Atherosclerosis最新文献

{"title":"Risk of atherosclerosis-related diseases in polymyositis and dermatomyositis patients: A large-scale population-based study","authors":"Lior Fisher ,&nbsp;Niv Ben-Shabat ,&nbsp;Omer Gendelman ,&nbsp;Kassem Sharif ,&nbsp;Scott Ehrenberg ,&nbsp;Uria Shani ,&nbsp;Yonatan Shneor Patt ,&nbsp;Nour Karra ,&nbsp;Abdulla Watad ,&nbsp;Howard Amital ,&nbsp;Arnon Cohen ,&nbsp;Israel Dudkiewicz","doi":"10.1016/j.atherosclerosis.2024.119100","DOIUrl":"10.1016/j.atherosclerosis.2024.119100","url":null,"abstract":"<div><h3>Background and aims</h3><div>Several systemic autoimmune diseases predispose to the enhancement of Atherosclerotic Cardiovascular Disease (ASCVD). These findings underline the role of inflammation in atherogenesis. Dermatomyositis (DM) and polymyositis (PM) are polygenic autoimmune disorders involving mainly skeletal muscles. The association between PM/DM and ASCVD has not been well addressed and explored. We aimed to investigate the association between PM/DM and ASCVD events, we examined the incidence, mortality, and interaction of disease-modifying agents, autoantibodies, and traditional cardiovascular disease (CVD) risk factors in a large population-based sample.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study using the electronic database of Clalit Health Services (CHS), the largest health organization in Israel. All DM and PM patients diagnosed between 2000 and 2016 were included and matched with healthy controls by age and sex in a 1:5 ratio. Follow-up continued until the first diagnosis of ASCVD or death. The incidence of ASCVD was compared between the groups using univariate and multivariate models adjusting for baseline cardiovascular risk factors.</div></div><div><h3>Results</h3><div>The study population included 1899 PM/DM patients and 7676 controls. The mean age at the index date was 32.5 years (SD ± 19 years), and the female proportion was 60.3 %, similar for both groups. Traditional cardiovascular risk factors were similar in both groups. The Median follow-up time was 8.4 years (3.6–12.8) in the PM/DM group compared to 8.6 (3.7–12.9) in the control group. 47 (3.0 %) PM/DM patients were diagnosed with ischemic heart disease (IHD) compared to 1.8 % (140) in the controls, yielding a multivariate HR (95%CI) of 1.61 (1.15–2.25). Multivariate HR for cerebrovascular accident (CVA) in the PM/DM group was (95%CI) 2.45 (1.63–3.70). Multivariate HR for ASCVD. (95%CI) was 1.75 (1.35–2.27) in the PM/DM group. APLA-associated antibodies presence was more associated with ASCVD among PM/DM groups than non-ASCVD PM and DM patients (OR 2.33, 95 % CI 1.41–3.86, <em>p</em> <em>&lt;</em> 0.001).</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that PM and DM are associated with an increased risk of IHD and CVA. Furthermore, PM and DM patients positive for APLA-associated antibodies exhibited excessive rates of ASCVD. These findings support the increased need for awareness and surveillance of cardiological, neuronal, and vascular outcomes in patients suffering from PM/DM.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"401 ","pages":"Article 119100"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VLDL triglycerides and cholesterol in non-alcoholic fatty liver disease and myocardial infarction","authors":"Lærke Kristine Kyhl ,&nbsp;Børge Grønne Nordestgaard ,&nbsp;Anne Tybjærg-Hansen ,&nbsp;George Davey Smith ,&nbsp;Sune Fallgaard Nielsen","doi":"10.1016/j.atherosclerosis.2024.119094","DOIUrl":"10.1016/j.atherosclerosis.2024.119094","url":null,"abstract":"<div><h3>Background and aims</h3><div>Myocardial infarction is a leading cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The two diseases share elevated very low-density lipoproteins (VLDL) carrying both triglycerides and cholesterol; however, in NAFLD mainly triglycerides accumulate in liver cells while in myocardial infarction mainly cholesterol accumulates in the atherosclerotic plaque. We hypothesized that VLDL triglycerides preferentially associate with risk of NAFLD, while VLDL cholesterol preferentially associates with risk of myocardial infarction.