Atherosclerosis最新文献_第9页

The role of ANGPTL8 in metabolism and cardiovascular diseases: Consensus and controversy ANGPTL8在代谢和心血管疾病中的作用：共识与争议

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-30 DOI: 10.1016/j.atherosclerosis.2025.120556

Yutong Lin , Danan Wang , Duanbin Li , Fomin Zhang , Qiongjun Zhu , Xiaoyi Bao , Ning Zhang , Zakareya M. Alsalman , Shengyu Chen , Xiaolu Jiao , Wenbin Zhang

Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein (ANGPTL) family, is a physiological inhibitor of lipoprotein lipase (LPL), and plays a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 is implicated in a wide range of systemic and cellular processes and is closely associated with metabolic and cardiovascular diseases (CVD). Circulating ANGPTL8 is primarily secreted by the liver, with adipose tissue as a secondary source. Its expression is regulated by multiple transcription factors and microRNAs, and is responsive to fasting/refeeding states, hormonal signals, and stress conditions. In lipid metabolism, ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4 to modulate LPL activity under fasting and feeding conditions. In glucose metabolism, ANGPTL8 plays a complex role. While some studies suggest it may improve glucose tolerance and insulin resistance, others indicate it could exacerbate glucose metabolism disorders and diabetes, or have no effect. Cardiovascular diseases are intricately linked to metabolic disorders and diseases. Increasing evidence also links ANGPTL8 to various cardiovascular pathologies, including atherosclerosis, hypertension, cardiomyopathy, cardiac hypertrophy, aortic aneurysm, and dissection. Given the strong interplay between metabolic dysregulation and CVDs, elucidating the role of ANGPTL8 in these processes is of significant interest. This review provides a balanced assessment of ANGPTL8's roles in key pathophysiological processes, highlighting its established functions in metabolism alongside its emerging involvement in CVDs. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states will lead to new opportunities for therapeutic intervention in cardiometabolic disorders.

血管生成素样蛋白8 （ANGPTL8）是血管生成素样蛋白（ANGPTL）家族的成员，是脂蛋白脂肪酶（LPL）的生理抑制剂，在营养提示下的脂蛋白和甘油三酯代谢中起关键作用。ANGPTL8参与广泛的系统和细胞过程，并与代谢和心血管疾病（CVD）密切相关。循环ANGPTL8主要由肝脏分泌，脂肪组织是次要来源。它的表达受多种转录因子和microrna的调控，并对禁食/再进食状态、激素信号和应激条件作出反应。在脂质代谢中，ANGPTL8与ANGPTL3和ANGPTL4形成复合物，在禁食和摄食条件下调节LPL活性。在葡萄糖代谢中，ANGPTL8起着复杂的作用。虽然一些研究表明它可以改善葡萄糖耐量和胰岛素抵抗，但其他研究表明它可能会加剧葡萄糖代谢紊乱和糖尿病，或者没有效果。心血管疾病与代谢紊乱和疾病有着错综复杂的联系。越来越多的证据表明ANGPTL8与多种心血管疾病有关，包括动脉粥样硬化、高血压、心肌病、心脏肥厚、主动脉瘤和夹层。鉴于代谢失调与心血管疾病之间的强烈相互作用，阐明ANGPTL8在这些过程中的作用具有重要意义。这篇综述对ANGPTL8在关键病理生理过程中的作用进行了平衡评估，强调了它在代谢中的既定功能以及它在心血管疾病中的新参与。了解ANGPTL8在不同组织和代谢状态下的不同功能，将为心脏代谢疾病的治疗干预带来新的机会。

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引用次数: 0

Molecular mechanisms linking adipose tissue browning to reduced cardiovascular risk 脂肪组织褐变与降低心血管风险相关的分子机制。

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-30 DOI: 10.1016/j.atherosclerosis.2025.120564

Ana Checa-Ros , Luis D'Marco

Recent research elucidates the complex molecular mechanisms linking adipose tissue (AT) browning to improved metabolic and cardiovascular health. Pro-inflammatory signaling pathways, such as NLRP3 inflammasome, TLR4, and NF-κB, typically inhibit browning, whereas their disruption promotes it. Conversely, anti-inflammatory pathways mediated by IL-4, IL-13, and M2 macrophages stimulate browning and are associated with enhanced glucose tolerance and insulin sensitivity. Mitochondrial regulation is central to this process, with UCP-1 and PGC1-α as key effectors. Interventions like ASK-1 knockout, nitrate, and melatonin have increased thermogenesis and improved metabolic outcomes in preclinical models. A limited number of studies directly measuring cardiovascular endpoints report improved endothelial function, reduced hypertension, reduced atherosclerotic plaque inflammation with attenuated atherosclerosis progression and decreased liver steatosis, suggesting significant cardioprotective potential.

