Atherosclerosis Research Articles

Auto/Paracrine C-Type Natriuretic Peptide/Cyclic GMP Signaling Prevents Endothelial Dysfunction.

Endothelial dysfunction is cause and consequence of cardiovascular diseases. The endothelial hormone C-type natriuretic peptide (CNP) regulates vascular tone and the vascular barrier. Its cGMP-synthesizing guanylyl cyclase-B (GC-B) receptor is expressed in endothelial cells themselves. To characterize the role of endothelial CNP/cGMP signaling, we studied mice with endothelial-selective GC-B deletion. Endothelial EC GC-B KO mice had thicker, stiffer aortae and isolated systolic hypertension. This was associated with increased proinflammatory E-selectin and VCAM-1 expression and impaired nitric oxide bioavailability. Atherosclerosis susceptibility was evaluated in such KO and control littermates on Ldlr (low-density lipoprotein receptor)-deficient background fed a Western diet for 10 weeks. Notably, the plaque areas and heights within the aortic roots were markedly increased in the double EC GC-B/Ldlr KO mice. This was accompanied by enhanced macrophage infiltration and greater necrotic cores, indicating unstable plaques. Finally, we found that EC GC-B KO mice had diminished vascular regeneration after critical hind-limb ischemia. Remarkably, all these genotype-dependent changes were only observed in female and not in male mice. Auto/paracrine endothelial CNP/GC-B/cGMP signaling protects from arterial stiffness, systolic hypertension, and atherosclerosis and improves reparative angiogenesis. Interestingly, our data indicate a sex disparity in the connection of diminished CNP/GC-B activity to endothelial dysfunction.

New Modifiable Risk Factors Influencing Coronary Artery Disease Severity.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide with coronary artery disease (CAD) being the first culprit in this group. In terms of CAD, not only its presence but also its severity plays a role in the patient's treatment and prognosis. CAD complexity can be assessed with the indicator named the SYNTAX score (SS). A higher SS is associated with major adverse cardiovascular event (MACE) occurrence in short- and long-term observations. Hence, the risk factors affecting CAD severity based on SS results may help lower the risk among patients with already developed CAD to reduce their impact on coronary atherosclerosis progression. The well-established risk factors of CAD are consistent with those associated with the coronary plaque burden. However, recently, it was shown that new indicators exist, which we present in this paper, that significantly contribute to CAD complexity such as inflammatory parameters, C-reactive protein (CRP), ratios based on blood smear results, and uric acid. Moreover, microbiota alteration, vitamin D deficiency, and obstructive sleep apnea (OSA) also predicted CAD severity. However, sometimes, certain indicators were revealed as significant only in terms of chronic coronary syndromes (CCSs) or specific acute coronary syndromes (ACSs). Importantly, there is a need to apply the interdisciplinary and translational approach to the novel CAD severity risk assessment to maximize the impact of secondary prevention among patients at risk of coronary atherosclerosis progression.

Association between smoking status and subclinical coronary atherosclerosis in asymptomatic Korean individuals.

In this study, we sought to evaluate the association between smoking status and subclinical coronary atherosclerosis, as detected by coronary computed tomography angiography (CCTA), in asymptomatic individuals. We retrospectively analyzed 9,285 asymptomatic participants (mean age, 53.7±8.0 years; n=6,017, 64.8% male) with no history of coronary artery disease (CAD) who had undergone self-referred CCTA. Of these participants, 4,333 (46.7%) were considered never smokers, 2,885 (31.1%) former smokers, and 2,067 (22.3%) current smokers. We assessed the degree and characteristics of subclinical coronary atherosclerosis using CCTA, with obstructive CAD defined as a diameter stenosis of at least 50%. Compared with never-smokers, former smokers exhibited no significant differences in the probabilities of obstructive CAD, any coronary plaque, calcified plaque, or mixed plaque, as determined using adjusted odds ratios (aORs; p>0.05 for all). However, the risk of non-calcified plaque was significantly higher in former smokers (aOR, 1.34; 95% confidence interval [CI], 1.00 to 1.78; p=0.048). Current smokers had significantly higher rates of obstructive CAD (aOR, 1.46; 95% CI, 1.10 to 1.96; p=0.010), any coronary plaque (aOR, 1.41; 95% CI, 1.20 to 1.65; p<0.001), calcified plaque (aOR, 1.32; 95% CI, 1.13 to 1.55; p=0.001), non-calcified plaque (aOR, 1.72; 95% CI, 1.28 to 2.32; p<0.001), and mixed plaque (aOR, 2.00; 95% CI, 1.39 to 2.86; p<0.001) compared to never smokers. This cross-sectional study revealed a significant association between current smoking and subclinical coronary atherosclerosis, as detected on CCTA. Additionally, former smoking demonstrated an association with non-calcified plaque, indicating elevated cardiovascular risk.

