Atherosclerosis最新文献_第4页

Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques 剪切应力与动脉粥样硬化斑块中具有动脉粥样硬化保护作用的 KLK10 脱钩

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-10-04 DOI: 10.1016/j.atherosclerosis.2024.118622

Ziqi Zhou , Suze-Anne Korteland , Blanca Tardajos-Ayllon , Junxi Wu , Emily Chambers , Julia Weninck , Michael Simons , Mark Dunning , Torsten Schenkel , Mannekomba Diagbouga , Jolanda Wentzel , Maria Fragiadaki , Paul C. Evans

Background and aims

Physiological shear stress promotes vascular homeostasis by inducing protective molecules in endothelial cells (EC). However, physiological shear stress has been linked to atherosclerosis progression in some individuals with heightened cardiovascular risk. To address this apparent paradox, we hypothesized that diseased arteries may exhibit reduced responsiveness to the protective effects of physiological shear stress. Consequently, we compared the transcriptome of EC exposed to physiological shear stress in healthy arteries versus atherosclerotic conditions.

Methods

Employing 3D light sheet imaging and computational fluid dynamics, we identified NOS3 as a marker of physiological shear stress in both healthy and atherosclerotic murine arteries. Single-cell RNA sequencing was performed on EC from healthy (C57BL/6) mice, mildly diseased (Apoe^−/− normal diet) mice, and highly diseased (Apoe^−/− high fat diet) mice. The transcriptomes of Nos3^high cells (exposed to physiological shear stress) were compared among the groups.

Results

Nos3^high EC were associated with several markers of physiological shear stress in healthy arteries. Clustering of Nos3^high EC revealed 8 different EC subsets that varied in proportion between healthy and diseased arteries. Cluster-specific nested functional enrichment of gene ontology terms revealed that Nos3^high EC in diseased arteries were enriched for inflammatory and apoptotic gene expression. These alterations were accompanied by changes in several mechanoreceptors, including the atheroprotective factor KLK10, which was enriched in Nos3^high EC in healthy arteries but markedly reduced in severely diseased arteries.

Conclusions

Physiological shear stress is uncoupled from atheroprotective KLK10 within atherosclerotic plaques. This sheds light on the complex interplay between shear stress, endothelial function, and the progression of atherosclerosis in individuals at risk of cardiovascular complications.

背景和目的生理性剪切应力通过诱导内皮细胞（EC）中的保护性分子促进血管稳态。然而，在一些心血管风险较高的人群中，生理性剪切应力却与动脉粥样硬化的进展有关。为了解决这一明显的悖论，我们假设，病变动脉可能对生理性剪切应力的保护作用反应迟钝。因此，我们比较了健康动脉和动脉粥样硬化条件下暴露于生理性剪切应力的EC的转录组。方法利用三维光片成像和计算流体动力学，我们确定了NOS3是健康和动脉粥样硬化鼠动脉中生理性剪切应力的标志物。我们对健康（C57BL/6）小鼠、轻度患病（载脂蛋白-/-正常饮食）小鼠和高度患病（载脂蛋白-/-高脂饮食）小鼠的动脉血管进行了单细胞RNA测序。结果Nos3高的EC与健康动脉中生理剪切应力的几个标记相关。对Nos3高的心肌细胞进行聚类发现了8个不同的心肌细胞亚群，它们在健康动脉和患病动脉中的比例各不相同。基因本体论术语的簇特异性嵌套功能富集显示，患病动脉中的Nos3高EC富含炎症和凋亡基因表达。这些变化伴随着几种机械感受器的变化，其中包括动脉粥样硬化保护因子 KLK10，它在健康动脉的 Nos3high EC 中富集，但在严重病变动脉中则明显减少。这揭示了剪切应力、内皮功能和心血管并发症高危人群动脉粥样硬化进展之间复杂的相互作用。

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引用次数: 0

Age drives the impact of vascular disease on ischemic stroke in patients with atrial fibrillation: Role of hypertension and prediabetes. 年龄导致血管疾病对心房颤动患者缺血性中风的影响：高血压和糖尿病前期的作用

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-10-03 DOI: 10.1016/j.atherosclerosis.2024.118619

Pasquale Mone, Florindo D'Onofrio, Tommaso Dazzetti, Thais Luma De Oliveira Roza, Germano Guerra, Gaetano Santulli

引用次数: 0

Targeted plasma multi-omics propose glutathione, glycine and serine as biomarkers for abdominal aortic aneurysm growth on serial CT scanning 靶向血浆多组学提出谷胱甘肽、甘氨酸和丝氨酸是连续 CT 扫描显示腹主动脉瘤生长的生物标记物。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-10-02 DOI: 10.1016/j.atherosclerosis.2024.118620