However, most evidence remains preclinical, derived from in vitro and animal studies. Interpretations are complicated by context-dependent effects, such as variable responses in IL-6 signaling. The current literature indicates that white AT browning mitigates inflammation and improves cardiometabolic health through multiple pathways that include key atherosclerosis-related risk factors; direct clinical confirmation is needed. Future research should prioritize human validation of preclinical findings to determine sex-specific responses, identify target patient populations, particularly those at high risk of atherosclerotic cardiovascular disease, and develop AT-targeted therapies with fewer off-target cardiovascular and systemic adverse effects.

最近的研究阐明了脂肪组织（AT）褐变与改善代谢和心血管健康之间复杂的分子机制。促炎信号通路，如NLRP3炎性体、TLR4和NF-κB，通常抑制褐变，而它们的破坏则促进褐变。相反，由IL-4、IL-13和M2巨噬细胞介导的抗炎途径刺激褐变，并与葡萄糖耐量和胰岛素敏感性增强有关。线粒体调控是这一过程的核心，UCP-1和PGC1-α是关键的效应器。在临床前模型中，诸如敲除ASK-1、硝酸盐和褪黑素等干预措施可以增加产热和改善代谢结果。有限数量的直接测量心血管终点的研究报告改善了内皮功能，降低了高血压，减少了动脉粥样硬化斑块炎症，减缓了动脉粥样硬化的进展，减少了肝脏脂肪变性，表明具有显著的心脏保护潜力。然而，大多数证据仍然是临床前的，来自体外和动物研究。由于上下文相关的影响，例如IL-6信号的可变反应，解释变得复杂。目前的文献表明，白色AT褐化通过多种途径减轻炎症并改善心脏代谢健康，包括关键的动脉粥样硬化相关危险因素；需要直接临床证实。未来的研究应优先考虑临床前研究结果的人体验证，以确定性别特异性反应，确定目标患者群体，特别是那些动脉粥样硬化性心血管疾病高风险人群，并开发具有更少脱靶心血管和全身不良反应的at靶向治疗。

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引用次数: 0

Mechanisms of matrix stiffness affecting calcific aortic valve disease by regulating Piezo1 基质刚度通过调节Piezo1影响钙化主动脉瓣病变的机制

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-30 DOI: 10.1016/j.atherosclerosis.2025.120553

Naifang Cao , Si Cheng , Haochang Hu , Yi Qian , Juan Fang , Ningjing Qian , Jinyong Chen , Dilin Xu , Shuangshuang Yang , Wangxing Hu , Junhui Xue , Dao Zhou , Jin Lu , Hanyi Dai , Jian'an Wang , Xianbao Liu

Background and aims

Mechanical factors have been found to trigger and promote calcific aortic valve disease (CAVD). Extracellular matrix (ECM) stiffness, one of the main mechanical factors, plays an important role in valve calcification. However, the specific mechanisms underlying ECM stiffness during CAVD progression remain unclear and require further investigation.

Methods

Atomic force microscopy was used to analyze the Young's modulus of the human aortic valves. Western blotting was performed to detect the COL4A3, COL1A1, ALP, RUNX2, and Piezo1 protein levels in valvular interstitial cells (VICs) cultured on a soft matrix. After Piezo1 was silenced in vitro, we evaluated ECM remodeling and osteogenic differentiation of VICs. We established an aortic valve calcification model in LDLR^−/− mice by a high-fat/cholesterol diet and evaluated the effect of AAV2-sh-Piezo1 on CAVD. RNA-seq was used to explore the mechanism by which Piezo1 affects CAVD.

Results

The Young's modulus of human calcified aortic valves was higher than that of normal aortic valves. Increased matrix stiffness upregulated Piezo1 and promoted ECM remodeling and osteogenic differentiation of VICs. In vitro, silencing of Piezo1 decreased COL4A3 expression and prevented the osteogenic differentiation of VICs. In vivo, Piezo1 knockdown ameliorated mouse aortic valve ECM remodeling and calcification. We found that Piezo1 may influence the Wnt pathway.

Conclusion

A Piezo1-mediated feedback loop may interconnect ECM stiffening, VIC osteogenic differentiation, and pathological ECM remodeling during CAVD progression.

