Atherosclerosis-related Cardiovascular Disease Research Articles

Exploring apolipoprotein C-III: pathophysiological and pharmacological relevance.

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody.

Appropriate Use of Primary Statin Preventive Therapy Among Patients with High Atherosclerosis-Related Cardiovascular Disease Risks: Cross-Sectional Study, Northeast Ethiopia

Appropriate Use of Primary Statin Preventive Therapy Among Patients with High Atherosclerosis-Related Cardiovascular Disease Risks: Cross-Sectional Study, Northeast Ethiopia

Association Between Atherosclerosis-Related Cardiovascular Disease and Uveitis: A Systematic Review and Meta-Analysis.

Uveitis is not only an intraocular inflammatory disease, but also an indicator of systemic inflammation. It is unclear whether uveitis can increase the risk of cardiovascular disease (CVD) through the atherosclerotic pathway. PubMed and Embase databases were searched until 5 September, 2022. Original studies investigating uveitis and cardiovascular events were selected. The random-effects model was used to calculate the difference of groups in pooled estimates. A total of six observational studies that included mainly ankylosing spondylitis (AS) patients were included. Of these, three studies reported data on carotid plaques and carotid intima-media thickness (cIMT) and the other three studies provided data on atherosclerosis-related CVD. No significant difference was found in cIMT between uveitis and controls (MD = 0.01, 95% CI = -0.03-0.04, p = 0.66), consistent with the findings of carotid plaque incidence (OR = 1.30, 95% CI = 0.71-2.41, p = 0.39). However, uveitis was associated with a 1.49-fold increase in atherosclerosis-related CVD (HR = 1.49, 95% CI = 1.20-1.84, p = 0.0002). Uveitis is a predictor of atherosclerosis-related CVD in AS patients. For autoimmune disease patients with uveitis, earlier screening of cardiovascular risk factors and the implementation of corresponding prevention strategies may be associated with a better prognosis.

Oxidized phospholipids and lipoprotein-associated phospholipase A2 (Lp-PLA2 ) in atherosclerotic cardiovascular disease: An update.

Inflammation and oxidative stress conditions lead to a variety of oxidative modifications of lipoprotein phospholipids implicated in the occurrence and development of atherosclerotic lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is established as an independent risk biomarker of atherosclerosis-related cardiovascular disease (ASCVD) and mediates vascular inflammation through the regulation of lipid metabolism in the blood and in atherosclerotic lesions. Lp-PLA2 is associated with low- and high-density lipoproteins and Lipoprotein (a) in human plasma and specifically hydrolyzes oxidized phospholipids involved in oxidative stress modification. Several oxidized phospholipids (OxPLs) subspecies can be detoxified through enzymatic degradation by Lp-PLA2 activation, forming lysophospholipids and oxidized non-esterified fatty acids (OxNEFAs). Lysophospholipids promote the expression of adhesion molecules, stimulate cytokines production (TNF-α, IL-6), and attract macrophages to the arterial intima. The present review article discusses new data on the functional roles of OxPLs and Lp-PLA2 associated with lipoproteins.

Anti-atherosclerotic Effects of Myrtenal in High-Fat Diet-Induced Atherosclerosis in Rats

The major cause of death worldwide is atherosclerosis-related cardiovascular disease (ACD). Myrtenal was studied to determine control rats were given standard diets and a high-fat diet was given to AS model groups. Atherosclerosis-related cardiovascular disease (ACD) is globally attributed to being a predominant cause of mortality. While the beneficial effects of Myrtenal, the monoterpene from natural compounds, are increasingly being acknowledged, its anti-atherosclerotic activity has not been demonstrated clearly. The present study is proposed to determine the anti-atherosclerotic activity of Myrtenal in high-fat diet-induced atherosclerosis (AS) rat models. Control groups were maintained with standard diets, the AS model rats were provided a high-fat diet, two of the experimental groups fed with a high-fat diet were treated with Myrtenal (50mg/kg and 100mg/kg), and one experimental group on high-fat diet was treated with simvastatin (10mg/kg) for 30days. The levels of inflammatory cytokines were analyzed using kits. The lipoproteins and the lipid profile were estimated using an auto-analyzer. The atherogenic index and marker enzyme activities were also determined. Serum concentrations of 6-keto-prostaglandin F1α (6-keto-PGF1α), thromboxaneB2 (TXB2), endothelin (ET), and nitric oxide (NO) were measured. The AS model groups indicated altered lipid profile, lipoprotein content, atherogenic index, calcium levels, HMG-CoA reductase activity, collagen level, and mild mineralization indicating atherosclerosis, while the AS-induced Myrtenal-treated groups demonstrated anti-atherogenic activity. The Myrtenal-treated groups exhibited a decreased TC, TG, and LDLc levels; increased HDLc levels; and a decline in the inflammatory cytokines such as CRP, IL-1β, IL-8, and IL-18 when compared to the untreated AS rats. Furthermore, Myrtenal decreased ET, TXB2, and 6-keto-PGF1α levels indicating its anti-atherosclerotic activity. The study results thus indicate that Myrtenal modulates the lipid metabolic pathway to exert its anti-atherosclerotic activity.