Alexander Vanmaele , Elke Bouwens , Sanne E. Hoeks , Alida Kindt , Lieke Lamont , Bram Fioole , Ricardo PJ. Budde , Sander ten Raa , Burhan Hussain , José Oliveira-Pinto , Arne S. Ijpma , Felix van Lier , K. Martijn Akkerhuis , Danielle F. Majoor-Krakauer , Jorg L. de Bruin , Thomas Hankemeier , Yolanda de Rijke , Hence JM. Verhagen , Eric Boersma , Isabella Kardys

Background and aims

Abdominal aortic aneurysm (AAA) patients undergo uniform imaging surveillance until reaching the surgical threshold. In spite of the ongoing exploration of AAA pathophysiology, biomarkers for personalized surveillance are lacking. This study aims to identify potential circulating biomarkers for AAA growth on serial CT scans.

Methods

Patients with an AAA (maximal diameter ≥40 mm) were included in this multicentre, prospective cohort study. Participants underwent baseline blood sampling and yearly CT-imaging to determine AAA diameter and volume. Proteins and metabolites were measured using proximity extension assay (Olink Cardiovascular III) or separate ELISA panels, and mass-spectrometry (LC-TQMS), respectively. Linear mixed-effects, orthogonal partial least squares, and Cox regression were used to explore biomarker associations with AAA volume growth rate and the risk of surpassing the surgical threshold, as formulated by current guidelines.

Results

271 biomarkers (95 proteins, 176 metabolites) were measured in 109 (90.8 % male) patients with mean age 72. Median baseline maximal AAA diameter was 47.8 mm, volume 109 mL. Mean annual AAA volume growth rate was 11.5 %, 95 % confidence interval (CI) (10.4, 12.7). Median follow-up time was 23.2 months, 49 patients reached the surgical threshold. Patients with one standard deviation (SD) higher glutathione and glycine levels at baseline had an AAA volume growth rate that respectively was 1.97 %, 95%CI (0.97, 2.97) and 1.74 %, 95%CI (0.78, 2.71) larger, relative to the actual aneurysm size. Serine was associated with the risk of reaching the surgical threshold, independent of age and baseline AAA size (cause-specific hazard ratio per SD difference 1.78, 95%CI (1.30, 2.44)).

Conclusions

Among multiple intertwined biomarkers related to AAA pathophysiology and progression, glutathione, glycine and serine were most promising.

背景和目的：腹主动脉瘤（AAA）患者在达到手术临界值之前都要接受统一的成像监测。尽管人们一直在探索 AAA 的病理生理学，但仍缺乏用于个性化监测的生物标志物。本研究旨在通过连续 CT 扫描确定 AAA 生长的潜在循环生物标志物：这项多中心前瞻性队列研究纳入了 AAA 患者（最大直径≥40 毫米）。参与者接受基线血液采样和每年一次的 CT 扫描，以确定 AAA 的直径和体积。蛋白质和代谢物分别采用近距离延伸测定法（Olink Cardiovascular III）或单独的酶联免疫吸附测定法（ELISA）和质谱分析法（LC-TQMS）进行测定。采用线性混合效应、正交偏最小二乘法和 Cox 回归来探讨生物标记物与 AAA 体积增长率和超过现行指南规定的手术阈值风险之间的关系。结果：在平均年龄为 72 岁的 109 名患者（90.8% 为男性）中测量了 271 种生物标记物（95 种蛋白质、176 种代谢物）。AAA 最大基线直径中位数为 47.8 毫米，体积为 109 毫升。AAA 体积年平均增长率为 11.5%，95% 置信区间 (CI) (10.4, 12.7)。中位随访时间为 23.2 个月，49 名患者达到了手术阈值。基线时谷胱甘肽和甘氨酸水平高出一个标准差（SD）的患者，其 AAA 体积增长率相对于实际动脉瘤大小分别大 1.97%，95% 置信区间（0.97，2.97）和 1.74%，95% 置信区间（0.78，2.71）。丝氨酸与达到手术阈值的风险相关，与年龄和基线 AAA 大小无关（每 SD 差异的特异性危险比为 1.78，95%CI (1.30，2.44)）：结论：在与 AAA 病理生理学和进展相关的多个相互交织的生物标志物中，谷胱甘肽、甘氨酸和丝氨酸最有希望。

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引用次数: 0

Targeting the adaptive immune continuum in atherosclerosis and post-MI injury 针对动脉粥样硬化和心肌梗死后损伤中的适应性免疫连续体。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-28 DOI: 10.1016/j.atherosclerosis.2024.118616