背景与目的：力学因素可诱发和促进钙化性主动脉瓣病变（CAVD）。细胞外基质（ECM）刚度是瓣膜钙化的主要力学因素之一。然而，CAVD进展过程中ECM刚度的具体机制尚不清楚，需要进一步研究。方法：采用原子力显微镜对人主动脉瓣的杨氏模量进行分析。Western blotting检测软基质培养的心瓣膜间质细胞（VICs）中COL4A3、COL1A1、ALP、RUNX2、Piezo1蛋白水平。在体外沉默Piezo1后，我们评估了VICs的ECM重塑和成骨分化。我们通过高脂/高胆固醇饮食建立了LDLR-/-小鼠主动脉瓣钙化模型，并评估了AAV2-sh-Piezo1对CAVD的影响。利用RNA-seq技术探索Piezo1影响CAVD的机制。结果：人主动脉瓣钙化后的杨氏模量明显高于正常主动脉瓣。增加基质刚度可上调Piezo1，促进血管内皮细胞重构和成骨分化。在体外，沉默Piezo1可降低COL4A3的表达，阻止vic的成骨分化。在体内，Piezo1敲除可改善小鼠主动脉瓣ECM重构和钙化。我们发现Piezo1可能影响Wnt通路。结论：在CAVD进展过程中，piezo1介导的反馈回路可能将ECM硬化、VIC成骨分化和病理性ECM重塑联系起来。

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引用次数: 0

Not all fibrates are made equal: Learning from biology and clinical trials 并不是所有的贝特都是一样的：从生物学和临床试验中学习

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-29 DOI: 10.1016/j.atherosclerosis.2025.120555

Alberto Zambon , Bart Staels , Michel Farnier , Michal Vrablik , Alberico L. Catapano

Atherogenic dyslipidemia is an important risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes, obesity, and metabolic disorders. Statin therapy, the standard treatment for dyslipidemia management, falls short of controlling the residual risk of adverse cardiovascular events, even with good control of low-density lipoprotein cholesterol (LDL-C). Apolipoprotein B (apoB), in addition to non-high-density lipoprotein cholesterol (non-HDL-C), is considered a better measure of residual risk and a more comprehensive treatment target in atherogenic dyslipidemia. Fibrates in combination with statins represent a proven therapeutic modality for atherogenic dyslipidemia. Fibrates lower triglyceride-rich lipoproteins (TRL), TRL remnants, and small dense LDL particles while increasing HDL-C levels. However, only fenofibrate appears to reduce apoB, whereas gemfibrozil and pemafibrate do not. This leads to a reduction in atherogenic lipids, as measured by a significant decrease in apoB/non-HDL-C levels, and a corresponding reduction in CVD risk. Real-world efficacy studies and CVD outcome trials have shown that fenofibrate may be an option in combination with statins compared to other fibrates and is well tolerated. Additionally, evidence from real-world studies of the fenofibrate-statin combination in patients over a period of up to 20 years has dispelled safety concerns regarding long-term use of fenofibrate.

动脉粥样硬化性血脂异常是2型糖尿病、肥胖和代谢紊乱患者心血管疾病（CVD）的重要危险因素。他汀类药物治疗是血脂异常管理的标准治疗方法，即使在低密度脂蛋白胆固醇（LDL-C）控制良好的情况下，也无法控制不良心血管事件的剩余风险。除非高密度脂蛋白胆固醇（non-HDL-C）外，载脂蛋白B （apoB）被认为是动脉粥样硬化性血脂异常的残留风险的更好测量和更全面的治疗靶点。贝特类药物联合他汀类药物是治疗动脉粥样硬化性血脂异常的有效方法。贝特酸盐降低富甘油三酯脂蛋白（TRL）， TRL残留物和小密度低密度脂蛋白颗粒，同时增加HDL-C水平。然而，只有非诺贝特似乎能降低载脂蛋白ob，而吉非纤维齐和培马巴特则没有。通过显着降低载脂蛋白/非hdl - c水平测量，这导致动脉粥样硬化性脂质降低，并相应降低心血管疾病风险。实际疗效研究和心血管疾病结局试验表明，与其他贝特类药物相比，非诺贝特可与他汀类药物联合使用，并且耐受性良好。此外，来自非诺贝特-他汀类药物联合治疗患者长达20年的真实世界研究的证据消除了长期使用非诺贝特的安全性担忧。

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引用次数: 0

Inflammation mediates the association between metabolic syndrome and vascular dementia: A large prospective cohort study 炎症介导代谢综合征和血管性痴呆之间的关联：一项大型前瞻性队列研究

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-27 DOI: 10.1016/j.atherosclerosis.2025.120554

Ting Jiang , Qianlin Zuo , Lingling Song , Xinxin Gao , Xihang Fu , Shifan Qin , Jing Wu

Background and aims

The association between Metabolic Syndrome (MetS) and Vascular Dementia (VaD) remains unclear, we investigated the impact of MetS on VaD in a large prospective study in the UK Biobank.