Enhancement of high-density lipoprotein-associated protease inhibitor activity prevents atherosclerosis progression

Background and aimsInflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as a modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis were examined using mouse models. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after administration to Apoe−/− mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr−/− mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

Differentiation of Acute Internal Carotid Artery Occlusion Etiology on Computed Tomography Angiography: Diagnostic Tree for Preparing Endovascular Treatment.

This study aimed to identify the imaging characteristics and discriminate the etiology of acute internal carotid artery occlusion (ICAO) on computed tomography angiography (CTA) in patients with acute ischemic stroke. We retrospectively evaluated consecutive patients who underwent endovascular thrombectomy for acute ICAO. Contrast filling of the extracranial ICA in preprocedural CTA was considered apparent ICAO. Non-contrast filling of the extracranial ICA was evaluated according to the contrast-filled lumen configuration, lumen margin and location, Hounsfield units of the non-attenuating segment, and presence of calcification or an intimal flap. Digital subtraction angiography findings were the reference standard for ICAO etiology and the occlusion site. A diagnostic tree was derived using significant variables according to pseudo-occlusion, atherosclerotic vascular disease (ASVD), thrombotic occlusion, and dissection. A total of 114 patients showed apparent ICAO (n = 21), pseudo-occlusion (n = 51), ASVD (n = 27), thrombotic occlusion (n = 9), or dissection (n = 6). Most pseudo-occlusions (50/51, 98.0%) showed dependent locations with ill-defined contrast column margins and classic flame or beak shapes. The most common occlusion site of pseudo-occlusion was the petro-cavernous ICA (n = 32, 62.7%). Apparent ICAO mainly appeared in cases with occlusion distal to the posterior communicating artery orifice. ASVD showed beak or blunt shapes in the presence of low-density plaques or dense calcifications. Dissection revealed flame- or beak-shaped appearances with circumscribed margins. Thrombotic occlusions tended to appear blunt-shaped. The decision-tree model showed a 92.5% overall accuracy. CTA characteristics may help diagnose ICAO etiology. We provide a simple and easy decision-making model to inform endovascular thrombectomy.

Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis.

Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported. In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS. Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data. As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB. Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.

Exploring the relationship between epicardial fat and coronary plaque burden and characteristics: insights from cardiac ct imaging.

Epicardial adipose tissue (EAT) may enhance the risk of coronary artery disease (CAD). We investigated the relationship between EAT density (a maker of local inflammation) and coronary plaque characteristics in stable CAD patients. This study included 123 individuals who underwent coronary artery calcium scan and coronary CT angiography to evaluate CAD. Plaque characteristics were analyzed by semi-automated software (QAngio, Leiden, Netherlands). Non-contrast CT scans were used to measure EAT density (HU) and volume (cc) (Philips, Cleveland, OH). Multivariate regression models were used to evaluate the association of EAT density and volume with different plaque types. The mean (SD) age was 59.4±10.1 years, 53% were male, the mean (SD) EAT density was -77.2±4.6 HU and the volume was 118.5±41.2 cc. After adjustment for cardiovascular risk factors, EAT density was associated with fibrous fatty (FF) plaque (p<0.03). A 1 unit increase in HU was associated with a 7% higher FF plaque, and lower EAT density is independently associated to FF plaque. The association between EAT density and fibrous (p=0.08), and total noncalcified (p=0.09) plaque trended toward but did not reach significance. There was no association between EAT volume and any plaque type. These results suggest that inflammatory EAT may promote coronary atherosclerosis. Therefore, non-contrast cardiac CT evaluation of EAT quality can help better assess cardiovascular risk.

