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BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. METHODS: A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. RESULTS: Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1–77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06–1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46–2.48]). CONCLUSIONS: These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (LDLR , APOB , and PCSK9). METHODS: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us). RESULTS: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39–5.20]; P =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26–6.32]; P =4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: –32.3 mg/dL; P <5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31–0.75]; P =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30–0.97]; P =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P =1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (–6.9 cm/s; P =0.022). CONCLUSIONS: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development. [ABSTRACT FROM AUTHOR]

Background The association between low-density lipoprotein (LDL-C) levels and cardiovascular disease (CVD) risk in different age groups within the diabetes mellitus (DM) population remains unclear. The cohort study was conducted to investigate this relationship. Methods We assessed the 2009 to 2012 Korean National Health Screening and National Health Insurance Service records, with follow-up to the primary outcome (myocardial infarction [MI] or stroke) or December 2018. After excluding the participants with a history of MI or stroke, 2,227,394 participants with DM were included and categorized according to baseline LDL-C levels and age. Cox proportional hazards modeling was conducted. The CVD risk of age

OBJECTIVE: To derive an equation for accurate estimation of low-density lipoprotein cholesterol (LDL-C) in the Pakistani population. METHODS: A modified equation was derived on the dataset (n = 59,148) from the Pakistani population, comprising directly measured LDL-C (dLDL-C) and other lipids using a regression model. The equation was validated on an internal (n = 29,633) and external dataset (n = 385,434), and the results were compared with the standard equations being used in the Pakistani population: Friedewald and Teerakanchana equation. The concordance between the dLDL-C and calculated LDL-C (cLDL-C) was determined by median difference (MD) and the agreement between dLDL-C and cLDL-C was analyzed by Bland Altman graphics. RESULTS: The modified equation (M.Eq) displayed best correlation (r = 0.974) and MD of -0.07 mmol/L on the derivation dataset. Similarly, the equation provided the best correlation and least MD on the internal (r = 0.970, MD = -0.13) and external validation datasets (r = 0.953, MD = -0.02). The Bland-Altman plot for the modified equation displayed the least bias in the derivation (-0.0012 mmol/L), internal validation (-0.13 mmol/L), and external validation (-0.02 mmol/L). CONCLUSION: The modified equation can be utilized for clinical settings in Pakistan that do not facilitate direct measurements of LDL-C.

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of lowdensity lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was −1.68% (95% CI, −29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was −60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non−high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate gender difference in non-traditional cardiovascular risk factors among Saudi patients with angiographically defined coronary artery disease (CAD). METHODS: We recruited 144 (male=105, female=39) patients with CAD who underwent coronary angiography. Laboratory analysis of total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), lipoprotein(a) [Lp(a)], and high sensitivity C-reactive protein (hs-CRP) were performed along with echocardiographic evaluation. RESULTS: Systolic blood pressure (SBP) was significantly higher in females (138.65±18.67 vs 129.59±21.03 mmHg; p=0.0363). Although no significant difference was observed in TC (4.30±1.36 vs 4.67±1.07 mmol/L), however significantly higher levels of both HDL and LDL were seen in females (0.86±0.17 vs 0.70±0.23 mmol/L; p=0.0592 and 3.50±0.67 vs 2.72±1.13; p=0.0466 respectively). There were no significant differences in TG, Lp(a) and hs-CRP, however females had comparatively higher Lp(a) (30.43±28.89 vs 24.02±23.42 mg/dl) and hs-CRP (1.14±1.46 vs 0.95±1.25 mg/L). On angiography, greater extent of stenosis was observed in left anterior descending and right coronary arteries among males, while the left circumflex artery was affected more in the female patients without statistical significance (p=0.0797; 0.3890 and 0.5032 respectively). Gensini Score in males & females was 60.46±46.17 and 74.39±39.52 respectively (p=0.3013). Significantly narrower aortic root diameter (ARD) was observed among females (27.30±6.66 vs 29.73±3.40 mm; p=0.0293). CONCLUSION: Female patients have greater risk of cardiovascular diseases due to higher SBP and LDL levels which could lead to a greater Gensini score when compared to male patients. In addition, narrow ARD among females could also be a contributing factor to CAD.

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Background: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. Methods: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. Results: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels—down to very low levels <20 mg/dL—and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted P trend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. Conclusions: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC. Methods: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute –funded Multi-Ethnic Study of Atherosclerosis. Results: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04–1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06–1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87–1.18]). Similarly, a very high LDL-C level (> 193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59–3.67]) but not in those without CAC (aHR, 0.92 [0.48–1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis. Conclusions: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Aging is a well-established risk factor for the development and progression of atherosclerosis, but the molecular mechanisms underlying this relationship remain poorly defined, and its role in atherosclerosis regression is unknown. To uncover age-related alterations that may impair atherosclerosis regression, we investigated the response of young and old macrophages to atherogenic lipoproteins in vitro and in vivo., Methods: Metabolic and proteomic studies were performed in vitro using macrophages differentiated from the bone marrow of young or old mice. To test the role of immune cell aging in atherosclerosis regression, bone marrow from young and old donors was transplanted into irradiated young recipient mice expressing gain-of-function AAV-PCSK9. Following 14 weeks of Western diet feeding, atherosclerosis regression was induced by switching to a standard laboratory diet for 4 weeks., Results: Compared with young macrophages, old macrophages accumulated more lipid droplets upon lipid loading with the pro-atherogenic lipoprotein aggregated LDL (low-density lipoprotein), accompanied by a failure to proportionally induce autophagy and cholesterol efflux. Proteomic analysis of bone marrow-derived macrophages revealed that pathways related to endocytosis, engulfment, and phagocytosis were downregulated in old lipid-loaded macrophages. Functional studies confirmed a reduction in efferocytic capacity in old macrophages. In recipient mice transplanted with old bone marrow, atherosclerosis regression was impaired, as evidenced by inefficient resolution of circulating inflammatory cell levels, reduced activation of plaque autophagy and apoptotic cell clearance, and persistent plaque CD45 + and CD68 + content., Conclusions: Aging impairs macrophage function through reduced efferocytosis and autophagy activation, limiting atherosclerosis regression. These results highlight the need to better define the mechanisms linking aging to atherosclerosis to develop targeted therapies for the aging population.