Methods

313,179 participants were enrolled in the UK Biobank between 2006 and 2010 to explore the associations of MetS and its components with VaD, using Cox proportional hazards models and restricted cubic spline regression. The potential mediating effect of inflammation was further investigated within these associations. A series of sensitivity analyses were conducted to assess the robustness of the results.

Results

During the 3,808,722.27 person-years of follow-up, 994 cases of VaD were identified. MetS at baseline significantly affected the risk of developing VaD (HR: 1.362, 95 % CI: 1.195, 1.551), with 13 % of this significant association mediated by INFLA-index, an inflammation factor. MetS components such as central obesity, hyperglycemia, and low high-density lipoprotein (HDL) levels each contributed to an elevated risk of VaD to varying degrees (HR: Central obesity: 1.261, Hyperglycemia: 2.373, low HDL: 1.194, all P < 0.001). MetS patients under 60 years had a greater risk of developing VaD compared to older MetS patients. Moreover, the results of sensitivity analyses aligned with formal findings, indicating that MetS increased the risk of developing VaD.

Conclusions

Individuals with MetS are at an increased risk of developing VaD in their later life, with population under 60 years having a relatively higher risk. These findings emphasize the importance of managing MetS, particularly before old age.

背景与目的代谢综合征（MetS）与血管性痴呆（VaD）之间的关系尚不清楚，我们在英国生物银行（UK Biobank）的一项大型前瞻性研究中调查了MetS对VaD的影响。方法在2006年至2010年期间，英国生物银行（UK Biobank）招募了s313179名参与者，采用Cox比例风险模型和限制性三次样条回归，探讨MetS及其组成部分与VaD的关系。在这些关联中，进一步研究了炎症的潜在介导作用。进行了一系列敏感性分析以评估结果的稳健性。结果在3,808,722.27人年的随访中，发现994例VaD。基线met显著影响VaD发生的风险（HR: 1.362, 95% CI: 1.195, 1.551），其中13%的显著关联是由炎症因子INFLA-index介导的。met成分，如中心性肥胖、高血糖和低高密度脂蛋白（HDL）水平，都不同程度地增加了VaD的风险（HR：中心性肥胖：1.261，高血糖：2.373，低高密度脂蛋白：1.194，P均为0.001）。与老年MetS患者相比，60岁以下的MetS患者发生VaD的风险更大。此外，敏感性分析的结果与正式研究结果一致，表明MetS增加了发生VaD的风险。结论：met患者在老年生活中发生VaD的风险增加，60岁以下人群的风险相对较高。这些发现强调了管理MetS的重要性，特别是在老年之前。

{"title":"Inflammation mediates the association between metabolic syndrome and vascular dementia: A large prospective cohort study","authors":"Ting Jiang , Qianlin Zuo , Lingling Song , Xinxin Gao , Xihang Fu , Shifan Qin , Jing Wu","doi":"10.1016/j.atherosclerosis.2025.120554","DOIUrl":"10.1016/j.atherosclerosis.2025.120554","url":null,"abstract":"<div><h3>Background and aims</h3><div>The association between Metabolic Syndrome (MetS) and Vascular Dementia (VaD) remains unclear<strong>,</strong> we investigated the impact of MetS on VaD in a large prospective study in the UK Biobank.</div></div><div><h3>Methods</h3><div>313,179 participants were enrolled in the UK Biobank between 2006 and 2010 to explore the associations of MetS and its components with VaD, using Cox proportional hazards models and restricted cubic spline regression. The potential mediating effect of inflammation was further investigated within these associations. A series of sensitivity analyses were conducted to assess the robustness of the results.</div></div><div><h3>Results</h3><div>During the 3,808,722.27 person-years of follow-up, 994 cases of VaD were identified. MetS at baseline significantly affected the risk of developing VaD (HR: 1.362, 95 % CI: 1.195, 1.551), with 13 % of this significant association mediated by INFLA-index, an inflammation factor. MetS components such as central obesity, hyperglycemia, and low high-density lipoprotein (HDL) levels each contributed to an elevated risk of VaD to varying degrees (HR: Central obesity: 1.261, Hyperglycemia: 2.373, low HDL: 1.194, all <em>P</em> < 0.001). MetS patients under 60 years had a greater risk of developing VaD compared to older MetS patients. Moreover, the results of sensitivity analyses aligned with formal findings, indicating that MetS increased the risk of developing VaD.</div></div><div><h3>Conclusions</h3><div>Individuals with MetS are at an increased risk of developing VaD in their later life, with population under 60 years having a relatively higher risk. These findings emphasize the importance of managing MetS, particularly before old age.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120554"},"PeriodicalIF":5.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145414283","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}