Flow Cytometry Analysis of Hematopoietic Stem/Progenitor Cells and Mature Blood Cell Subsets in Atherosclerosis.

Advancing age causesphysiologic decline in tissue function. In the hematopoietic system this manifests as a progressive reduction in blood or immune cell function and clonal hematopoiesis, where a mutated hematopoietic stem cell candominate blood cell production andconfer an increased propensity for myeloid malignancy. In the aging cardiovascular system, atherosclerosis causes an inflammatory cell- driven accumulation of lipid-derived plaques in major arteries which constrains blood flow and can lead to myocardial infarction and stroke. Clonal hematopoiesis in the elderly has recently been associated with a substantially increased risk of atherosclerosis-related cardiovascular disease. However, the direct association between deregulated hematopoiesis in clonal hematopoiesis and atherosclerosis is poorly defined. Herein, we describe a flow cytometry method to prospectively analyze the crucial hematopoietic stem/progenitor, inflammatory and lymphoid cell participants in atherosclerosis. This analysis can be applied to decipher the complex relationship between hematopoietic cell types involved in clonal hematopoiesis and atherosclerosis in mouse models.

Genetically-engineered hamster models: applications and perspective in dyslipidemia and atherosclerosis-related cardiovascular disease.

Cardiovascular disease is the leading cause of morbidity and mortality in both developed and developing countries, in which atherosclerosis triggered by dyslipidemia is the major pathological basis. Over the past 40 years, small rodent animals, such as mice, have been widely used for understanding of human atherosclerosis-related cardiovascular disease (ASCVD) with the advantages of low cost and ease of maintenance and manipulation. However, based on the concept of precision medicine and high demand of translational research, the applications of mouse models for human ASCVD study would be limited due to the natural differences in metabolic features between mice and humans even though they are still the most powerful tools in this research field, indicating that other species with biological similarity to humans need to be considered for studying ASCVD in future. With the development and breakthrough of novel gene editing technology, Syrian golden hamster, a small rodent animal replicating the metabolic characteristics of humans, has been genetically modified, suggesting that gene-targeted hamster models will provide new insights into the precision medicine and translational research of ASCVD. The purpose of this review was to summarize the genetically-modified hamster models with dyslipidemia to date, and their potential applications and perspective for ASCVD.

Chronic Exposure to HIV-Derived Protein Tat Impairs Endothelial Function via Indirect Alteration in Fat Mass and Nox1-Mediated Mechanisms in Mice.

People living with human immunodeficiency virus (HIV) (PLWH) have increased risk for atherosclerosis-related cardiovascular disease (CVD), the main cause of death in this population. Notwithstanding, the mechanisms of HIV-associated vascular pathogenesis are not fully elucidated. Therefore, we sought to determine whether HIV-regulatory protein Tat mediates HIV-induced endothelial dysfunction via NADPH oxidase 1 (Nox1)-dependent mechanisms. Body weight, fat mass, leptin levels, expression of reactive oxygen species (ROS)-producing enzymes and vascular function were assessed in C57BL/6 male mice treated with Tat for 3 days and 4 weeks. Aortic rings and human endothelial cells were also treated with Tat for 2–24 h in ex vivo and in vitro settings. Chronic (4 weeks) but not acute (3 days and 2–24 h) treatment with Tat decreased body weight, fat mass, and leptin levels and increased the expression of Nox1 and its coactivator NADPH oxidase Activator 1 (NoxA1). This was associated with impaired endothelium-dependent vasorelaxation. Importantly, specific inhibition of Nox1 with GKT771 and chronic leptin infusion restored endothelial function in Tat-treated mice. These data rule out direct effects of HIV-Tat on endothelial function and imply the contribution of reductions in adipose mass and leptin production which likely explain upregulated expression of Nox1 and NoxA1. The Nox1 and leptin system may provide potential targets to improve vascular function in HIV infection-associated CVD.

Association and Implications of Blood and Plaque n-3 Polyunsaturated Fatty Acid Composition in Patients Treated with Oral Eicosapentaenoic Acid before Carotid Endarterectomy.