</div></div><div><h3>Methods</h3><div>We examined 25,428 individuals without clinically diagnosed NAFLD or myocardial infarction at baseline, nested within 109,776 individuals from the prospective Copenhagen General Population Study and followed these individuals for a mean of 10 years. VLDL triglycerides, VLDL cholesterol, and low-density lipoprotein (LDL) cholesterol were determined using nuclear magnetic resonance spectrometry.</div></div><div><h3>Results</h3><div>Continuously higher VLDL triglycerides were associated with continuously higher risk of NAFLD; however, this was not the case for VLDL cholesterol, LDL cholesterol, or apolipoprotein B. In contrast, continuously higher VLDL cholesterol, LDL cholesterol, and plasma apolipoprotein B were all associated with continuously higher risk of myocardial infarction. Compared to individuals with both VLDL triglycerides and VLDL cholesterol ≤66th percentile, the hazard ratios for NAFLD in individuals with VLDL triglycerides &gt;66th percentile were 1.61(95 % confidence intervals:1.25–2.06) at high VLDL cholesterol and 1.41(0.90–2.21) at low VLDL cholesterol. Corresponding hazard ratios for myocardial infarction in individuals with VLDL cholesterol &gt;66th percentile were 1.51(1.36–1.67) at high VLDL triglycerides and 1.42(1.18–1.69) at low VLDL triglycerides.</div></div><div><h3>Conclusions</h3><div>VLDL triglycerides predominated in NAFLD while VLDL cholesterol predominated in myocardial infarction; however, VLDL cholesterol was also elevated slightly in NAFLD while VLDL triglycerides was also elevated in myocardial infarction.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"401 ","pages":"Article 119094"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of sex and the cheese matrix on cholesterol metabolism in middle-aged adults","authors":"Martina Rooney ,&nbsp;Aileen O'Connor ,&nbsp;Simone Dunne ,&nbsp;Emma L. Feeney ,&nbsp;Eileen R. Gibney","doi":"10.1016/j.atherosclerosis.2025.119112","DOIUrl":"10.1016/j.atherosclerosis.2025.119112","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cheese has been shown to lower total and LDL cholesterol concentrations, despite being a source of saturated fat. The dairy matrix is purported to be responsible for this effect. There is increasing recognition of sexual dimorphism in the development and progression of cardiovascular disease (CVD), in addition to sex-related differences in response to nutrition interventions. This analysis aims to explore the effect of sex on the cholesterol-lowering effect of cheese compared to butter.</div></div><div><h3>Methods</h3><div>The present study is secondary analysis of pooled data from two parallel-arm randomised controlled trials (RCT) with similar protocols, where participants (<em>n</em> 197, 41.6 % male) received either 120g cheese (<em>n</em> 104) or deconstructed cheese (49g butter, 30g calcium caseinate and a calcium supplement, <em>n</em> 93) for 6 weeks. Each arm provided ∼40g fat per day.</div></div><div><h3>Results</h3><div>In the group as a whole, cheese was found to lower total and LDL cholesterol, compared to deconstructed cheese. No sex × treatment interactions were observed although, within-sex analysis found men and women to respond differently. Within males, cholesterol concentrations decreased in response to dairy fat. Within the female group cheese lowered total and LDL cholesterol concentrations, whereas deconstructed cheese was found to increase the same lipid markers.</div></div><div><h3>Conclusions</h3><div>Cheese was found to lower cholesterol concentrations in the cohort as a whole, while men and women were found to respond differently to dairy fat. Females appear to respond more favourably to cheese compared to deconstructed cheese. These findings indicate the cheese matrix may have a stronger effect in females and thus may play a role in personalised nutrition.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119112"},"PeriodicalIF":4.