引用次数: 0

Aortic atherosclerotic plaques are more thrombogenic than carotid and femoral plaques: the role of fibrillar collagen 主动脉粥样硬化斑块比颈动脉和股动脉斑块更容易形成血栓：纤维胶原蛋白的作用

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-25 DOI: 10.1016/j.atherosclerosis.2025.120552

Miao Feng , Andréa Thevenot , Salomé Kuntz , Chu Liu , Célia Schellenberg , Lise Charle , Nathalie Brouard , Christine Schaeffer , Sarahi Jaramillo Ortiz , Judith M.E.M. Cosemans , Nabil Chakfé , Pierre H. Mangin

Background and aims

Atherothrombosis is the leading cause of mortality worldwide, responsible for more deaths than any other condition. Although the determinants of atherothrombosis are well established, the thrombogenic potential of atherosclerotic plaques in different arterial territories remains unexplored. This study aimed to perform an in-depth characterization of plaques from aortic, carotid and femoral arteries by comparing their intrinsic composition and thrombogenicity.

Methods

Human atherosclerotic plaques were collected from the abdominal aorta and the common carotid and femoral arteries of symptomatic patients undergoing endarterectomy, and plaque composition was characterized using histology, ELISA and quantitative label-free proteomic analysis. Plaque thrombogenicity was evaluated using platelet aggregometry, flow cytometry, microfluidic assays and thrombin generation tests.

Results

All plaque homogenate supernatants induced strong platelet P-selectin exposure, integrin αIIbβ3 activation and platelet aggregation, with aortic plaque extracts being more potent than carotid or femoral extracts. Under high shear flow, aortic plaques were the most thrombogenic and the only ones to promote occlusive thrombus formation. Moreover, aortic plaque supernatants enhanced phosphatidylserine exposure on platelets and subsequent thrombin generation, displaying a greater potential to promote the procoagulant function of platelets than carotid or femoral supernatants. Compositional analysis demonstrated that aortic plaques contained significantly larger amounts of fibrillar collagen (types I and III) than carotid or femoral plaques.

Conclusion

This study shows that aortic atherosclerotic plaques present a higher degree of thrombogenicity as compared to carotid or femoral plaques, an effect mainly attributable to their distinct collagen composition.

背景和目的静脉血栓形成是世界范围内死亡的主要原因，造成的死亡人数超过任何其他疾病。尽管动脉粥样硬化血栓形成的决定因素已经确定，但不同动脉区域的动脉粥样硬化斑块的血栓形成潜力仍未被探索。本研究旨在通过比较主动脉、颈动脉和股动脉的内在成分和血栓形成性，对斑块进行深入表征。方法采集有症状的行动脉内膜切除术患者的腹主动脉、颈总动脉和股动脉粥样硬化斑块，采用组织学、ELISA和定量无标记蛋白质组学分析对斑块组成进行表征。采用血小板聚集、流式细胞术、微流体试验和凝血酶生成试验评估斑块的血栓形成性。结果所有斑块匀浆上清液均诱导血小板p选择素暴露、整合素α ib β3活化和血小板聚集，其中主动脉斑块提取物的作用强于颈动脉和股动脉提取物。在高剪切血流下，主动脉斑块是最具血栓形成性的，也是唯一促进闭塞性血栓形成的斑块。此外，主动脉斑块上清液增强了血小板上的磷脂酰丝氨酸暴露和随后的凝血酶生成，显示出比颈动脉或股动脉上清液更大的促进血小板促凝功能的潜力。成分分析表明，主动脉斑块中纤维性胶原蛋白（I型和III型）的含量明显高于颈动脉或股动脉斑块。本研究表明，与颈动脉或股动脉斑块相比，主动脉粥样硬化斑块具有更高程度的血栓形成性，这主要归因于其独特的胶原成分。

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引用次数: 0

Metabolic dysfunction-associated steatotic liver disease, cardiometabolic risk factors, and cardiovascular disease 代谢功能障碍相关的脂肪变性肝病、心脏代谢危险因素和心血管疾病。

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-17 DOI: 10.1016/j.atherosclerosis.2025.120551

Lærke Kristine Kyhl , Børge Grønne Nordestgaard , Anne Tybjærg-Hansen , Sune Fallgaard Nielsen

Background and aims

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over one third of adults worldwide and represents a growing public health challenge. In addition to becoming the leading cause of end-stage liver disease and liver transplantation in the United States, MASLD is currently a major risk factor for metabolic and cardiovascular disease.

The diagnosis of MASLD is defined by the presence of a fatty liver in combination with one or more of five cardiometabolic risk factors, excluding excessive alcohol consumption. While the individual risk factors are all observationally associated with a fatty liver, the connection between these cardiometabolic risk factors and fatty liver has not been fully explained.