Long-chain n-3 polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), have been shown to prevent atherosclerosis-related cardiovascular disease, including stroke. Recently, the ratio of serum EPA to arachidonic acid (AA; EPA/AA ratio) has been reported to be a biomarker to prevent cardiovascular disease. In this study, we evaluate whether the serum EPA/AA ratio would be a useful biomarker for determining the efficacy of orally administered EPA in preventing stroke by investigating tissue and serum EPA/AA ratios, serum inflammatory markers, and carotid artery intimamedia thickness (IMT). Patients with dyslipidemia, as the primary illness scheduled for carotid endarterectomy (CEA), were included and randomly assigned to the EPA group (EPA: 1,800 mg/day plus statin; 10 patients) or non-EPA group (statin only; 15 patients). PUFA fraction was evaluated in the tissue (post-CEA) and serum (pre-CEA and 6 months thereafter). As for the tissue PUFA fraction in the plaque, the EPA group had a significantly higher EPA/AA ratio (EPA group, 0.46; non-EPA group, 0.28; p = 0.01). At 6 months postoperatively, the EPA group had a significantly higher serum EPA/AA ratio (baseline, 0.83; follow-up, 1.60; p = 0.05). No significant differences were found for inflammatory markers and IMT. Both serum and tissue EPA/AA ratios were higher in patients treated with oral EPA. Serum EPA/AA ratio might be a useful biomarker for the efficacy of orally administered EPA.

How to Use Statins in Secondary Prevention of Atherosclerotic Diseases: from the Beneficial Early Initiation to the Potentially Unfavorable Discontinuation.

Statins, a class of lipid-lowering drugs, reduce morbidity and mortality in patients with established atherosclerosis-related cardiovascular disease. Early initiation of statin therapy after admission for acute coronary syndromes (ACS), stroke, or transient ischemic attack (TIA) is associated with improved cardiovascular outcomes. Moreover, high-dose statin treatment prior to coronary or carotid revascularization has been shown to reduce cardiovascular events in these patients. However, many patients may be undertreated, and a residual cardiovascular risk remains in current clinical practice. Despite the beneficial role of statins, their discontinuation rate among patients is still elevated leading to severe adverse cardiovascular events due to atherosclerotic plaque destabilization. In this review, we summarized the impact of statin treatment among patients, focusing on the initiation time-points as well as the potential harm derived by their discontinuation.

On the present and future role of Lp-PLA2 in atherosclerosis-related cardiovascular risk prediction and management.

Circulating concentration and activity of secretory phospholipase A2 (sPLA2) and lipoprotein-associated phospholipase A2 (Lp-PLA2) have been proven as biomarkers of increased risk of atherosclerosis-related cardiovascular disease (ASCVD). Lp-PLA2 might be part of the atherosclerotic process and may contribute to plaque destabilisation through inflammatory activity within atherosclerotic lesions. However, all attempts to translate the inhibition of phospholipase into clinically beneficial ASCVD risk reduction, including in randomised studies, by either non-specific inhibition of sPLA2 (by varespladib) or specific Lp-PLA2 inhibition by darapladib, unexpectedly failed. This gives us a strong imperative to continue research aimed at a better understanding of how Lp-PLA2 and sPLA2 regulate vascular inflammation and atherosclerotic plaque development. From the clinical viewpoint there is a need to establish and validate the existing and emerging novel anti-inflammatory therapeutic strategies to fight against ASCVD development, by using potentially better animal models and differently designed clinical trials in humans.

Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.

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Prediction Models and Scores in Adult Congenital Heart Disease.

Nowadays, most patients with congenital heart disease survive to adulthood due to advances in pediatric cardiac surgery but often present with various comorbidities and long-term complications, posing challenges in their management. The development and clinical use of risk scores for the prediction of morbidity and/or mortality in adults with congenital heart disease (ACHD) is fundamental in achieving optimal management for these patients, including appropriate follow-up frequency, treatment escalation, and timely referral for invasive procedures or heart transplantation. In comparison with other fields of cardiovascular medicine, there are relatively few studies that report prediction models developed in the ACHD population, given the small sample size, heterogeneity of the population, and relatively low event rate. Some studies report risk scores originally developed in pediatric congenital or non-congenital population, externally validated in ACHD with variable success. Available risk scores are designed to predict heart failure or arrhythmic events, all-cause mortality, post-intervention outcomes, infective endocarditis, or atherosclerosis-related cardiovascular disease in ACHD. A substantial number of these scores are derived from retrospective studies and are not internally or externally validated. Adequately validated risk scores can be invaluable in clinical practice and an important step towards personalized medicine. Multicenter collaboration, adequate study design, and the potential use of artificial intelligence are important elements in the effort to develop reliable risk scores for the ACHD population.