Objective: To evaluate the protective effects of gentiopicroside (GPS) against reactive oxygen species (ROS)-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in endothelial cells, aiming to reduce atherosclerosis., Methods: Eight-week-old male ApoE-deficient mice were randomly divided into 2 groups (n=10 per group): the vehicle group and the GPS treatment group. Both groups were fed a high-fat diet for 16 weeks. GPS (40 mg/kg per day) was administered by oral gavage to the GPS group, while the vehicle group received an equivalent volume of the vehicle solution. At the end of the treatment, blood and aortic tissues were collected for assessments of atherosclerosis, lipid profiles, oxidative stress, and molecular expressions related to NLRP3 inflammasome activation, ROS production, and apoptosis. Additionally, in vitro experiments on human aortic endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) were conducted to evaluate the effects of GPS on NLRP3 inflammasome activation, pyroptosis, apoptosis, and ROS production, specifically examining the role of the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. SIRT1 and Nrf2 inhibitors were used to confirm the pathway's role., Results: GPS treatment significantly reduced atherosclerotic lesions in the en face aorta (P<0.01), as well as in the thoracic and abdominal aortic regions, and markedly decreased sinus lesions within the aortic root (P<0.05 or P<0.01). Additionally, GPS reduced oxidative stress markers and proinflammatory cytokines, including interleukin (IL)-1 β and IL-18, in lesion areas (P<0.05, P<0.01). In vitro, GPS inhibited ox-LDL-induced NLRP3 activation, as evidenced by reduced NLRP3 (P<0.01), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D expressions (all P<0.01). GPS also decreased ROS production, apoptosis, and pyroptosis, with the beneficial effects being significantly reversed by SIRT1 or Nrf2 inhibitors., Conclusion: GPS exerts an antiatherogenic effect by inhibiting ROS-dependent NLRP3 inflammasome activation via the SIRT1/Nrf2 pathway., Competing Interests: Conflicts of Interest. The authors declare no conflict of interest., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Atherosclerosis (AS) is a chronic inflammatory disease resulting from lipid metabolism disorders and immune imbalances. Dendritic cells (DCs) are key cells that regulate adaptive and adaptive immunity. When DCs engulf excessive amounts lipids, their function is altered, thereby, accelerating the inflammatory process of AS. Cellular lipophagy serves to reduce lipid accumulation and maintain cellular lipid metabolism balance. In this study, we investigated the effectiveness of 2,3,5,4'-tetrahydroxystilbene 2-O-β-D-glucoside (TSG) in intervening in the promotion of DCs lipid accumulation by ox-LDL, as well as its role in downregulating lipophagy. Our findings indicate that TSG reduces the maturity of DCs and promotes the differentiation of T cells towards Treg, thereby correcting the imbalanced Treg/Th17. These effects of TSG are closely associated with its inhibition of the PI3K-AKT-mTOR signaling pathway. After administering TSG to ApoE -/- mice that were fed a high-fat diet, there was a noticeable decrease in harmful blood lipids found in the serum. Additionally, the imbalanced Treg/Th17 levels in the spleen were restored, and the levels of pro-inflammatory factor IL-6 and IL-17A in the serum decreased, while the level of anti-inflammatory factor IL-10 increased. Furthermore, the arterial DCs showed a decrease in P62 content. Ultimately, these changes resulted in a reduction in plaque area. It is worth noting that the autophagy inhibitor chloroquine significantly altered the effects of TSG on ApoE -/- mice. In conclusion, this study reveals that TSG can alleviate AS. This is partly achieved through the activation of autophagy in DCs. By intervening in the lipophagy of DCs, it is possible to regulate the immune function of these cells, which in turn helps control the inflammation associated with AS. This presents a potential method for intervening in AS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Tricetin (TRI) has been reported to have anti-inflammatory and antioxidant effects; however, its therapeutic potential and molecular mechanisms in atherosclerosis remain unclear. In this study, we aimed to investigate the effects of TRI on atherosclerosis. Our findings revealed that TRI inhibits macrophage ferroptosis by activating the NRF2 pathway. In vivo, ApoE -/- mice fed a high-fat diet and injected with TRI showed improved atherosclerosis progression through reduced oxidative stress and suppression of macrophage ferroptosis. In vitro experiments demonstrated that TRI administration increases GPX4 and xCT levels, attenuates oxidative stress, improves mitochondrial function, and inhibits lipid peroxidation, thereby suppressing ox-LDL-induced macrophage ferroptosis. Furthermore, TRI enhanced the nuclear translocation of NRF2. Notably, the protective effects of TRI on antioxidant capacity and ferroptosis were reversed in macrophages treated with ML385 (a specific NRF2 inhibitor). NRF2 knockdown in ApoE -/- mice using AAV-sh-NRF2 significantly reversed TRI-mediated inhibition of atherosclerosis progression and exacerbated macrophage ferroptosis in the plaque. Conclusively, this study identifies TRI as a potential therapeutic agent for atherosclerosis by inhibiting macrophage ferroptosis and oxidative stress through activation of the NRF2 pathway, offering a novel strategy to combat disease progression., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Obesity is increasingly taking an important stage as a cause of death worldwide, and interventions with a good cost-effectiveness ratio are needed. Psychotria densinervia is one of these natural products with health benefits. Objective. The present study evaluated the cytotoxicity, antiadipogenic, low-density lipoprotein (LDL), oxidation inhibitory activities, and acute toxicity of Psychotria densinervia hydroethanolic leaf and bark extracts. Methods: The cytotoxicity evaluation of the extracts (62.5, 125, 250, and 500 μg/mL) using the MTT assay and the antiadipogenic activity (25, 50, 100, and 200 μg/mL) using oleic acid were carried out in SW-872 cells. Copper sulfate (CuSO 4 )-induced oxidation was used in the evaluation of the effect of extracts (0.25, 0.5, and 1 mg/mL) against LDL oxidation. The oral acute toxicity evaluation of a single dose of 2000 mg/kg of the extracts was performed in Wistar albino rats weighing 127 ± 2 g. Results: The leaf and bark extracts did not show any sign of cytotoxicity at the tested concentrations. The best antiadipogenic activity was observed by the standard orlistat (38.45 ± 1.70 μg/mL), followed by the leaf extract (IC 50 : 41.47 ± 0.50 μg/mL) and the least the bark extract (IC 50 : 107.50 ± 0.90 μg/mL). At a concentration of 1 mg/mL, the leaf extract presented an oxidation lag time of 130 min, which was higher and better than that of the bark extract (120 min). Quercetin (standard) presented an oxidation lag time longer than 3 h. The oral acute toxicity evaluation did not show any signs of toxicity indicating that the LD 50 was greater than 2000 mg/kg. Conclusion: Based on the results obtained, the P. densinervia hydroethanolic leaf extract possesses a better antioxidant and antiadipogenic activities than the bark extract., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Jean Romuald Mba et al.)