Methods

In this review we describe how fatty liver is associated with each of the cardiometabolic criteria of the MASLD diagnosis. We review the pathophysiological mechanisms between the cardiometabolic risk factors contributing to the MASLD diagnosis and development of fatty liver.

We describe how MASLD associates with cardiovascular disease and suggest that fatty liver is associated with cardiovascular disease through very low-density lipoproteins.

Finally, we describe current guidelines and ongoing pharmaceutical approaches in the treatment of MASLD with the focus on cardiovascular risk factors.

Results

This review provides a comprehensive overview of MASLD. Its association with common risk factors, including the mechanisms leading to cardiovascular disease, and finally an overview of the advised clinical approach according to current guidelines.

Conclusion

This review encompasses clinical aspects of MASLD from risk factors to outcome, including recommended clinical handling of these patients.

背景和目的：代谢功能障碍相关的脂肪变性肝病（MASLD）影响着全球超过三分之一的成年人，是一个日益严峻的公共卫生挑战。在美国，除了成为终末期肝病和肝移植的主要原因外，MASLD目前也是代谢和心血管疾病的主要危险因素。MASLD的诊断定义为脂肪肝合并五种心脏代谢危险因素中的一种或多种，过度饮酒除外。虽然观察到所有个体危险因素都与脂肪肝有关，但这些心脏代谢危险因素与脂肪肝之间的联系尚未得到充分解释。方法：在这篇综述中，我们描述了脂肪肝是如何与MASLD诊断的每个心脏代谢标准相关联的。我们回顾了心脏代谢危险因素对MASLD诊断和脂肪肝发展的病理生理机制。我们描述了MASLD与心血管疾病的关系，并提出脂肪肝通过极低密度脂蛋白与心血管疾病相关。最后，我们描述了目前的指南和正在进行的治疗MASLD的药物方法，重点是心血管危险因素。结果：本文综述了MASLD的全面概况。它与常见危险因素的关联，包括导致心血管疾病的机制，最后概述了根据现行指南建议的临床方法。结论：本综述涵盖了MASLD的临床方面，从危险因素到结果，包括这些患者的推荐临床处理。

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引用次数: 0

Metabolomics of aortic valve stenosis: Are aortic valve stenosis and sclerosis different diseases? 主动脉瓣狭窄的代谢组学：主动脉瓣狭窄和硬化是不同的疾病吗？

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-17 DOI: 10.1016/j.atherosclerosis.2025.120549

Elisa Koljonen , Olli Kärkkäinen , Retu Haikonen , Anu Turpeinen , Juha Hartikainen , Jaana Rysä

Background and aims

Calcific aortic valve disease (CAVD) shares the same risk factors as atherosclerotic vascular diseases (ASVD). However, in contrast to ASVD, treating the risk factors has not been shown to be effective in preventing CAVD and its progression to aortic stenosis (AS). Thus, the ultimate pathophysiology of CAVD remains unknown. This study aimed to evaluate metabolic signatures associated with CAVD.

Methods

We carried out metabolomic analyses on a total of 255 subjects: 82 patients with AS, 72 patients with aortic valve sclerosis (ASc) and 101 healthy controls. Blood lipoproteins and metabolites, including lipids, amino acids, and inflammatory markers, were measured using nuclear magnetic resonance (NMR) metabolomics.

Results

There were no significant differences in total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides. However, levels of small HDL particles were significantly lower in the AS group compared to the ASc and control groups, whereas no differences were found between the ASc and control groups. In addition, the levels of albumin and several amino acids were lower in the AS group when compared to the ASc group. These results suggest that patients with AS and ASc have different metabolic profiles.

Conclusions

Our study is the first to show that the levels of small HDL rather than plasma HDL concentration are significantly lower in AS patients. This suggests that small HDL may be one missing link in the pathophysiologic process between dyslipidemia and CAVD and generate innovative approaches for preventing CAVD. The results also prompt the question whether AS and ASc are distinct diseases.