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-acetylcysteine therapy reduces major adverse cardiovascular events in patients with type 2 diabetes mellitus","authors":"Mingyang Sun ,&nbsp;Zhongyuan Lu ,&nbsp;Wan-Ming Chen ,&nbsp;Shuang Lv ,&nbsp;Ningning Fu ,&nbsp;Yitian Yang ,&nbsp;Yangyang Wang ,&nbsp;Mengrong Miao ,&nbsp;Szu-Yuan Wu ,&nbsp;Jiaqiang Zhang","doi":"10.1016/j.atherosclerosis.2025.119117","DOIUrl":"10.1016/j.atherosclerosis.2025.119117","url":null,"abstract":"<div><h3>Background</h3><div>Effective preventive strategies for major adverse cardiovascular events (MACE) in T2DM patients are limited. Recent studies have explored the cardiovascular benefits of N-Acetylcysteine (NAC), an antioxidant with endothelial protective properties. This study investigates the long-term effects of NAC on MACE risk in T2DM patients, focusing on its potential as an adjunctive therapy.</div></div><div><h3>Methods</h3><div>This population-based cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) and included 46,718 T2DM patients diagnosed between 2008 and 2018, with follow-up until December 31, 2021. Propensity score matching (PSM) ensured balanced comparisons between NAC users and non-users. Cox regression and time-dependent Cox hazards models assessed MACE risk, adjusting for multiple covariates.</div></div><div><h3>Results</h3><div>In the matched cohort of 23,359 NAC users and 23,359 non-users, NAC users had a significantly lower incidence of MACE (41.74 % vs. 46.87 %, P &lt; .0001). Adjusted Hazard Ratios (aHRs) indicated a consistent protective effect of NAC against overall MACE (aHR: 0.84; 95 % CI: 0.81–0.86, P &lt; .0001). Higher cumulative defined daily doses (cDDD) of NAC correlated with reduced MACE risk, with the highest quartile (Q4) showing an aHR of 0.61 (95 % CI: 0.58–0.64, P &lt; .0001).</div></div><div><h3>Conclusion</h3><div>This study underscores the significant reduction in MACE risk among T2DM patients with long-term NAC therapy. Notably, the findings emphasize NAC's dose-dependent effectiveness in diminishing MACE incidence, indicating its potential as a valuable adjunctive therapy for managing cardiovascular risk in T2DM patients.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119117"},"PeriodicalIF":4.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143142541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trimethylamine N-oxide aggravates human aortic valve interstitial cell inflammation by regulating the macrophages polarization through a N6-methyladenosine-mediated pathway","authors":"Liming Wen ,&nbsp;Xiangjie Lin ,&nbsp;Dongtu Hu ,&nbsp;Juncong Li ,&nbsp;Kaiji Xie ,&nbsp;Shunyi Li ,&nbsp;Shuwen Su ,&nbsp;Xiaolin Duan ,&nbsp;Guoheng Zhong ,&nbsp;Yingwen Lin ,&nbsp;Yangchao Chen ,&nbsp;Tianyu Xu ,&nbsp;Qingchun Zeng","doi":"10.1016/j.atherosclerosis.2025.119109","DOIUrl":"10.1016/j.atherosclerosis.2025.119109","url":null,"abstract":"<div><h3>Background</h3><div>Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that promotes calcified aortic valve disease (CAVD), but the underlying mechanism remains obscure. Herein, we aim to test the hypothesis that TMAO regulated the inflammatory process in aortic valves via N6-methyladenosine (m6A) RNA methylation-mediated macrophage polarization.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, we stimulated macrophages (Phorbol-12-Myristate-13-Acetate-induced THP-1) with TMAO and assessed the expression of methyltransferase-like 3 (Mettl3), IL-1 receptor associated kinase M (IRAK-M) and polarization markers. The interaction between YTH domain family protein 2 (YTHDF2) and IRAK-M mRNA was explored by RNA-IP and RNA decay assay. Functionally, the effects of macrophages on human aortic valve interstitial cells (AVICs) were measured via macrophage adhesion assay and co-culture system. <em>In vivo,</em> the influence of IRAK-M on CAVD development was verified using <em>Irak-m</em>^{<em>−/−</em>} mice.</div></div><div><h3>Result</h3><div>Mettl3 was highly expressed while IRAK-M was decreased in human calcified aortic valves. <em>In vitro</em>, TMAO upregulated the expression of Mettl3, while the expression of IRAK-M, an important negative regulator of the NF-κB pathway, was remarkably decreased in macrophages. TMAO also induced classical macrophage activation (M1 polarization). Mechanistically, IRAK-M was identified as a target of Mettl3-mediated m6A modification, indicating the involvement of m6A methylation in the regulation of NF-κB activation. Moreover, RIP assay revealed the direct interaction between YTHDF2 and IRAK-M mRNA and this process was dependent on Mettl3. TMAO-treated macrophage conditioned medium induced inflammatory responses in human aortic valve interstitial cells (AVICs). <em>In vivo</em> experiments showed that the deletion of IRAK-M significantly accelerated the progression of aortic valve lesion in mice administrated with high-fat and choline diet (HFCD).