There is increasing evidence supporting the unique benefits of targeted therapy in treating atherosclerotic disease. Given the complex nature of atherosclerosis development, we proposed a novel strategy for the efficient delivery of rapamycin (RAPA) by targeting both the exposed subendothelial collagen and oxidized low-density lipoprotein (oxLDL) present in plaques. In response, we developed multifunctional peptide (MP) nanoparticles for targeted drug delivery. The ability of MP nanoparticles to load RAPA and target collagen/oxLDL was investigated through molecular dynamics simulations and in vitro experiments. The efficacy of MP nanoparticles in atherosclerosis treatment was assessed via in vivo experiments on ApoE -/- mice. Results indicate that MP nanoparticles have encapsulation and drug loading efficiencies for RAPA of 78.3 % and 43.9 %, respectively. By targeting collagen, MP nanoparticles create steric hindrance that inhibits 77.2 % of platelet adhesion. These nanoparticles can also target oxLDL, delivering RAPA into plaques and significantly reducing macrophage uptake of oxLDL. In vivo experiments showed that MP nanoparticles effectively targeted and accumulated in plaques. Treating mice with MP@RAPA nanoparticles for 10 weeks led to an 81.3 % reduction in the aortic vascular plaque area and decreased concentrations of MCP-1, hs-CRP, MMP-1, P-selectin, IL-1β, and IL-8 inflammatory factors, as well as the optical density of platelet-associated proteins (CD42, CD61, and PECAM-1). These results highlight the promising potential of MP nanoparticles for atherosclerotic disease treatment., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Crocin-4 is a water-soluble carotenoid that exhibits cardiovascular protection effects through anti-inflammatory and antioxidant effects. However, the pharmacodynamic effects and mechanisms of its analogues crocin-1 and crocin-2' have not been reported. In this study, we evaluated the protective effects of rare crocins on cardiovascular systems. In ox-LDL induced HUVECs model, 0.02, 0.1, 0.5, 1, 2, 3, 4, 5, 6 μg/mL crocin-1 and crocin-2' can increase cell viability by up to 80 %. Meanwhile, rare crocins at concentrations between 25-100 μg/mL crocin-1 and crocin-2' reduced the lipid accumulation by 30 % in cholesterol-induced zebrafish larvae. What's more, the therapeutic potential of rare crocins on thrombosis has also been explored. In vitro experiments, rare crocin-1 and crocin-2' at concentrations of 0.02, 0.05, 0.2, 0.5, 1, 2, 5, 10 μg/mL protected Human Umbilical Vein Endothelial Cells (HUVECs) against lipopolysaccharides-induced oxidative stress and inflammation. In vivo studies revealed that rare crocins at concentrations of 25, 50, 100, 150, 200, and 300 μg/mL exerted significant antithrombotic effect on arachidonic acid (AA)-induced zebrafish and there was nearly no potential risk for the deformity of zebrafish at 300 μg/mL dosages. In brief, rare crocins was viewed as a potentially useful candidate for the treatment of cardiovascular diseases because of its anti-inflammatory, antioxidant, and anticoagulant properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Several leukocyte to high-density lipoprotein cholesterol (HDL-C) ratios, including monocyte to HDL-C ratio (MHR), neutrophil to HDL-C ratio (NHR) and lymphocyte to HDL-C ratio (LHR), have been proposed as novel inflammatory indicators. We performed a cross-sectional study to investigate the relationships between these leukocyte to HDL-C ratios and coronary artery disease (CAD) in patients with chest pain with controlled low-density lipoprotein cholesterol (LDL-C). A total of 3482 patients with chest pain with LDL-C <1.8 mmol/L were enrolled. We evaluated the relationships between MHR, NHR, LHR and HDL-C and the occurrence of CAD as well as severe stenosis. We found that in patients with chest pain, higher MHR (adjusted OR=2.83, 95% CI 1.61 to 4.99, p<0.001) and NHR (adjusted OR=1.08, 95% CI 1.04 to 1.13, p<0.001), as well as lower HDL-C (adjusted OR=0.53, 95% CI 0.36 to 0.78, p=0.001), but not higher LHR (adjusted OR=1.06, 95% CI 0.94 to 1.20, p=0.341), had a stronger association with the occurrence of CAD. Moreover, unlike LHR (adjusted OR=1.02, 95% CI 0.93 to 1.13, p=0.654), higher MHR (adjusted OR=2.10, 95% CI 1.43 to 3.07, p<0.001) and NHR (adjusted OR=1.06, 95% CI 1.04 to 1.09, p<0.001) and lower HDL-C (adjusted OR=0.38, 95% CI 0.26 to 0.56, p<0.001) were risk factors for severe stenosis. A receiver operating characteristic curve analysis exhibited comparable abilities between MHR and NHR in predicting the presence and severity of CAD. In conclusion, even though patients with chest pain have achieved LDL-C <1.8 mmol/L, the inflammatory indicators MHR and NHR maintained their predictive abilities and remained associated with the occurrence and severity of CAD. [ABSTRACT FROM AUTHOR]

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS)., Methods: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project., Results: FCS was relatively common in non-Europeans and those with parental consanguinity ( P <0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P =0.001), recurrent pancreatitis (92% versus 63%; P <0.001), unexplained abdominal pain (84% versus 52%; P <0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P <0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P <0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS ( P <0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS ( P =0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS., Conclusions: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS., Competing Interests: H. Soran received personal fees from Amgen, Akcea, Synageva, Napp, Novartis, Takeda, Sanofi, Pfizer, and Kowa and research grants and donations from Akcea, Pfizer, Merck Sharp & Dohme, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva, and Alexion. A.S. Wierzbicki is a site investigator on trials from Akcea and Regeneron; received royalties from Elsevier for a book on familial chylomicronemia syndrome; and is a board member for the Familial Hyperlipidaemia group, Europe. D. Datta received honoraria for advisory board from Swedish Orphan Biovitrum. N. Forrester received honoraria for presentations from SOBI. Y. Teoh received speakers fee from Daiichi Sankyo and Amarin. P. Downie received honoraria from SOBI, Novartis, Amgen, and Daiichi Sankyo. R.A. Hegele received consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi, and UltraGenyx. The other authors report no conflicts.