Viktoria Juhasz , Fiona T. Charlier , Tian X. Zhao , Dimitrios Tsiantoulas

Atherosclerotic disease is a cholesterol-rich lipoprotein particle-driven disease resulting in the formation of atherosclerotic plaques in large and medium size arteries. Rupture or erosion of atherosclerotic plaques can trigger the formation of a thrombus causing the obstruction of the blood flow in the coronary artery and thereby leading to myocardial infarction (MI). Inflammation is a crucial pillar of the mechanisms leading to atherosclerosis and governing the cardiac repair post-MI. Dissecting the complex and sophisticated networks of the immune responses underlying the formation of atherosclerotic plaques and affecting the healing of the heart after MI will allow the designing of highly precise immunomodulatory therapies for these settings. Notably, MI also accelerates atherosclerosis via modulating the response of the immune system. Therefore, for the identification of effective and safe therapeutic targets, it is critical to consider the inflammatory continuum that interconnects the two pathologies and identify immunomodulatory strategies that confer a protective effect in both settings or at least, affect each pathology independently. Adaptive immunity, which consists of B and T lymphocytes, is a major regulator of atherosclerosis and post-MI cardiac repair. Here, we review and discuss the effect of potential adaptive immunity-targeting therapies, such as cell-depleting therapies, in atherosclerosis and post-MI cardiac injury.

动脉粥样硬化症是一种富含胆固醇的脂蛋白颗粒驱动的疾病，会在大中型动脉中形成动脉粥样硬化斑块。动脉粥样硬化斑块的破裂或侵蚀可引发血栓形成，导致冠状动脉血流受阻，从而引发心肌梗死（MI）。炎症是导致动脉粥样硬化和心肌梗塞后心脏修复机制的重要支柱。剖析动脉粥样硬化斑块形成和影响心肌梗塞后心脏愈合的复杂而精密的免疫反应网络，将有助于针对这些情况设计高度精确的免疫调节疗法。值得注意的是，心肌梗死也会通过调节免疫系统的反应加速动脉粥样硬化。因此，要确定有效、安全的治疗目标，就必须考虑将这两种病症相互关联的炎症连续体，并确定在两种情况下都能产生保护作用或至少能独立影响每种病症的免疫调节策略。由 B 淋巴细胞和 T 淋巴细胞组成的适应性免疫是动脉粥样硬化和心肌梗死后心脏修复的主要调节因素。在此，我们回顾并讨论了潜在的适应性免疫靶向疗法（如细胞损耗疗法）对动脉粥样硬化和心肌梗死后心脏损伤的影响。

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引用次数: 0

Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials. 他汀类药物、依折麦布和他汀类药物-依折麦布疗法对杂合性家族性高胆固醇血症儿童和青少年的疗效和安全性：随机对照试验的系统综述、配对分析和网络荟萃分析。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-28 DOI: 10.1016/j.atherosclerosis.2024.118598

Alexis Llewellyn, Mark Simmonds, David Marshall, Melissa Harden, Beth Woods, Steve E Humphries, Uma Ramaswami, Lorraine Priestley-Barnham, Mark Fisher, Laila J Tata, Nadeem Qureshi

Background and aims: Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons.

Methods: We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage.

Results: Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I² = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo.

Conclusions: Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.

背景和目的：他汀类药物、依折麦布和他汀类药物-依折麦布联合疗法是杂合子家族性高胆固醇血症（HeFH）患儿的推荐降脂疗法（LLTs）。然而，人们对它们的相对有效性还不甚了解。我们旨在通过直接和间接比较来比较这些疗法的安全性和有效性：我们对他汀类药物、依折麦布和他汀类药物-依折麦布联合疗法的随机对照试验（RCT）进行了系统回顾、配对分析和网络荟萃分析（NMAs）：共纳入 13 项随机对照试验（n = 1649，中位年龄 13 岁，随访 6 周-2 年）。所有低密度脂蛋白胆固醇疗法都能降低低密度脂蛋白胆固醇（LDL-C）和总胆固醇；他汀类药物能增加高密度脂蛋白胆固醇并降低甘油三酯。与安慰剂相比，他汀类药物可使低密度脂蛋白胆固醇降低 33.61%（95 % CI 27.58 至 39.63，I2 = 83 %）。在他汀类药物基础上添加依折麦布可使低密度脂蛋白胆固醇再降低 15.85 %（95 % CI 11.91 至 19.79）。NMA显示，与低剂量他汀类药物相比，中等剂量他汀类药物可额外降低4.77%的LDL-C（95 % CrI -11.22至1.05）；高剂量他汀类药物和中等剂量他汀类药物+依折麦布可能具有类似的效果，并且可能优于依折麦布、中等剂量和低剂量他汀类药物。没有证据表明LLTs与安慰剂在成熟度、安全性或耐受性方面存在差异：他汀类药物、依折麦布和他汀类药物-依折麦布都是治疗 HeFH 儿童的有效药物，但低密度脂蛋白胆固醇的降低幅度各不相同，可能取决于治疗剂量和组合。未发现安全性或耐受性问题。长期安全性和有效性尚不确定。