</div></div><div><h3>Conclusion</h3><div>TMAO induces the expression of Mettl3 in macrophages. Mettl3 promotes M1 polarization of macrophages by inhibiting IRAK-M through a m6A/YTHDF2 pathway. TMAO-treated macrophages aggravate the inflammation of human AVICs.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119109"},"PeriodicalIF":4.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mid-life physical activity and calcification of coronary arteries, aorta, and cardiac valves in late life: The Atherosclerosis Risk in Communities (ARIC) study","authors":"Yejin Mok ,&nbsp;Shoshana H. Ballew ,&nbsp;Jennifer A. Schrack ,&nbsp;Candace M. Howard ,&nbsp;Kenneth R. Butler ,&nbsp;Lynne Wagenknecht ,&nbsp;Josef Coresh ,&nbsp;Matthew Budoff ,&nbsp;Hirofumi Tanaka ,&nbsp;Michael J. Blaha ,&nbsp;Kunihiro Matsushita","doi":"10.1016/j.atherosclerosis.2025.119115","DOIUrl":"10.1016/j.atherosclerosis.2025.119115","url":null,"abstract":"<div><h3>Background and aims</h3><div>The association of physical activity (PA) with coronary artery calcification (CAC), one of the strongest predictors of cardiovascular disease, is unclear. Moreover, different domains of PA (e.g., exercise/sports vs. work) and extra-coronary calcification (ECC) have not been extensively studied. We comprehensively evaluated the association of PA with CAC and ECC.</div></div><div><h3>Methods</h3><div>We investigated 2025 ARIC participants (age 73–95 years) without coronary heart disease at visit 7 (2018–19). Mid-life total and domain-specific (sport, leisure, and work) PA scores were estimated using a modified Baecke questionnaire. We modeled the averaged PA scores at visit 1 (1987–89; age 44–65 years) and visit 3 (1993–95; age 49–70 years). We explored continuous CAC and ECC (log-transformed [Agatston score+1]) or the presence of any CAC and ECC (Agatston score &gt;0 vs. 0) as dependent variables using multivariable linear regression and logistic regression models, as appropriate.</div></div><div><h3>Results</h3><div>Total PA scores showed a U-shaped association with both continuous and any vs. no CAC. Higher total PA scores were associated inversely with ECC and most pronounced for the descending aorta calcification. The associations were generally consistent across demographic subgroups. When specific PA domains were examined, higher sport and work PA scores were significantly associated with lower descending aorta calcification.</div></div><div><h3>Conclusions</h3><div>Mid-life PA showed a U-shaped association with late-life CAC. Among ECC, the association of higher PA with lower calcification of the descending aorta was the most consistent. Our results further corroborate a complex interplay between PA and vascular health and unique pathological processes across different vascular beds.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119115"},"PeriodicalIF":4.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143355262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of ongericimab in Chinese patients with heterozygous familial hypercholesterolemia: A randomized, double-blind, placebo-controlled phase 3 trial","authors":"Jie Lin ,&nbsp;Yuan Ji ,&nbsp;Gaopin Wang ,&nbsp;Xueping Ma ,&nbsp;Zhuhua Yao ,&nbsp;Xuebin Han ,&nbsp;Jie Chen ,&nbsp;Jiyan Chen ,&nbsp;Wei Huang ,&nbsp;Guangma Xu ,&nbsp;Daoquan Peng ,&nbsp;Peishi Yan ,&nbsp;Ping Qiao ,&nbsp;Yongming He ,&nbsp;Yida Tang ,&nbsp;Minghui Wang ,&nbsp;Mengqi Zhang ,&nbsp;Jianjun Yu ,&nbsp;Yu Hao ,&nbsp;Changsheng Ma","doi":"10.1016/j.atherosclerosis.2025.119120","DOIUrl":"10.1016/j.atherosclerosis.2025.119120","url":null,"abstract":"<div><h3>Background and aims</h3><div>Heterozygous familial hypercholesterolemia (HeFH) is a prevalent autosomal dominant disorder of lipid metabolism but severely underdiagnosed and undertreated in China. This phase 3 trial aims to evaluate the efficacy and safety of ongericimab, a novel monoclonal antibody that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), in Chinese patients with HeFH.