used in haematology with side effects on lipid metabolism and atherosclerosis, detailing their mechanisms of action and suggesting the most effective therapies.

Atherosclerosis is a progressive inflammatory disease leading to mortality and morbidity in the civilized world. Atherosclerosis manifests as an accumulation of plaques in the intimal layer of the arterial wall that, by its subsequent erosion or rupture, triggers cardiovascular diseases. Diabetes mellitus is a well-known risk factor for atherosclerosis. Indeed, Type 2 diabetes mellitus patients have an increased risk of atherosclerosis and its associated-cardiovascular complications than non-diabetic patients. Sodium-glucose co-transport 2 inhibitors (SGLT2i), a novel anti-diabetic drugs, have a surprising advantage in cardiovascular effects, such as reducing cardiovascular death in a patient with or without diabetes. Numerous studies have shown that atherosclerosis is due to a significant inflammatory burden and that SGLT2i may play a role in inflammation. In fact, several experiment results have demonstrated that SGLT2i, with suppression of inflammatory mechanism, slows the progression of atherosclerosis. Therefore, SGLT2i may have a double benefit in terms of glycemic control and control of the atherosclerotic process at a myocardial and vascular level. This review elaborates on the anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis.

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).

Aims Lomitapide is a lipid-lowering agent indicated as an adjunct therapy for adult homozygous familial hypercholesterolaemia (HoFH). This study evaluated the medium-term effectiveness and safety of lomitapide in a large cohort of HoFH patients in Europe. Methods and results In a multicentre retrospective, observational study including 75 HoFH patients treated with lomitapide in a real-world clinical setting from 9 European countries, low-density lipoprotein cholesterol (LDL-C) changes, adverse events (AEs), and major adverse cardiovascular events (MACE) were assessed. After a median 19 months (interquartile range 11–41 months) of treatment with a mean dosage of 20 mg of lomitapide. Low-density lipoprotein cholesterol decreased by 60%, from baseline 280.5 mg/dL (191.8–405.0 mg/dL) to 121.6 mg/dL (61.0–190.5 mg/dL). At the last visit, 32.0% of patients achieved LDL-C Conclusion In this medium-term real-world experience, lomitapide proved to be very effective in reducing LDL-C in HoFH. Gastrointestinal AEs were common, but liver safety was reassuring with no sign of increased risk of liver fibrosis. A signal of cardiovascular protection was also observed.

BACKGROUND: Carotid artery disease is highly prevalent and a main cause of ischemic stroke and vascular dementia. There is a paucity of information on predictors of serious vascular events. Besides percentage diameter stenosis, international guidelines also recommend the evaluation of qualitative characteristics of carotid artery disease as a guide to treatment, but with no agreement on which qualitative features to assess. This inadequate knowledge leads to a poor ability to identify patients at risk, dispersion of medical resources, and unproven use of expensive and resource-consuming techniques, such as magnetic resonance imaging, positron emission tomography, and computed tomography.OBJECTIVES: The Carotid Artery Multimodality imaging Prognostic (CAMP) study will: prospectively determine the best predictors of silent and overt ischemic stroke and vascular dementia in patients with asymptomatic subcritical carotid artery disease by identifying the noninvasive diagnostic features of the 'vulnerable carotid plaque'; assess whether 'smart' use of low-cost diagnostic methods such as ultrasound-based evaluations may yield at least the same level of prospective information as more expensive techniques.STUDY DESIGN: We will compare the prognostic/predictive value of all proposed techniques with regard to silent or clinically manifest ischemic stroke and vascular dementia. The study will include ≥300 patients with asymptomatic, unilateral, intermediate degree (40-60% diameter) common or internal carotid artery stenosis detected at carotid ultrasound, with a 2-year follow-up. The study design has been registered on Clinicaltrial.gov on December 17, 2020 (ID number NCT04679727).

Cardiovascular diseases (CVD) are the leading cause of global mortality and their pathogenesis lies mainly in the atherosclerotic process. There are close connections linking oxidative stress and inflammation to endothelial dysfunction, atherosclerosis and, consequently, to CVD. This review focuses on the role of xanthine oxidoreductase (XOR) and its products on the development of chronic inflammation and oxidative stress, responsible for atheromatous plaque formation. Evidence is reported that an excessive level of XOR products favors inflammatory response and plaque development, thereby promoting major cardiovascular risk factors. Also, the relationship between hyperuricemia and hypertension as well as between XOR activity and CVD is confirmed. In spite of the increasing number of clinical studies investigating the output of cardiovascular patients treated with urate-lowering therapies (including uricosuric drugs, XOR inhibitors and recombinant uricase) the results are still uncertain. The inhibition of XOR activity appears more promising than just the control of uricemia level in preventing cardiovascular events, possibly because it also reduces the intracellular accumulation of urate, as well as the production of reactive oxygen species. However, XOR inhibition also reduces the availability of the multifaced mediator nitric oxide and, at present, can be recommended only in hyperuricemic patients., Graphical abstract Image 1, Highlights • Oxidative stress and inflammation are strictly related to atherosclerosis and CVD. • XOR products can bring on oxidative stress and inflammation. • XOR and uric acid in serum are implicated in cardiovascular diseases. • XOR products favor plaque development, promoting major cardiovascular risk factors. • The nitrate reductase activity of XOR has protective outcomes.