Coronary Artery Calcium and Aging: Physiological Basis, Assessment, and Treatment Options in Percutaneous Coronary Intervention.

Coronary artery calcification is a complex anatomical and histological pathology with different pathways that contribute to calcium deposit and calcification progression. As part of the atherosclerotic process, extensive calcifications are becoming more common and are associated with poorer PCI outcomes if not properly addressed. Since no drug has shown to be effective in changing this process once it is started, proper knowledge of the underlying pathogenesis and how to diagnose and manage it is essential in contemporary coronary intervention. Atherosclerosis is a pandemic disease, quickly spreading across the world and not limited anymore to the industrialized Western world. In this paper, we review the role of intracoronary imaging and the main technologies available and propose a simple and rational algorithm for the choice of a preferential first strategy in the treatment of severely calcified coronary atherosclerosis, followed by three emblematic cases on how we successively applied it.

A Multiomic Analysis to Identify Drivers of Subclinical Vascular Disease in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) increases cardiovascular disease (CVD) risk, and this is not explained by traditional risk factors. Characterization of blood immunologic signatures that associate with subclinical CVD and predict its progression has been challenging and may help identify subgroups at risk. Patients with SLE (n = 77) and healthy controls (HCs) (n = 27) underwent assessments of arterial stiffness, vascular wall inflammation, and coronary atherosclerosis burden with cardio-ankle vascular index (CAVI); fluorodeoxyglucose-positron emission tomography/computed tomography (CT) (target-to-background ratio [TBR]); and coronary CT angiography. Whole blood bulk RNA sequencing was performed in a subset of study participants (HC n = 10, SLE n = 20). In a partially overlapping subset (HC n = 24, SLE n = 64), serum inflammatory protein biomarkers were quantified with an Olink platform. CAVI, TBR, and noncalcified coronary plaque burden (NCB) were increased in patients with SLE compared to HCs. When comparing patients with SLE with high CAVI scores to those with low CAVI scores or to HCs, there was a down-regulation of genes in pathways involved in the cell cycle and differentially regulated pathways related to metabolism. Distinct serum proteins associated with increased CAVI (CCL23, colony-stimulating factor 1, latency-activating peptide transforming growth factor β1, interleukin 33 [IL-33], CD8A, and IL-12B), NCB (monocyte chemotactic protein 4 and FMS-like tyrosine kinase 3 ligand [Flt3L]), and TBR (CD5, IL-1α, AXIN1, cystatin D [CST5], and tumor necrosis factor receptor superfamily 9; P < 0.05). Blood gene expression patterns and serum proteins that associate with worse vascular phenotypes suggest dysregulated immune and metabolic pathways linked to premature CVD. Cytokines and chemokines identified in associations with arterial stiffness, inflammation, and NCB in SLE may allow for characterization of new CVD biomarkers in lupus.

REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress

Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.

Association between organophosphorus insecticides exposure and osteoarthritis in patients with arteriosclerotic cardiovascular disease

BackgroundOrganic phosphorus insecticides (OPPs) are a class of environmental pollutants widely used worldwide with potential human health risks. We aimed to assess the association between exposure to OPPs and osteoarthritis (OA) particularly in participants with atherosclerotic cardiovascular disease (ASCVD).MethodsParticipants’ information was obtained from data in the National Health and Nutrition Examination (NHANES). Weighted logistic regression models were utilized to detect associations between OPPs metabolites and OA. Restricted cubic spline plots (RCS) were drawn to visualize the dose-response relationship between each metabolite and OA prevalence. Weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR), were applied to investigate the joint effect of mixtures of OPPs on OA.ResultsA total of 6871 samples were included in our study, no significant associations between OPPs exposure and OA incidence were found in whole population. However, in a subset of 475 individuals with ASCVD, significant associations between DMP (odds ratio [OR] as a continuous variable = 1.22, 95% confidence interval [CI]: 1.07,1.28), DEP ((odds ratio [OR] of the highest tertile compared to the lowest = 2.43, 95% confidence interval [CI]: 1.21,4.86), and OA were observed. DMP and DEP showed an increasing dose-response relationship to the prevalence of OA, while DMTP, DETP, DMDTP and DEDTP showed a nonlinear relationship. Multi-contamination modeling revealed a 1.34-fold (95% confidence intervals:0.80, 2.26) higher prevalence of OA in participants with high co-exposure to OPPs compared to those with low co-exposure, with a preponderant weighting (0.87) for the dimethyl dialkyl phosphate metabolites (DMAPs). The BKMR also showed that co-exposure of mixed OPPs was associated with an increased prevalence of OA, with DMP showing a significant dose-response relationship.ConclusionHigh levels of urine dialkyl phosphate metabolites (DAP) of multiple OPPs are associated with an increased prevalence of OA in patients with ASCVD, suggesting the need to prevent exposure to OPPs in ASCVD patients to avoid triggering OA and further avoid the occurrence of cardiovascular events caused by OA.