</div></div><div><h3>Methods</h3><div>Patients who have been diagnosed with definite HeFH according to Dutch Lipid Clinical Network criteria and receiving stable and optimized lipid-lowering therapy were enrolled. A total of 135 patients were randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks (Q2W), or ongericimab 450 mg or matching placebo every 4 weeks (Q4W) for 24 weeks. Patients were stratified according to the use of high-intensity statins. The primary endpoint was the percentage change in LDL-C from baseline to week 24.</div></div><div><h3>Results</h3><div>Our findings demonstrated that treatment with ongericimab resulted in a significant reduction in LDL-C at week 24. The least-squares mean difference was −69.4 % (95 % confidence interval [CI]: −80.9 %, −57.9 %; <em>p</em> &lt; 0.0001) for the ongericimab 150 mg Q2W group, and −80.6 % (95 % CI: −92.1 %, −69.1 %; <em>p</em> &lt; 0.0001) for ongericimab 450 mg Q4W group compared to respective matching placebo groups. Meanwhile, ongericimab also favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups.</div></div><div><h3>Conclusions</h3><div>Ongericimab administered at either 150 mg Q2W or 450 mg Q4W for 24 weeks, significantly reduced LDL-C levels and was well-tolerated in Chinese patients with HeFH.</div></div><div><h3>Clinical trial registration</h3><div><span><span>http://www.clinicaltrials.gov</span><svg><path></path></svg></span>; Unique Identifier: NCT05325203.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119120"},"PeriodicalIF":4.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143478488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA","authors":"Eliot A. Brinton ,&nbsp;Robert H. Eckel ,&nbsp;Daniel Gaudet ,&nbsp;Christie M. Ballantyne ,&nbsp;Brenda F. Baker ,&nbsp;Henry N. Ginsberg ,&nbsp;Joseph L. Witztum","doi":"10.1016/j.atherosclerosis.2025.119114","DOIUrl":"10.1016/j.atherosclerosis.2025.119114","url":null,"abstract":"<div><div>Familial chylomicronemia syndrome (FCS) is a rare, recessive monogenic disorder characterized by severely elevated plasma triglyceride (TG) levels due to absent or markedly impaired lipoprotein lipase activity, leading to a greatly increased risk of acute pancreatitis. Naturally occurring very low levels of apoC-III are associated with low TG levels; thus, apoC-III is a target for TG lowering, and therapies have been developed to reduce apoC-III. Strategies to inhibit hepatic apoC-III synthesis include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). In the last decade, technologies have been developed to enhance hepatic delivery of these potential therapeutic agents by conjugation of the ligand triantennary N-acetyl galactosamine to ASO and siRNA for receptor-mediated uptake by hepatocytes, where apoC-III is predominantly expressed. Enhanced delivery of these pharmacological agents to the target tissue has been found to support lower and/or less frequent dosing with consequent lower total systemic exposure. One antisense agent, the ASO olezarsen, is now approved by the US Food and Drug Administration (FDA) as an adjunct to diet to lower triglycerides in adults with FCS, and the other, the siRNA plozasiran, is in late-stage clinical development. Both agents have shown effectiveness in reducing both apoC-III and TG levels across several study populations. Reduced TG, lower rates of acute pancreatitis events, and similar proportions of adverse events in placebo and treated patients were recently demonstrated in placebo-controlled phase 3 trials of patients with FCS treated with olezarsen in Balance and with plozasiran in PALISADE. This review discusses causes and consequences of FCS and the rationale and progress made in developing <em>APOC3</em> RNA–targeted therapeutics for the treatment of FCS.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"403 ","pages":"Article 119114"},"PeriodicalIF":4.