背景和目的：主动脉瓣病变（CAVD）与动脉粥样硬化性血管疾病（ASVD）具有相同的危险因素。然而，与ASVD相比，治疗这些危险因素在预防CAVD及其进展为主动脉狭窄（AS）方面并没有被证明是有效的。因此，CAVD的最终病理生理机制尚不清楚。本研究旨在评估与CAVD相关的代谢特征。方法对255例受试者进行代谢组学分析：82例AS患者、72例主动脉瓣硬化（ASc）患者和101例健康对照。使用核磁共振（NMR）代谢组学测量血脂和代谢物，包括脂质、氨基酸和炎症标志物。结果两组总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和甘油三酯无显著差异。然而，与ASc组和对照组相比，AS组的小HDL颗粒水平明显降低，而ASc组和对照组之间没有差异。此外，与ASc组相比，AS组的白蛋白和几种氨基酸水平较低。这些结果表明，AS和ASc患者具有不同的代谢谱。结论我们的研究首次表明，AS患者的小HDL水平比血浆HDL浓度明显降低。这表明小HDL可能是血脂异常和CAVD之间病理生理过程中缺失的一个环节，并为预防CAVD提供了创新的方法。结果也提示了AS和ASc是否是不同的疾病的问题。

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引用次数: 0

Alamandine suppresses vascular calcification through inhibition of ferroptosis Alamandine通过抑制铁下垂抑制血管钙化

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-15 DOI: 10.1016/j.atherosclerosis.2025.120548

Zhanpeng Wen , Jingbin Guo , Keyang Li , Xingchen Zhou , Zirong Lan , An Chen , Li Feng , Jianyun Yan

Background and aims

Vascular calcification is commonly found in pathological processes of chronic kidney disease (CKD), diabetes and atherosclerosis, which increases the risk of adverse cardiac events. Recent studies have shown that Alamandine (ALA)/mas associated G protein coupled receptor D (MrgD), an axis of noncanonical renin-angiotensin system (RAS), exerts beneficial effects on cardiovascular systems. However, it is still unclear whether it protects against vascular calcification.

Methods

High phosphate and calcium were used to induce calcification of vascular smooth muscle cells (VSMCs) and mouse model of aortic calcification was induced by vitamin D₃. Alizarin red staining and calcium content assay were used to assess calcification. Western blot analysis was used to examine the protein expression levels.

Results

ALA serum levels were significantly lower in patients with thoracic calcification compared to healthy controls. High calcium and phosphate induced calcification of VSMCs. ALA treatment inhibited VSMC calcification and blockage of receptor MrgD abrogated the inhibitory effect of ALA on VSMC calcification. Consistently, ALA/MrgD significantly attenuated calcification of rat and human arterial rings ex vivo, and inhibited mouse aortic calcification in vivo. Mechanistically, VSMC calcification was accompanied by the occurrence of ferroptosis as indicated by increased cell death, increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased expression of ferroptosis inhibition signaling molecules SLC7A11 and glutathione peroxidase 4 (GPX4). Furthermore, inhibition of GPX4 by RAS-selective lethal 3 (RSL3) exacerbated calcification of VSMCs under osteogenic conditions. Of note, ALA antagonized RSL3-induced VSMC calcification, suggesting ALA attenuated VSMCs calcification through inhibiting ferroptosis.

Conclusions

our study for the first time revealed that ALA/MrgD suppressed VSMC calcification under osteogenic condition and aortic calcification in VitD₃-overloaded mice. Moreover, we unveiled that ALA/MrgD inhibited vascular calcification via modulation of ferroptosis. These findings present a novel targeting strategy for the treatment of vascular calcification.

背景和目的血管钙化常见于慢性肾脏疾病（CKD）、糖尿病和动脉粥样硬化的病理过程，它增加了心脏不良事件的风险。近年来的研究表明，Alamandine (ALA)/mas相关G蛋白偶联受体D （MrgD）是非规范肾素-血管紧张素系统（RAS）的一个轴，对心血管系统有有益的作用。然而，尚不清楚它是否能防止血管钙化。方法采用高磷酸盐和高钙诱导血管平滑肌细胞钙化，维生素D3诱导小鼠主动脉钙化模型。采用茜素红染色和钙含量测定法评价钙化程度。Western blot检测蛋白表达水平。结果胸椎钙化患者血清sala水平明显低于正常对照组。高钙高磷酸盐诱导VSMCs钙化。ALA处理可抑制VSMC钙化，阻断受体MrgD可消除ALA对VSMC钙化的抑制作用。与此一致，ALA/MrgD在体外显著减弱大鼠和人动脉环的钙化，在体内抑制小鼠主动脉的钙化。在机制上，VSMC钙化伴随着铁下垂的发生，表现为细胞死亡增加，活性氧（ROS）和丙二醛（MDA）水平升高，铁下垂抑制信号分子SLC7A11和谷胱甘肽过氧化物酶4 （GPX4）表达降低。此外，ras -选择性致死3 （RSL3）对GPX4的抑制加剧了成骨条件下VSMCs的钙化。值得注意的是，ALA拮抗rsl3诱导的VSMC钙化，提示ALA通过抑制铁下垂来减弱VSMC钙化。结论本研究首次发现ALA/MrgD抑制成骨状态下VSMC钙化和vitd3超载小鼠主动脉钙化。此外，我们发现ALA/MrgD通过调节铁下垂抑制血管钙化。这些发现为治疗血管钙化提供了一种新的靶向策略。