Factors Associated with High-Risk Plaque Characteristics Among Patients with Medium to Severe Carotid Artery Stenosis

ObjectiveThere has been a large discussion in literature regarding the proper management of asymptomatic patients with significant carotid artery stenosis (CAS). This study aims to identify potential risk factors associated with high-risk carotid plaques. MethodsThis is a retrospective study based on a prospective database. Eligible patients had medium to severe symptomatic or asymptomatic carotid stenosis (≥50%, NASCET criteria). This study will analyze patients recruited by our institution as part of the multicenter TAXINOMISIS project (NCT03495830). According to protocol, all patients underwent a colored Duplex ultrasound examination and a magnetic resonance angiography (MRA) at baseline. Carotid plaques were classified according to Gray-Weale ultrasonographic criteria (Types I-V). Main outcomes included the occurrence of symptoms, the high/low echogenicity of the plaque, the existence of intraplaque hemorrhage (IPH) and the existence of lipidic/necrotic core. Secondary, risk factors associated with the aforementioned outcomes were evaluated. ResultsA total of 62 patients (mean age: 68.7+/-9.3 years, 66.1% males, 24.2% symptomatic) were recruited by our department. Mean carotid stenosis was 70.81%±13.53%. In multivariate regression analysis, CRP > 2mg/l was strongly associated with symptomatic stenosis (OR=9.92 [1.12-88.178]; P=0.039), and low HDL levels (<1200mmol/l) were associated with lipidic/necrotic plaque core (OR=16.88 [1.10-259.30]; P=0.043). Low HDL levels (OR=7.22 [1.00-51.95], P=0.049) and HbA1c >7% (OR=0.08 [0.01-0.93], P=0.044) were associated with type III/IV plaques whereas HgAbc1 >7% (OR=14.26 [1.21-168.34], P=0.035) was associated with Type V plaques. ConclusionsThis preliminary study has revealed some potential risk factors associated with unstable carotid plaques. This data could help the future development of prognostic models in order to early detect patients that could benefit from further intervention.

Bacillus amyloliquefaciens Protect Against Atherosclerosis Through Alleviating Foam Cell Formation and Macrophage Polarization.

This study was to investigate the therapeutic effect of Bacillus amyloliquefaciens (Ba) on atherosclerosis (AS). THP-1 monocyte was differentiated to THP-1 macrophage (THP-M) through phorbol 12-myristate 13-acetate. After pre-treatment by 108cfu/ml Ba lasting 6h, THP-M was induced with 100mg/l ox-LDL lasting 48h to form macrophage foam cell (THP-F). RT-qPCR and flow cytometry were employed to determine the polarization of THP-M and THP-F. ApoE-/- mice with high-fat and high-cholesterol diet were used for constructing an AS model to evaluate the effect of Ba on AS. Our in vitro results showed that Ba vegetative cells pre-treatment distinctly inhibited the levels of iNOS and CD16/CD32 (M1 macrophage markers), and increased the levels of FIZZ1, Ym1, Arg1, CD163, and CD206 (M2 macrophage markers), indicating that Ba pre-treatment promoted anti-inflammatory M2-like polarization both in THP-M and THP-F. Meanwhile, it also suppressed cholesterol uptake, esterification, and hydrolysis, and efflux by THP-M and THP-F. Additionally, our animal experiments demonstrated that Ba vegetative cells treatment suppressed high cholesterol, hyperglycemia, hyperlipidemia, and the release of inflammatory factors (TNF-α, IL-6 and IL-1β) in ApoE-/- AS mice. In a word, our results indicated that Ba may protect against AS through alleviating foam cell formation and macrophage polarization through targeting certain stages of AS.