The complexity of cardiovascular diseases (CVDs), which remains the leading cause of death worldwide, makes the current clinical pathway for cardiovascular risk assessment unsatisfactory, as there remains a substantial unexplained residual risk. Simultaneous assessment of a large number of plasma proteins may be a promising tool to further refine risk assessment, and lipoprotein-associated proteins have the potential to fill this gap. Technical advances now allow for high-throughput proteomic analysis in a reproducible and cost-effective manner. Proteomics has great potential to identify and quantify hundreds of candidate marker proteins in a sample and allows the translation from isolated lipoproteins to whole plasma, thus providing an individual multiplexed proteomic fingerprint. This narrative review describes the pathophysiological roles of atherogenic apoB-containing lipoproteins and the recent advances in their mass spectrometry-based proteomic characterization and quantitation for better refinement of CVD risk assessment.

Introduction: Different models have been proposed for the prediction of the risk/benefit ratio of surgery in patients with carotid atheromasic disease, mainly based on clinical patients’ characteristics and risk factors, but no definite biological markers predictive of plaque instability and disease evolution have emerged so far, able to help the surgeon in the choice and timing of treatment. The main purpose of the present study was to assess the role of the polymorphism for genes commonly implicated in cell proliferation and neoangiogenesis in the clinical and histopathological carotid plaque vulnerability. Materials and methods: We retrospectively studied 29 consecutive patients who underwent carotid endarterectomy in 6 months. All histological variables were collected, as well as patients’ cardiovascular risk factors, clinical presentation, and brain computed tomography (CT) for the presence of ischemic lesions. Next-Generation Sequencing (NGS) was performed on 10-µm FFPE sections by means of a multi-gene panel used for sequencing 343 amplicons in 28 genes. Results: Among the gene variants observed, the polymorphism p.(Gln787=) in the EGFR gene was inversely correlated with intraplaque hemorrhage (p = 0.014), but also with the presence of ischemic brain lesions at CT (p = 0.001). Also p.(Gly105=) polymorphism in the IDH1 gene was inversely correlated with the presence of ischemic brain lesions (p = 0.038). Conclusions: The variant p.(Gln787=) in the EGFR gene seems to play a role in plaque stability in patients with carotid atheromasic disease, on both histopathological and clinical grounds, probably acting on plaque matrix remodeling. This can open new scenarios on the pre-surgical management of these patients.

The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the disease complexity, but still many questions remain unanswered, both mechanistically and pharmacologically. Here, we provided evidence that the pro-oxidant enzyme Prenylcysteine Oxidase 1 (PCYOX1), in the human atherosclerotic lesions, is both synthesized locally and transported within the subintimal space by proatherogenic lipoproteins accumulating in the arterial wall during atherogenesis. Further, Pcyox1 deficiency in Apoe-/- mice retards atheroprogression, is associated with decreased features of lesion vulnerability and lower levels of lipid peroxidation, reduces plasma lipid levels and inflammation. PCYOX1 silencing in vitro affects the cellular proteome by influencing multiple functions related to inflammation, oxidative stress, and platelet adhesion. Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as an emerging player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide additional therapeutic opportunities in addressing atherosclerosis., Banfi et al. investigate the role of Prenylcysteine oxidase 1 (PCYOX1), an enzyme implicated in catabolism of prenylated cysteine, in human and murine atherosclerosis. They find that loss of PCYOX1 is anti-atherogenic and understanding its biology and functions can potentially provide significant therapeutic opportunities in addressing atherosclerosis.

Theranostics, literally derived from the combination of the words diagnostics and therapy, is an emerging field of clinical and preclinical research, where contrast agents, drugs and diagnostic techniques are combined to simultaneously diagnose and treat pathologies. Nanoparticles are extensively employed in theranostics due to their potential to target specific organs and their multifunctional capacity. In this review, we will discuss the current state of theranostic nanomedicine, providing key examples of its application in the imaging and treatment of cardiovascular inflammation.

Objective We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients. Methods Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up. Results Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P, Highlights • The identification of novel molecular targets of atherosclerosis progression is of utmost importance in diabetic patients. • The occurrence of SGLT2 receptors on the endothelial cells of atherosclerotic plaques may be an attractive therapeutic option for atherosclerosis in patients with diabetes. • SGLT2/SIRT6 represents an attractive option, given its crucial involvement in atherosclerosis progression. • The endothelial SGLT2 inhibition increases the endothelial expression of SIRT6, yielding an improved atherosclerotic plaque phenotype and 2-year outcome. • The impairment of the endothelial SGLT2/SIRT6 pathway worsens outcomes in atherosclerotic patients with diabetes; this may be a potential preventive target.

Devil's Claw is a traditional medicine that has been long used a wide range of health conditions, including indigestion, fever, allergic reactions, and rheumatism. The main compounds are iridoid glycosides, including harpagoside, harpagide, and procumbide. However, harpagoside is the most responsible for therapeutic activity, and its content is used as reference standard. Here, we analyzed and summarized preclinical and clinical studies focusing on therapeutic efficacy of devil's claw preparations in pathological conditions in which inflammation plays a key causative role.Devil's claw (Harpagophytum procumbens) is an herbaceous plant, which can be found in the arid steppes of South Africa, particularly in the Kalahari Desert. As traditional medicine, devil's claw has been long used in the forms of infusions, decoctions, tinctures, powders, and extracts. The main compounds of devil's claw are iridoid glycosides, such as harpagoside, harpagide, and procumbide, which are present in the plant tubers. Additionally, chemical constituents such as sugars (mainly the tetrasaccharide stachyose), triterpenoids (oleanolic and ursolic acid), phytosterols (primarily β-sitosterol), aromatic acids (caffeic, cinnamic, and chlorogenic acids), and flavonoids (luteolin and kaempferol) can be found in the plant. In order to investigate the applicative potential of devil's claw as therapeutic agent, we performed a review by focusing on its potential role in managing inflammation- and oxidative stress-related diseases, including arthritis, osteoporosis, inflammatory bowel disease, low-back pain, diabetes, and neurodegeneration.