Background: Atherosclerosis (AS) is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Leonurine (LEO) is a unique alkaloid compound with protective effects on the cardiovascular system. However, the exact mechanisms underlying its cardiovascular-protecting action are still not fully elucidated. The methyltransferase 3 (METTL3), the catalytic core of the N6-methyladenosine modification (m 6 A) methyltransferase complex, has been shown to inhibit autophagy and exacerbate the process of AS via regulation of m 6 A modification of mRNA., Purpose: We aimed to determine whether the inhibited effect of LEO on AS is related to METTL3-mediated AKT1S1 stability., Methods: The apolipoprotein E (ApoE) knockout mice was subjected to a high-fat diet (HFD), and THP-1 derived macrophages was exposed to oxidized low-density lipoprotein (ox-LDL), to establish the animal and cellular models of AS, respectively., Results: We found that LEO effectively improved AS and reduced the plaque area and inflammation via diminishing macrophage lipid accumulation and remodeling the lipid metabolism profile. LEO activated ox-LDL-induced macrophage autophagy, enhancing lipid metabolism decrease, according to the lipidomic and molecular biology analyses. Additionally, LEO caused a marked increase in autophagy marker levels in mouse models with advanced AS. Furthermore, we found that LEO reactivated autophagy and reversed lipid accumulation by suppressing METTL3 expression. The m 6 A-seq from ox-LDL-induced macrophages showed that a total of five autophagy-related mRNA transcripts (AKT1S1, AKT1, RB1CC1, CFLAR, and MTMR4) were altered, and AKT1S1 was significantly upregulated by LEO. Mechanistically, LEO-mediated regulation of METTL3 decreased AKT1S1 expression by attenuating its mRNA stability. Silencing AKT1S1 inhibited LEO-METTL3 axis-mediated autophagy and enhanced lipid accumulation in ox-LDL-induced macrophages., Conclusion: The study first revealed that LEO exerts anti-atherosclerotic effect by activating METTL3-mediated macrophage autophagy in vivo and in vitro. The mechanism of LEO was further found to be the enhancement of METTL3-mediated AKT1S1 stability to activate autophagy thereby reducing lipid accumulation. This study provides a new perspective of natural medicines on the treatment of AS via an epigenetic manner., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Natural antioxidants have been shown to be effective against atherosclerosis. Ginkgo flavone aglycone (GA) has strong antioxidant properties and can protect against endothelial damage. However, the mechanisms by which GA protects against atherosclerosis remain largely unexplored. This study hopes to find the anti-atherosclerotic mechanism of GA. ApoE -/- mice fed a high-fat diet were used for modeling atherosclerosis. The efficacy of GA on mice with atherosclerosis was evaluated based on the following indicators: Oil Red O staining, Masson staining, lipid content, and apoptosis. Transmission electron microscopy, Western blot, immunofluorescence staining, and propidium iodide staining were used to analyze the effects of GA on ox-LDL-treated human aortic endothelial cells. GA activated Nrf2 by promoting the nuclear translocation of Nrf2, thereby inhibiting endothelial pyroptosis. GA prevented endothelial pyroptosis suppressed oxidative stress, and inhibited the development of atherosclerosis in ApoE -/- mice fed high-fat diets. At the cellular level, GA suppressed ox-LDL-induced pyroptosis of HAECs by reducing reactive oxygen species (ROS) levels and inhibiting NLRP3 inflammasome. Furthermore, siRNA targeting Nrf2 or ML385, an Nrf2 inhibitor, reversed these effects. GA liberated Nrf2 from Keap1 sequestration, enhanced the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, reinforced the antioxidant defense system, and inhibited oxidative stress, thereby preventing endothelial cell pyroptosis, and attenuating the progression of atherosclerosis. This study indicated that GA mitigated endothelial pyroptosis by modulating Keap1/Nrf2 interactions, shedding light on the potential mechanisms underlying the protective effects of natural antioxidants against atherosclerosis., (© 2024 John Wiley & Sons Ltd.)

Background: Atherosclerosis is a progressive inflammatory disease in which macrophage foam cells play a central role in disease pathogenesis. SPA (surfactant protein A) is a lipid-associating protein involved with regulating macrophage function in various inflammatory diseases. However, the role of SPA in atherosclerosis and macrophage foam cell formation has not been investigated., Methods: SPA expression was assessed in healthy and atherosclerotic human coronary arteries and the brachiocephalic arteries of wild-type or ApoE-deficient mice fed high-fat diets for 4 weeks. Hypercholesteremic wild-type and SPA-deficient mice fed a high-fat diet for 6 weeks were investigated for atherosclerotic lesions in vivo. In vitro experiments using RAW264.7 macrophages, primary resident peritoneal macrophages extracted from wild-type or SPA-deficient mice, and human monocyte-derived macrophages from the peripheral blood of healthy donors determined the functional effects of SPA in macrophage foam cell formation., Results: SPA expression was increased in atherosclerotic lesions in humans and ApoE-deficient mice and in response to a proatherosclerotic stimulus in vitro. SPA deficiency reduced the lipid profiles induced by hypercholesterolemia, attenuated atherosclerosis, and reduced the number of lesion-associated macrophage foam cells. In vitro studies revealed that SPA deficiency reduced intracellular cholesterol accumulation and macrophage foam cell formation. Mechanistically, SPA deficiency dramatically downregulated the expression of scavenger receptor CD36 (cluster of differentiation antigen 36) cellular and lesional expression. Importantly, SPA also increased CD36 expression in human monocyte-derived macrophages., Conclusions: Our results elucidate that SPA is a novel factor promoting atherosclerosis development. SPA enhances macrophage foam cell formation and atherosclerosis by increasing scavenger receptor CD36 expression, leading to increasing cellular OxLDL influx., Competing Interests: None.