The impact of lipoprotein(a) level on cardiac pathologies in diabetes: a cardiac CT study.

We aimed to explore the imaging profile of coronary atherosclerosis, perivascular inflammation, myocardial perfusion, and interstitial fibrosis in diabetes stratified by lipoprotein(a) [Lp(a)] levels. In this prospective study, we enrolled diabetic patients who had undergone computed tomography (CT) angiography, stress CT-myocardial perfusion imaging, and late iodine enhancement in 20 months. Then, we categorized them into elevated and normal groups based on an Lp(a) cutoff level of 30 mg/dL. All imaging data, including coronary atherosclerosis parameters, pericoronary adipose tissue (PCAT) density, stress myocardial blood flow (MBF), and extracellular volume (ECV), were collected for further analysis. In total, 207 participants (mean age: 59.1 ± 12.0 years, 111 males) were included in this study. Patients with elevated Lp(a) level had more pronounced percent atheroma volume (2.55% (1.01-9.01%) versus 1.30% (0-4.95%), p = 0.010), and demonstrated a higher incidence of positive remodeling, spotty calcification, and high-risk plaque (HRP) than those with normal Lp(a) levels (75.6% versus 54.8%, p = 0.015; 26.8% versus 9.6%, p = 0.003; 51.2% versus 30.1%, p = 0.011, respectively). Results of the multivariate analysis revealed that after adjusting for all clinical characteristics, elevated Lp(a) levels were an independent parameter associated with HRP (odds ratio = 2.608; 95% confidence interval: 1.254-5.423, p = 0.010). However, no significant difference was found between the two groups in terms of PCAT density, stress MBF, and ECV. Elevated Lp(a) levels are associated with extensive coronary atherosclerosis and HRP development. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. Elevated lipoprotein(a) levels are associated with extensive coronary atherosclerosis and a high incidence of HRPs. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. Diabetes is a known risk factor that accelerates cardiovascular disease progression. Diabetics with elevated lipoprotein(a) (Lp(a)) levels had a higher percent atheroma volume and positive remodeling, spotty calcification, and HRPs. Patients with diabetes should be screened for elevated Lp(a) using CCTA for comprehensive evaluation of atherosclerotic characteristics.

A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

Low HDL-C/ApoA-I index is associated with cardiometabolic risk factors and coronary artery calcium: a sub-analysis of the genetics of atherosclerotic disease (GEA) study

BackgroundThe high-density lipoprotein cholesterol to apolipoprotein A-I index (HDL-C/ApoA-I) may be practical and useful in clinical practice as a marker of atherosclerosis. This study aimed to investigate the association between the HDL-C/ApoA-I index with cardiometabolic risk factors and subclinical atherosclerosis.MethodsIn this cross-sectional sub-analysis of the GEA study, 1,363 individuals, women (51.3%) and men (48.7%) between 20 and 75 years old, without coronary heart disease or diabetes mellitus were included. We defined an adverse cardiometabolic profile as excess adipose tissue metrics, non-alcoholic liver fat measured by non-contrasted tomography, metabolic syndrome, dyslipidemias, and insulin resistance. The population was stratified by quartiles of the HDL-C/Apo-AI index, and its dose-relationship associations were analysed using Tobit regression, binomial, and multinomial logistic regression analysis.ResultsBody mass index, visceral and pericardial fat, metabolic syndrome, fatty liver, high blood pressure, and CAC were inversely associated with the HDL-C/ApoA-I index. The CAC > 0 prevalence was higher in quartile 1 (29.2%) than in the last quartile (22%) of HDL-C/ApoA-I index (p = 0.035). The probability of having CAC > 0 was higher when the HDL-C/ApoA-I index was less than 0.28 (p < 0.001). This association was independent of classical coronary risk factors, visceral and pericardial fat measurements.ConclusionThe HDL-C/ApoA-I index is inversely associated with an adverse cardiometabolic profile and CAC score, making it a potentially useful and practical biomarker of coronary atherosclerosis. Overall, these findings suggest that the HDL-C/ApoA-I index could be useful for evaluating the probability of having higher cardiometabolic risk factors and subclinical atherosclerosis in adults without CAD.