Shotgun Mass Spectrometry-Based Lipid Profiling Identifies and Distinguishes Between Chronic Inflammatory Diseases

Aims: Inflammation impacts several acute and chronic diseases causing localized stress and cell death, releasing tissue-specific lipids into the circulation from inflamed cells and tissues. The plasma lipidome may be expected to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared. Methods and Results: We compared the plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related cardiovascular disease (CVD) including ischemic stroke (IS), and systemic lupus erythematosus (SLE), to each other and to age-matched controls. The controls had never suffered from any of these diseases. Plasma lipidomes were screened by a top-down shotgun MS-based analysis without liquid chromatographic separation. Lipid profiling of 596 lipids based on MS was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes of patients suffering from CVD and SLE allowed clear distinction of these two chronic inflammatory diseases from each other. We demonstrate convincing evidence for the capability of lipidomics to separate the studied chronic and inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.90, Specificity: 0.98; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control – Sensitivity: 1, Specificity: 0.88) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls. In addition, CVD severities, as classified into five clinical groups, were partially separable by linear discriminant analysis. Conclusions: Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes. Dysregulated lipids are partially but not fully counterbalanced by statin treatment. Clinical Trial Registration Details: This study was registered with the Clinical Trials number NCT04786431 Funding Information: This work was supported by PTDC/MED-PAT/29395/2017 financially supported by Fundacao paraKS is CEO and shareholder of of Lipotype GmbH. CL and MG are KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interestsemployees of Lipotype GmbH. All other authors declare that they do not have any competing interests424 a Ciencia e a Tecnologia (FCT), through national funds and co-funded by FEDER under the PT2020 Partnership. ND was a holder of PhD fellowship from the FCT (Ref. N°:SFRH/BD/51877/2012), attributed 10 by Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC). LA was a holder of a FCT PhD fellowship (PD/BD/114254/2016), attributed by the ProRegem Doctoral Programme in 2016. Declaration of Interests: KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interests. Ethics Approval Statement: The entire process was approved by the Ethical Review Board of the Faculty of Medicine of the New University of Lisbon and the Ethics Committee for Health of the Centro Hospitalar de Lisboa Ocidental, that includes the Hospital Santa Cruz, the Hospital Egas Moniz and Hospital Sao Francisco Xavier, and the Ethics Committee for Health of the Hospital Fernando Fonseca. All experiments were performed in accordance with the guidelines and regulations including, the Universal Declaration on Bioethics and Human Rights of UNESCO, 2005; The Charter of Fundamental rights of the EU, 2012; Ethical principles for medical research involving human subjects - Declaration of Helsinki, 2013; EU Regulation 2016/679 and Good Clinical Practice guidelines (Directive 2001/20/EC) and EU Clinical Trials Directive (2005/28/EC). Moreover, they complied with national legislations for the scientific use of human biological samples (Law No 12/2005 and No 131/2014).

Literature-Based Drug Repurposing in Traditional Chinese Medicine: Reduced Inflammatory M1 Macrophage Polarization by Jisil Haebaek Gyeji-Tang Alleviates Cardiovascular Disease In Vitro and Ex Vivo.

Relatively high proportions of proinflammatory M1-like macrophages in tissues may lead to vascular impairment and trigger numerous diseases including atherosclerosis-related cardiovascular disease (CVD). Jisil Haebaek Gyeji-tang (JHGT), a polyherbal decoction, is traditionally used to treat various human ailments including chest pain, angina, and myocardial infarction. In the present study, we investigated the anti-inflammatory effects of JHGT on lipopolysaccharide- (LPS-) stimulated M1 macrophage polarization generated via the mitogen-activated protein kinases (MAPKs) pathway in RAW 264.7 mouse macrophages. The reducing power of JHGT was also investigated using DAF-FA DA in a zebrafish model. JHGT significantly reduced inflammatory mediator levels, including iNOS, COX2, TNF-α, IL-6, and IL-1β, as compared with LPS-stimulated controls in vitro and ex vivo. Furthermore, JHGT suppressed the ERK1/2, JNK, and p38 MAPK pathways and reduced p-IκBα levels and the nuclear translocation of NF-κB in RAW 264.7 cells. In addition, treatment with JHGT significantly reduced the NO levels in LPS-treated zebrafish larva ex vivo. Our findings show the potent anti-inflammatory properties of JHGT are due to its suppression of MAPK signaling, NF-κB translocation, and M1 macrophage polarization.