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引用次数: 0

Effects of vitamin K2 and D3 supplementation on epicardial adipose tissue and systemic inflammation: A substudy of the AVADEC trial 维生素K2和D3补充对心外膜脂肪组织和全身性炎症的影响：AVADEC试验的一项亚研究

IF 5.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2025-10-12 DOI: 10.1016/j.atherosclerosis.2025.120540

Selma Hasific , Emil Johannes Ravn , Lars Melholt Rasmussen , Anna Mejldal , Damini Dey , Niels Erik Frandsen , Jes S. Lindholt , Søren Auscher , Jess Lambrechtsen , Susanne Hosbond , Dilek Alan , Grazina Urbonaviciene , Søren Becker , Kristian Altern Øvrehus , Axel Diederichsen

Background and aims

Vitamins K2 and D3 may improve cardiovascular health by modulating inflammation and vascular calcification. Inflammation contributes to atherosclerosis and can be assessed through imaging and systemic biomarkers. This study investigated whether vitamin K2 and D3 supplementation reduces inflammation in epicardial adipose tissue (EAT), including pericoronary adipose tissue (PCAT), and systemic inflammation in elderly men at cardiovascular risk.

Methods

In the Aortic Valve DECalcification (AVADEC) trial, 388 men aged 65–74 received daily vitamin K2 (720 μg) and D3 (25 μg) or placebo for 24 months. EAT inflammation was assessed using non-contrast CT [EAT volume and attenuation] and contrast-enhanced CT [PCAT attenuation]. Systemic inflammation was evaluated via hs-CRP, IL-6, TNF-α, Fetuin-A, and osteopontin (OPN). Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), the inactive form of MGP, served as a proxy for vitamin K2 status.

Results

After 24 months, EAT volume increased in the placebo group (Δ5.66 cm³,95% CI 1.35; 9.98) and non-significantly in the vitamin group (Δ3.44 cm³, 95% CI -0.44; 7.33), with an intergroup difference of −2.22 cm³ (95% CI -8.01; 3.57). EAT attenuation declined similarly (intergroup difference: 0.32 HU, 95% CI -0.23; 0.87). PCAT attenuation remained unchanged. No significant changes were seen in systemic markers, though OPN increased modestly in the vitamin group (Δ25.72 pg/mL, 95% CI 2.40; 49.05). dp-ucMGP decreased significantly with supplementation (intergroup difference: 255.31 pmol/L, 95% CI -289.56; −221.05).

Conclusions

Despite reduction in dp-ucMGP, high-dose vitamin K2 and D3 supplementation did not affect EAT, PCAT or systemic inflammation over 24 months. Alternative strategies may be needed to target inflammatory pathways in cardiovascular disease prevention.

背景和目的：维生素K2和D3可能通过调节炎症和血管钙化来改善心血管健康。炎症有助于动脉粥样硬化，可以通过成像和系统生物标志物进行评估。本研究调查了维生素K2和D3补充剂是否能减少心血管风险老年男性心外膜脂肪组织（EAT），包括冠状动脉周围脂肪组织（PCAT）的炎症和全身炎症。方法：在主动脉瓣脱钙（AVADEC）试验中，388名65-74岁的男性每天服用维生素K2 （720 μg）和D3 （25 μg）或安慰剂，持续24个月。通过非对比CT [EAT体积和衰减]和对比增强CT [PCAT衰减]评估EAT炎症。通过hs-CRP、IL-6、TNF-α、Fetuin-A和骨桥蛋白（OPN）评估全身性炎症。去磷酸化非羧化基质Gla蛋白（dp-ucMGP）是MGP的非活性形式，可作为维生素K2状态的代理。结果：24个月后，安慰剂组的EAT体积增加（Δ5.66 cm3,95% CI 1.35; 9.98），维生素组的EAT体积增加（Δ3.44 cm3,95% CI -0.44; 7.33），组间差异为-2.22 cm3 （95% CI -8.01; 3.57）。EAT衰减同样下降（组间差异：0.32 HU, 95% CI -0.23; 0.87）。PCAT衰减保持不变。虽然维生素组的OPN略有增加（Δ25.72 pg/mL, 95% CI 2.40; 49.05），但系统标志物未见显著变化。添加后dp-ucMGP显著降低（组间差异：255.31 pmol/L, 95% CI: -289.56; -221.05）。结论：尽管dp-ucMGP降低，高剂量维生素K2和D3补充在24个月内对EAT、PCAT或全身性炎症没有影响。可能需要其他策略来针对心血管疾病预防中的炎症途径。

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引用次数: 0