Relationships between systemic sclerosis and atherosclerosis: screening for mitochondria-related biomarkers.

Patients with systemic sclerosis (SSc) are known to have higher incidence of atherosclerosis (AS). Mitochondrial injuries in SSc can cause endothelial dysfunction, leading to AS; thus, mitochondria appear to be hubs linking SSc to AS. This study aimed to identify the mitochondria-related biomarkers of SSc and AS. We identified common differentially expressed genes (DEGs) in the SSc (GSE58095) and AS (GSE100927) datasets of the Gene Expression Omnibus (GEO) database. Considering the intersection between genes with identical expression trends and mitochondrial genes, we used the least absolute shrinkage and selection operator (LASSO) as well as random forest (RF) algorithms to identify four mitochondria-related hub genes. Diagnostic nomograms were then constructed to predict the likelihood of SSc and AS. Next, we used the CIBERSORT algorithm to evaluate immune infiltration in both disorders, predicted the transcription factors for the hub genes, and validated these genes for the two datasets. A total of 112 genes and 13 mitochondria-related genes were identified; these genes were then significantly enriched for macrophage differentiation, collagen-containing extracellular matrix, collagen binding, antigen processing and presentation, leukocyte transendothelial migration, and apoptosis. Four mitochondria-related hub DEGs (IFI6, FSCN1, GAL, and SGCA) were also identified. The nomograms showed good diagnostic values for GSE58095 (area under the curve (AUC) = 0.903) and GSE100927 (AUC = 0.904). Further, memory B cells, γδT cells, M0 macrophages, and activated mast cells were significantly higher in AS, while the resting memory CD4+ T cells were lower and M1 macrophages were higher in SSc; all of these were closely linked to multiple immune cells. Gene set enrichment analysis (GSEA) showed that IFI6 and FSCN1 were involved in immune-related pathways in both AS and SSc; GAL and SGCA are related to mitochondrial metabolism pathways in both SSc and AS. Twenty transcription factors (TFs) were predicted, where two TFs, namely BRCA1 and PPARγ, were highly expressed in both SSc and AS. Four mitochondria-related biomarkers were identified in both SSc and AS, which have high diagnostic value and are associated with immune cell infiltration in both disorders. Hence, this study provides new insights into the pathological mechanisms underlying SSc and AS. The specific roles and action mechanisms of these genes require further clinical validation in SSc patients with AS.

Unstable plaque is a treatable cause of cognitive decline

While many risk factors are modifiable, there remains a compelling need for novel approaches to prevent cognitive impairment. We propose that unstable carotid plaque causes microemboli that, in turn, cause microinfarcts and other adverse pathophysiological cerebral processes, which individually do not manifest clinically but cumulatively manifest as cognitive decline and ultimately cognitive impairment. Animal models support multiple cerebral microemboli having adverse effects on cognition. By addressing the source for microembolization by endarterectomy or stenting, patients with high-grade atherosclerotic stenosis may have better cognitive outcomes. If our hypothesis is verified, then treatment of carotid plaque at elevated risk of generating cerebral microemboli would be effective in preserving cognition, regardless of whether the stenosis is high-grade or causing cerebral hemispheric hypoperfusion.

Oral Nanoformulations in Cardiovascular Medicine: Advances in Atherosclerosis Treatment.

Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS.

Black phosphorus quantum dots prevent atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases such as coronary heart disease. Black phosphorus quantum dots (BPQDs) are a novel nanomaterial with good optical properties and biocompatibility, which was applied in the treatment of AS in mice, with good results shown in our previous study. In this study, BPQDs were injected into high-fat diet-fed apolipoprotein E knockout mice as a preventive drug for 12 weeks. Simvastatin, a classic preventive drug for AS, was used as a control to verify the preventive effect of BPQDs. The results showed that after preventive treatment with BPQDs, the plaque area in mice was significantly reduced, the vascular elasticity was increased, and serum lipid levels were significantly lower than those in the model group. To explore the mechanism, macrophages were induced to become foam cells using oxidized low-density lipoprotein. We found that BPQDs treatment could increase cell autophagy, thereby regulating intracellular lipid metabolism. Taken together, these data revealed that BPQDs may serve as a functional drug in preventing the development of AS.