Atherosclerosis is a key etiological event in the development of cardiovascular diseases (CVDs), strongly linked to the formation of foam cells. This study explored the effects of two blue mussel-derived bioactive peptides (BAPs), PIISVYWK (P1) and FSVVPSPK (P2), on inhibiting foam cell formation and mitigating inflammation in oxLDL-treated RAW264.7 macrophages. Both peptides significantly suppressed intracellular lipid accumulation and cholesterol levels while promoting cholesterol efflux by downregulating cluster of differentiation 36 (CD36) and class A1 scavenger receptors (SR-A1) and upregulating ATP binding cassette subfamily A member 1 (ABCA-1) and ATP binding cassette subfamily G member 1 (ABCG-1) expressions. The increased expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further validated their role in enhancing cholesterol efflux. Additionally, P1 and P2 inhibited foam cell formation in oxLDL-treated human aortic smooth muscle cells and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines, nitric oxide (NO), prostaglandin E 2 (PGE 2 ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), primarily through inhibiting NF-κB activation. Furthermore, P1 and P2 alleviated oxidative stress by activating the Nrf2/HO-1 pathway. Our findings demonstrate that P1 and P2 have significant potential in reducing foam cell formation and inflammation, both critical factors in atherosclerosis development. These peptides may serve as promising therapeutic agents for the prevention and treatment of CVDs associated with oxidative stress and inflammation.

Background: The hypothesized link between low-density lipoprotein (LDL) and oncogenesis has garnered significant interest, yet its explicit impact on lung adenocarcinoma (LUAD) remains to be elucidated. This investigation aims to demystify the function of LDL-related genes (LRGs) within LUAD, endeavoring to shed light on the complex interplay between LDL and carcinogenesis., Methods: Leveraging single-cell transcriptomics, we examined the role of LRGs within the tumor microenvironment (TME). The expression patterns of LRGs across diverse cellular phenotypes were delineated using an array of computational methodologies, including AUCell, UCell, singscore, ssGSEA, and AddModuleScore. CellChat facilitated the exploration of distinct cellular interactions within LDL&#95;low and LDL&#95;high groups. The findmarker utility, coupled with Pearson correlation analysis, facilitated the identification of pivotal genes correlated with LDL indices. An integrative approach to transcriptomic data analysis was adopted, utilizing a machine learning framework to devise an LDL-associated signature (LAS). This enabled the delineation of genomic disparities, pathway enrichments, immune cell dynamics, and pharmacological sensitivities between LAS stratifications., Results: Enhanced cellular crosstalk was observed in the LDL&#95;high group, with the CoxBoost+Ridge algorithm achieving the apex c-index for LAS formulation. Benchmarking against 144 extant LUAD models underscored the superior prognostic acuity of LAS. Elevated LAS indices were synonymous with adverse outcomes, diminished immune surveillance, and an upsurge in pathways conducive to neoplastic proliferation. Notably, a pronounced susceptibility to paclitaxel and gemcitabine was discerned within the high-LAS cohort, delineating prospective therapeutic corridors., Conclusion: This study elucidates the significance of LRGs within the TME and introduces an LAS for prognostication in LUAD patients. Our findings accentuate putative therapeutic targets and elucidate the clinical ramifications of LAS deployment., (© 2024 Wiley Periodicals LLC.)

Objective: To investigate the protective effect of miR-328-3p on oxidized low-density lipoprotein (ox-LDL)-induced coronary artery endothelial cell injury and the potentially relevant mechanisms., Methods: Human coronary artery endothelial cells (HCAECs) were induced with ox-LDL, and the cells were divided into a control group consisting of normal cells, an ox-LDL group receiving ox-LDL treatment, an ox-LDL+miR-NC group transfected with miR-NC and treated with ox-LDL, an ox-LDL+miR-328-3p group transfected with miR-328-3p and treated with ox-LDL, and ox-LDL+miR-328-3p+pcDNA group co-transfected miR-328-3p and pcDNA and treated with ox-LDL, and an ox-LDL+miR-328-3p+insulin-like growth factor 2 (IGF2) group co-transfected miR-328-3p and IGF2 and treated with ox-LDL. The expression level of miR-328-3p was determined with RT-qPCR. Cell proliferation was determined by MTT. Cell apoptosis was measured by flow cytometry. Western blot was conducted to examine the protein expression levels of cleaved cas-3 and IGF2. ELISA was performed to determine the levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β. Dual luciferase reporter experiment was performed to verify the targeting relationship between miR-328-3p and IGF2., Results: Compared with those of the control group, miR-328-3p expression level and cell activity were significantly reduced in the ox-LDL group ( P <0.05), while the apoptotic rate, the protein expression levels of cleaved cas-3, IGF2, Bax, and Bcl-2, and the levels of TNF-α, IL-6, and IL-1β were significantly increased ( P <0.05). Compared with those of the ox-LDL+miR-NC group, miR-328-3p expression level and cell activity significantly increased in the ox-LDL+miR-328-3p group ( P <0.05), while the apoptosis rate, the protein expression levels of cleaved cas-3 and IGF2, and the levels of TNF-α, IL-6, and IL-1β were significantly reduced. IGF2 was a functional target of miR-328-3p. Compared with those of the ox-LDL+miR-328-3p+pcDNA co-transfection group, the IGF2 protein level was significantly increased ( P <0.05) and cell activity was significantly decreased ( P <0.05) in the ox-LDL+miR-328-3p+IGF2 co-transfection group, while the apoptosis rate, cleaved cas-3 protein level, and the levels of TNF-α, IL-6, and IL-1β were significantly elevated ( P <0.05)., Conclusion: miR-328-3p inhibits ox-LDL-induced apoptosis and inflammatory in coronary artery endothelial cell injury through targeted negative regulation of IGF2., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Glucose-dependent insulinotropic polypeptide (GIP) of the incretin group has been shown to exert pleiotropic actions. There is growing evidence that advanced glycation end products (AGEs), senescent macromolecules formed at an accelerated rate under chronic hyperglycemic conditions, play a role in the pathogenesis of atherosclerotic cardiovascular disease in diabetes. However, whether and how GIP could inhibit the AGE-induced foam cell formation of macrophages, an initial step of atherosclerosis remains to be elucidated. In this study, we address these issues. We found that AGEs increased oxidized low-density-lipoprotein uptake into reactive oxygen species (ROS) generation and Cdk5 and CD36 gene expressions in human U937 macrophages, all of which were significantly blocked by [D-Ala 2 ]GIP(1-42) or an inhibitor of NADPH oxidase activity. An inhibitor of AMP-activated protein kinase (AMPK) attenuated all of the beneficial effects of [D-Ala 2 ]GIP(1-42) on AGE-exposed U937 macrophages, whereas an activator of AMPK mimicked the effects of [D-Ala 2 ]GIP(1-42) on foam cell formation, ROS generation, and Cdk5 and CD36 gene expressions in macrophages. The present study suggests that [D-Ala 2 ]GIP(1-42) could inhibit the AGE-RAGE-induced, NADPH oxidase-derived oxidative stress generation in U937 macrophages via AMPK activation and subsequently suppress macrophage foam cell formation by reducing the Cdk5-CD36 pathway.