Cooperation networks of ambulatory health care providers: exploration of mechanisms that influence coordination and uptake of recommended cardiovascular care (ExKoCare): a mixed-methods study protocol

BackgroundAs the number of elderly and multimorbid patients increases, healthcare has become more complex. This requires good coordination of treatment and care given the various health care professionals involved (e.g. general practitioners, medical specialists, physicians’ assistants). Lack of coordination jeopardizes seamless, evidence-based treatment and care, and eventually reduces clinical effectiveness. The aim of the study is a) to describe and explore information transfer and interprofessional collaboration in ambulatory cardiac care, b) to describe and explore the role of provider networks from the perspective of patients and providers, focusing on healthcare coordination and the uptake of recommended practices.MethodsTwo related studies are planned: a) an observational study of healthcare provider networks, involving 600 patients with chronic (atherosclerosis-related) cardiovascular disease from 40 general practices and up to 320 healthcare providers (general practitioners, medical specialist, physicians’ assistants), and b) a qualitative interview study with up to 80 healthcare professionals and patients. Furthermore, we will analyse claims data of a large German health insurer to explore provider networks in ambulatory cardiac care.DiscussionThe project aims to provide insight into factors, processes and mechanisms of information transfer and interprofessional collaboration, which affect seamless, evidence-based healthcare practice. This will contribute to the design of strategies for improving health care practice and to the development of measures of coordination for future research.Trial registrationWe registered the study prospectively on 7 November 2019 at the German Clinical Trials Register (DRKS, www.drks.de) under ID no. DRKS00019219.

Cardiovascular risk factors in children with hereditary loading

Aim. To study the prevalence of CVRF in schoolchildren with a family history of atherosclerosis-related cardiovascular disease. Material and methods . The study included 106 schoolchildren aged 10 to 17 years. The main group consisted of children (n=55) with a family history of cardiovascular diseases (CVD) and the control group (n=51) — without hereditary loading. The study was conducted using a specially designed questionnaire, including medical history, clinical and laboratory data. Levels of total cholesterol, high density lipoproteins and triglycerides were determined with a Mindray kit using a photometric method on a BS-360E chemistry analyzer (Mindray). Results. There was a 60% of paternal family history of CVD and 34,5% — of maternal. Smoking was detected in 10,4%, sedentary life-style — in 83,6%, and a tendency to hypertension — in 33% of children. Dyslipidemia, as the main CVRF, was observed in 63,6% of children with a positive family history. Conclusion. The results of the study suggest that CVRF in adults is widespread among children. The prevalence of CVRF in children with family history of CVD is higher than in children with negative family history.

EXOSOME-DERIVED CIRCITGB1 REGULATES DENDRITIC CELL MATURATION AND CARDIAC INFLAMMATION VIA MIR-342-3P/NFAM1

Acute myocardial infarction (AMI) is caused by sustained ischemia and is often the manifestation of atherosclerosis-related cardiovascular disease. Circular RNAs (circRNAs) are known to be associated with cardiovascular disease and are enriched in exosomes. However, the expression profile and

Cancer patients receiving immune checkpoint inhibitor therapy are at an increased risk for atherosclerotic cardiovascular disease

The widespread clinical use of immune checkpoint inhibitors (ICI) has increased our knowledge on their adverse effects on chronic inflammatory diseases. Atherosclerosis, a low-grade lipid-driven inflammatory disease of the larger...

Araloside C attenuates atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy

Atherosclerosis-related cardiovascular disease is still the predominant cause of death worldwide. Araloside C (AsC), a natural saponin, exerts extensive anti-inflammatory properties. In this study, we explored the protective effects and mechanism of AsC on macrophage polarization in atherosclerosis in vivo and in vitro. Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW264.7 macrophages exposed to ox-LDL, AsC was evaluated for its effects on polarization and autophagy. AsC significantly reduced the plaque area in atherosclerotic mice and lipid accumulation in ox-LDL-treated macrophages, promoted M2 phenotype macrophage polarization, increased the number of autophagosomes and modulated the expression of autophagy-related proteins. Moreover, the autophagy inhibitor 3-methyladenine and BECN1 siRNA obviously abolished the antiatherosclerotic and M2 macrophage polarization effects of AsC. Mechanistically, AsC targeted Sirt1and increased its expression, and this increase in expression was associated with increased autophagy and M2 phenotype polarization. In contrast, the effects of AsC were markedly blocked by EX527 and Sirt1 siRNA. Altogether, AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.