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caveolin-1-mediated LDL transcytosis across endothelial cells in atherosclerosis","authors":"Yifei Zhang ,&nbsp;Xiong Jia ,&nbsp;Yayu Wang ,&nbsp;Qijun Zheng","doi":"10.1016/j.atherosclerosis.2025.119113","DOIUrl":"10.1016/j.atherosclerosis.2025.119113","url":null,"abstract":"<div><div>Atherosclerosis is widely recognized as a chronic inflammatory disease of the arterial wall characterized by the progressive accumulation of lipids, inflammatory cells, and fibrous material in the subendothelial space of large arteries. The occurrence and pathogenesis of atherosclerosis are intricately linked to the deposition of low-density lipoprotein (LDL) in the arterial wall. LDL must cross the intact endothelium to reach the subendothelial space, with caveolin-1 assuming a crucial role in this process. Caveolin-1 is a 21–24 kDa membrane protein located in caveolae and highly expressed in endothelial cells. Previous investigations have demonstrated the pivotal role of caveolin-1 in fostering atherosclerosis through its modulation of membrane trafficking, cholesterol metabolism, and cellular signaling. However, how caveolin-1 regulates LDL transcytosis across endothelial cells in atherosclerosis remains unclear. We provide a comprehensive overview of recent research on the interplay between caveolin-1 and atherosclerosis, with a specific focus on elucidating the role of caveolin-1 in mediating LDL transcytosis across endothelial cells. This review furnishes theoretical foundations supporting the pivotal role of caveolin-1 in both the inception and progression of atherosclerosis. It underscores the prospective viability of caveolin-1 as a new therapeutic target for atherosclerosis and introduces novel perspectives for treatment strategies in the early stages of atherosclerosis.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119113"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143354545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization","authors":"Dilin Xu ,&nbsp;Jin Lu ,&nbsp;Yanfang Yang ,&nbsp;Wangxing Hu ,&nbsp;Jinyong Chen ,&nbsp;Junhui Xue ,&nbsp;Shuangshuang Yang ,&nbsp;Naifang Cao ,&nbsp;Haochang Hu ,&nbsp;Ningjing Qian ,&nbsp;Dao Zhou ,&nbsp;Hanyi Dai ,&nbsp;Jian'an Wang ,&nbsp;Xianbao Liu","doi":"10.1016/j.atherosclerosis.2025.119110","DOIUrl":"10.1016/j.atherosclerosis.2025.119110","url":null,"abstract":"<div><h3>Background and aims</h3><div>Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease regulation. This study aimed to uncover novel therapeutic targets for CAVD using Mendelian randomization (MR) integrated with transcriptomic analysis.</div></div><div><h3>Methods</h3><div>Protein quantitative trait loci (pQTL) from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) plasma protein databases were used as exposure data. The FinnGen cohort (9870 cases, 402,311 controls) served as the discovery set, while the TARGET cohort (13,765 cases, 640,102 controls) provided validation. MR and summary data-based Mendelian randomization (SMR) were employed to screen for potential causal targets of CAVD. Colocalization analysis was conducted to assess whether CAVD and target proteins shared common causal SNPs. Additional analyses included trancriptomic profiling at multiple RNA levels. Protein-level validation was conducted via Western blot and immunostaining.</div></div><div><h3>Results</h3><div>Six proteins (ANGPTL4, PCSK9, ITGAV, CTSB, GNPTG, and FURIN) with strong genetic colocalization were identified by MR and SMR analysis. Among these, cellular trancriptomic analysis revealed ANGPTL4 and ITGAV with significantly greater expression in osteogenic group, which was further validated in calcified aortic valves and osteogenic valvular interstitial cells in protein level.</div></div><div><h3>Conclusions</h3><div>This study identified six causal proteins with strong genetic colocalization for CAVD, with ANGPTL4 and ITGAV emerging as the most promising targets for further investigation.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"402 ","pages":"Article 119110"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143354547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}