Background: Natural antioxidants, exemplified by quercetin (Qu), have been shown to exert a protective effect against atherosclerosis (AS). However, the precise pharmacological mechanisms of Qu also remain elusive., Purpose: Here, we aimed to uncover the anti-atherosclerotic mechanisms of Qu., Methods/study Designs: The inflammatory cytokine expression, activity of NLRP3 inflammasome and NF-κB, as well as mechanically activated currents and intracellular calcium levels were measured in endothelial cells (ECs). In addition, to explore whether Qu inhibited atherosclerotic plaque formation via Piezo1 channels, Ldlr -/- and Piezo1 endothelial-specific knockout mice (Piezo1 △EC ) were established., Results: Our findings revealed that Qu significantly inhibited Yoda1-evoked calcium response in human umbilical vein endothelial cells (HUVECs), underscoring its role as a selective modulator of Piezo1 channels. Additionally, Qu effectively reduced mechanically activated currents in HUVECs. Moreover, Qu exhibited a substantial inhibitory effect on inflammatory cytokine expression and reduced the activity of NF-κB/NLRP3 in ECs exposed to ox-LDL or mechanical stretch, and these effects remained unaffected after Piezo1 genetic depletion. Furthermore, our study demonstrated that Qu substantially reduced the formation of atherosclerotic plaques, and this effect remained consistent even after Piezo1 genetic depletion., Conclusion: These results collectively provide compelling evidence that Qu ameliorates atherosclerosis by inhibiting the inflammatory response in ECs by targeting Piezo1 channels. In addition, Qu modulated atherosclerosis via inhibiting Piezo1 mediated NFκB/IL-1β and NLRP3/caspase1/ IL-1β axis to suppress the inflammation. Overall, this study reveals the potential mechanisms by which natural antioxidants, such as Qu, protect against atherosclerosis., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024. Published by Elsevier GmbH.)

• Cerebral microbleeds are risk factors for hemorrhagic stroke. • Low serum lipid levels may be related to prevalent cerebral microbleeds. • There are insufficient evidence that statin is related to cerebral microbleeds. Previous studies have shown that low serum lipids and statins may be related to cerebral hemorrhage. We made the meta-analysis to evaluate the associations between serum lipid levels or statins treatment and cerebral microbleeds (CMBs) to identify whether the similar correlation also existed. We comprehensively searched the Medline, Embase, Cochrane library, Web of Science, only included English journal articles, and systematically collected the observational studies and randomized controlled trials (RCTs) from September 1975 to August 2021. Random-effects model was used to pool data. Statistical heterogeneity was assessed by I2 statistic and chi-square. 11 items checklists recommended by the Agency for Healthcare Research and Quality (AHRQ), Newcastle–Ottawa Scale (NOS), and Cochrane Risk of Bias tool (ROB) were used to evaluate the methodological quality of cross-sectional studies, cohort studies and randomized controlled trial, respectively. Five cohort studies, two RCTs, and ten cross-sectional studies, including 16,637 subjects and 2663 CMBs patients, were included in our quantitative synthesis. Our study found that after adjusting the covariates, total cholesterol (TC) was significantly inversely correlated with the prevalent CMBs in any location, while total triglycerides (TG) and High-density lipoprotein (HDL) were significantly inversely associated with prevalent deep CMBs. Low-density lipoprotein (LDL) was negatively associated with incident CMBs after adjusted confounders. We did not found statistical differences between statin and CMBs after adjusted covariates. Serum major lipid (TC TG HDL LDL) levels may be inversely associated with CMBs. Currently, no sufficient evidence proves that statin therapy is the risk factor of CMBs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Aortic valve calcification (AVC), Lp(a) [lipoprotein(a)], and low-density lipoprotein cholesterol (LDL-C) are associated with severe aortic stenosis (AS). We aimed to determine which of these risk factors were most strongly associated with the risk of incident severe AS. METHODS: A total of 6792 participants from the MESA study (Multi-Ethnic Study of Atherosclerosis) had computed tomography-quantified AVC, Lp(a), and LDL-C values at MESA visit 1 (2000–2002). We calculated the absolute event rate of incident adjudicated severe AS per 1000 person-years and performed multivariable adjusted Cox proportional hazards regression. RESULTS: The mean age was 62 years old, and 47% were women. Over a median 16.7-year follow-up, the rate of incident severe AS increased exponentially with higher AVC, regardless of Lp(a) or LDL-C values. Participants with AVC=0 had a very low rate of severe AS even with elevated Lp(a) ≥50 mg/dL (<0.1/1000 person-years) or LDL-C ≥130 mg/dL (0.1/1000 person-years). AVC >0 was strongly associated with severe AS when Lp(a) <50 mg/dL hazard ratio (HR) of 33.8 (95% CI, 16.4–70.0) or ≥50 mg/dL HR of 61.5 (95% CI, 7.7–494.2) and when LDL-C <130 mg/dL HR of 31.1 (95% CI, 14.4–67.1) or ≥130 mg/dL HR of 50.2 (95% CI, 13.2–191.9). CONCLUSIONS: AVC better identifies people at high risk for severe AS compared with Lp(a) or LDL-C, and people with AVC=0 have a very low long-term rate of severe AS regardless of Lp(a) or LDL-C level. These results suggest AVC should be the preferred prognostic risk marker to identify patients at high risk for severe AS, which may help inform participant selection for future trials testing novel strategies to prevent severe AS. [ABSTRACT FROM AUTHOR]

Abstract Background: A sizeable proportion of patients have discordant low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). Objectives: We assessed the relationship between discordance of LDL-C and non-HDL-C and coronary artery disease (CAD) severity. Methods: We retrospectively evaluated the data of 574 consecutive patients who underwent coronary angiography. Fasting serum lipid profiles were recorded, SYNTAX and Gensini scores were calculated to establish CAD complexity and severity. We determined the medians for LDL-C and non-HDL-C to examine the discordance between LDL-C and non-HDL-C. Discordance was defined as LDL-C greater than or equal to the median and non-HDL-C less than median; or LDL-C less than median and non-HDL-C greater than or equal to median. A p value < 0.05 was accepted as statistically significant. Results: LDL-C levels were strongly and positively correlated with non-HDL-C levels (r = 0.865, p < 0.001) but 15% of patients had discordance between LDL-C and non-HDL-C. The percentage of patients with a Gensini score of zero or SYNTAX score of zero did not differ between discordant or concordant groups (p = 0.837, p = 0.821, respectively). Mean Gensini and SYNTAX scores, percentage of patients with Gensini score ≥20 and SYNTAX score >22 were not different from group to group (p = 0.635, p = 0.733, p = 0.799, p = 0.891, respectively). Also, there was no statistically significant correlation between LDL-C and Gensini or SYNTAX scores in any of the discordant or concordant groups. Additionally, no correlation was found between non-HDL-C and Gensini or SYNTAX score. Conclusions: While there was discordance between LDL-C and non-HDL-C (15% of patients), there is no difference regarding CAD severity and complexity between discordant and concordant groups.

Objective To explore the risk factors of carotid plaques in middle-aged and old women, and to analyze the factors affecting the occurrence and stability of plaque. Methods From March 2016 to March 2018, middle-aged and old women aged 45-80 years old were selected from the General Hospital of Tianjin Medical University. Carotid artery ultrasonography was performed to observe the intima-media thickness and plaque characteristics. According to the presence or absence of plaque, the patients were divided into plaque group (n=403) and non plaque group (n=551). According to the characteristics of plaque, patients with plaque were divided into two groups: stable plaque group (n=305) and unstable plaque group (n=98). The clinical data, laboratory test results and carotid ultrasound results were collected. The influencing factors of carotid plaque formation were analyzed. Results A total of 954 middle-aged and elderly women were included in this study, with an average of (62.24±13.24) years old. Compared with non plaque group, age, low density lipoprotein cholesterol (LDL-C) and systolic blood pressure were significantly higher in plaque group (P＜0.05). Logistic regression analysis found that age, LDL-C and menopause were independent risk factors of carotid plaque formation in middle-aged and elderly women. LDL-C was significantly lower in stable plaque group than that in unstable plaque group (P＜0.05). Analysis showed that the higher LDL-C was an independent risk factor for plaque stability. Conclusion Age, LDL-C and menopause are related to the occurrence of carotid plaques in middle-aged and old women, and LDL-C level affects the stability of carotid plaques. [ABSTRACT FROM AUTHOR]

Keywords: adiposity; alanine aminotransferase; cardiovascular diseases; glycated hemoglobin A; lifestyle factors; lipoproteins, LDL; triglycerides EN adiposity alanine aminotransferase cardiovascular diseases glycated hemoglobin A lifestyle factors lipoproteins, LDL triglycerides 77 79 3 07/12/22 20220712 NES 220712 Although the therapeutic importance of managing low-density lipoprotein cholesterol (LDL-C) to reduce atherosclerotic cardiovascular disease (ASCVD) risk is well established, the best course of action for modest or marked elevations of circulating triglycerides remains uncertain. Adiposity, alanine aminotransferase, cardiovascular diseases, glycated hemoglobin A, lifestyle factors, lipoproteins, LDL, triglycerides. [Extracted from the article]

Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment.Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching.Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL.Conclusions: After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402. [ABSTRACT FROM AUTHOR]

Background: Periodontal disease results in oral dysbiosis, increasing plaque virulence and oxidative stress. Stannous fluoride (SnF 2 ) binds lipopolysaccharides to reduce plaque virulence. This study prospectively assessed SnF 2 effects on oxidative stress in adults with gingivitis., Methods: This was a 2-month, single-center, single-treatment clinical trial. Twenty "disease" (> 20 bleeding sites with ≥ 3 pockets 3 mm-4 mm deep) and 20 "healthy" (≤ 3 bleeding sites with pockets ≤ 2 mm deep) adults were enrolled. All participants were instructed to use SnF 2 dentifrice twice daily for 2 months. An oral examination, Modified Gingival Index (MGI) examination and Gingival Bleeding Index (GBI) examination were conducted at baseline, 1 month and 2 months. Gingival crevicular fluid (GCF), saliva, oral lavage and supragingival plaque were collected at each visit to evaluate: Endotoxins, Protein Carbonyls, L-lactate dehydrogenase (LDH), Ferric reducing antioxidant power (FRAP), Oxidized low density lipoproteins (oxi-LDL), IL-6 and C-reactive protein (CRP). A subset-analysis examined participants considered at higher risk of cardiovascular disease. Change-from-baseline analyses within each group were of primary interest., Results: The disease group showed statistically significant reductions in GBI at Month 1 (67%) and Month 2 (85%) and in MGI at Month 1 (36%) and Month 2 (51%) versus baseline (p < 0.001). At baseline, the disease group showed greater LDH in GCF and oxi-LDL levels in saliva versus the healthy group (p ≤ 0.01). Total antioxidant capacity (FRAP) in saliva increased versus baseline for the disease group at Months 1 and 2 (p < 0.05), and levels for the disease group were greater than the healthy group at both timepoints (p < 0.05). SnF 2 treatment reduced endotoxins (lavage) for both disease and healthy groups at Month 2 (p ≤ 0.021) versus baseline. There was a reduction in oxidative stress markers, namely protein carbonyl in saliva, at Months 1 and 2 (p < 0.001) for both groups and a reduction in cytokine IL-6 (lavage) in the disease group at Month 2 (p = 0.005). A subset analysis of participants at higher coronary disease risk showed reductions in endotoxins in lavage, oxi-LDL, and CRP in saliva at Month 2 (p ≤ 0.04)., Conclusion: SnF 2 dentifrice use reversed gingival inflammation, suppressed endotoxins and reduced some harmful oxidant products in saliva and gingiva., Clinical Trial Registration: Clinicaltrials.gov NCT05326373, registered on 13/04/2022., (© 2024. The Author(s).)

Background: Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS., Methods: We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations., Results: A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P =0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P <0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P <0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P =0.001)., Conclusions: Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization., Competing Interests: Dr Matter reports receiving grants from Merck Sharp & Dohme, Eli Lilly, AstraZeneca, Roche, Bayer, Novo Nordisk; expert testimony from Merck Sharp & Dohme; payment for lectures from Merck Sharp & Dohme, AstraZeneca, and Roche. Dr Mach has received honoraria for advisory boards and conferences on dyslipidemia from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Sanofi, and Pfizer. The other authors report no conflicts.

Atherosclerosis is a chronic multifactorial cardiovascular disease. To combat atherosclerosis effectively, it is necessary to develop precision and targeted therapy in the early stages of plaque formation. In this study, a simvastatin (SV)-containing prodrug micelle SPCPV was developed by incorporating a peroxalate ester bond (PO). SPCPV could specifically target VCAM-1 overexpressed at atherosclerotic lesions. SPCPV contains a carrier (CP) composed of cyclodextrin (CD) and polyethylene glycol (PEG). At the lesions, CP and SV exerted multifaceted anti-atherosclerotic effects. In vitro studies demonstrated that intracellular reactive oxygen species (ROS) could induce the release of SV from SPCPV. The uptake of SPCPV was higher in inflammatory cells than in normal cells. Furthermore, in vitro experiments showed that SPCPV effectively reduced ROS levels, possessed anti-inflammatory properties, inhibited foam cell formation, and promoted cholesterol efflux. In vivo studies using atherosclerotic rats showed that SPCPV reduced the thickness of the vascular wall and low-density lipoprotein (LDL). This study developed a drug delivery strategy that could target atherosclerotic plaques and treat atherosclerosis by integrating the carrier with SV. The findings demonstrated that SPCPV possessed high stability and safety and had great therapeutic potential for treating early-stage atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care., Competing Interests: Disclosures Dr Joshi has received honoraria from Regeneron and Bayer; research grants from the American Heart Association, Novo Nordisk, GlaxoSmithKline, Sanofi/Regeneron, AstraZeneca, and NASA; and is a stock shareholder for G3 Therapeutics. Dr Peterson has received research funding to his institution from BMS, Esperion, Janssen, and Amgen; and honoraria and consulting fees from Bayer, Janssen, Novo Nordisk, and Novartis. Dr Rohatgi has served as a consultant for CSL Limited, Raydel, and HDL Diagnostics; and received research grants from CSL and Quest. Dr Navar has received research funding to her institution from BMS, Esperion, and Janssen; and honoraria and consulting fees from Astra Zeneca, BI, Bayer, Janssen, Eli Lilly, Merck, Novo Nordisk, Novartis, New Amsterdam, Pfizer, and Silence Therapeutics. The remaining authors have no disclosures to report.

Competing Interests: Disclosures S. Tsimikas is a coinventor and receives royalties from patents owned by the University of California San Diego (UCSD) and is a cofounder and has an equity interest in Oxitope and Kleanthi Diagnostics and has a dual appointment at UCSD and Ionis Pharmaceuticals. The terms of this arrangement have been reviewed and approved by the UCSD in accordance with its conflicts-of-interest policies.

Background: Atherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear., Purpose: To evaluate the efficacy and mechanism of Geniposide in treating AS., Study Design and Methods: Geniposide was administered to high-fat diet-fed ApoE -/- mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression., Results: In vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1., Conclusion: Geniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Mesoporous silica nanoparticles (MSNPs) coated by chitosan (CS) were shown to be a proper candidate as a carrier for drug delivery purposes. However, choosing the suitable drug-containing complexes to be applied on MSNPs-CS is of much greater importance to evaluate the possible candidate for an efficient combination of cell viability, drug release kinetics, and atherosclerosis prevention. In this regard, this study concentrates on the synthesis and assessment of coated MSNPs-CS designed for drug delivery purposes. The MSNPs are coated with polyelectrolyte complexes (PEC) composed of CS and dextran sulfate (MSNPs-CS-DX), serving as a versatile drug carrier with favorable biological characteristics. CS-DX is applied to MSNPs without requiring complex or multi-step synthesis procedures. Rosuvastatin, a cholesterol-lowering medication, is chosen for its therapeutic relevance. Additionally, CS-DX is found to relatively impede the uptake of low-density lipoproteins (LDLs) by macrophages, enhancing their potential therapeutic utility. FTIR pattern, FESEM, and TEM images prove MSNPs-CS-DX formation. DLS measurement demonstrates the average particle size of 110 nm for MSNPs, with the combined thickness of CS and DX layers ranging from 10 to 15 nm. BET test is carried out to evaluate the pore size and porosity of structure, showing outstanding results that cause an entrapment efficiency of 57% for MSNPs-CS-DX. Furthermore, the findings demonstrate the pH sensitivity of MSNPs-CS-DX on drug release kinetics. Notably, the CS-DX layer exhibits a significant enhancement in cell viability of human umbilical vein endothelial cells (HUVEC) by approximately 24% within a 24 h timeframe compared to MSNPs lacking CS-DX., (© 2024. The Author(s).)

Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein-protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE -/- ) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1β pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1β, and IL-18, in vivo and in vitro., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

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