{"title":"Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials.","authors":"Alexis Llewellyn, Mark Simmonds, David Marshall, Melissa Harden, Beth Woods, Steve E Humphries, Uma Ramaswami, Lorraine Priestley-Barnham, Mark Fisher, Laila J Tata, Nadeem Qureshi","doi":"10.1016/j.atherosclerosis.2024.118598","DOIUrl":"https://doi.org/10.1016/j.atherosclerosis.2024.118598","url":null,"abstract":"<p><strong>Background and aims: </strong>Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons.</p><p><strong>Methods: </strong>We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage.</p><p><strong>Results: </strong>Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I<sup>2</sup> = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo.</p><p><strong>Conclusions: </strong>Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.</p>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":" ","pages":"118598"},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340190","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

Association of HDL cholesterol with all-cause and cardiovascular mortality in primary hypercholesterolemia. 高密度脂蛋白胆固醇与原发性高胆固醇血症患者的全因死亡率和心血管死亡率的关系。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-26 DOI: 10.1016/j.atherosclerosis.2024.118617

Ana M Bea, Anton González-Guerrero, Ana Cenarro, Itziar Lamiquiz-Moneo, Elisenda Climent, Estibaliz Jarauta, Irene Gracia-Rubio, David Benaiges, Martín Laclaustra, Teresa Tejedor, Juan Pedro-Botet, Fernando Civeira, Victoria Marco-Benedí

Background and aims: Recent reports have shown that subjects with high high-density lipoprotein cholesterol (HDLc) levels are paradoxically at increased risk for all-cause and cardiovascular mortality. The aim was to study the association of HDLc concentration with mortality in subjects with high cholesterol.

Methods: We analyzed total mortality, cardiovascular mortality, and non-cardiovascular mortality in a cohort of 2992 subjects with primary hypercholesterolemia, who were followed for 10.2 years (range 1-25 years), with a total of 30,602 subject-years of follow-up.

Results: During follow-up, 168 subjects died, with 52 (13.7 %), 105 (4.80 %), and 11 (2.60 %) in the low, normal, and high HDLc groups, respectively (p < 0.001). The risk of death was 2.89 times higher (95 % confidence interval (CI), 1.50-5.57, p < 0.001) in subjects in the low HDLc group compared to those in the high HDLc group and 1.48 times higher (95 % CI 0.80-2.76, p = 0.214) in the normal HDLc group compared to the high HDLc group. However, HDLc concentration and HDLc groups based on HDLc concentration were not independently associated with mortality in Cox regression analysis. Cardiovascular and non-cardiovascular mortalities showed similar results.

Conclusions: All types of mortality were lower in subjects with primary hypercholesterolemia and with high HDLc in univariate analysis. Elevated HDLc was not associated with total, cardiovascular, and non-cardiovascular mortality when adjusted for major cardiovascular risk factors.

背景和目的：最近的报告显示，高密度脂蛋白胆固醇（HDLc）水平高的受试者全因死亡率和心血管死亡率风险反而增加。我们的目的是研究高密度脂蛋白胆固醇浓度与高胆固醇人群死亡率的关系：我们分析了 2992 名原发性高胆固醇血症患者的总死亡率、心血管死亡率和非心血管死亡率：在随访期间，168 名受试者死亡，其中低 HDLc 组、正常 HDLc 组和高 HDLc 组分别有 52 人（13.7%）、105 人（4.80%）和 11 人（2.60%）死亡（P 结论：低 HDLc 组、正常 HDLc 组和高 HDLc 组的各种死亡率均较低：在单变量分析中，原发性高胆固醇血症和高 HDLc 患者的各类死亡率均较低。调整主要心血管风险因素后，高密度脂蛋白胆固醇升高与总死亡率、心血管死亡率和非心血管死亡率无关。

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引用次数: 0

Relationship of proteins and subclinical cardiovascular traits in the population-based LIFE-Adult study 基于人群的 LIFE-成人研究中蛋白质与亚临床心血管特征的关系

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-21 DOI: 10.1016/j.atherosclerosis.2024.118613

Tarcyane Garcia , Agnese Petrera , Stefanie M. Hauck , Ronny Baber , Kerstin Wirkner , Holger Kirsten , Janne Pott , Anke Tönjes , Sylvia Henger , Markus Loeffler , Annette Peters , Markus Scholz

Background and aims

Understanding molecular processes of the early phase of atherosclerotic cardiovascular disease conditions is of utmost importance for early prediction and intervention measures.

Methods

We measured 92 cardiovascular-disease-related proteins (Olink, Cardiovascular III) in 2024 elderly participants of the population-based LIFE-Adult study. We analysed the impact of 27 covariables on these proteins including blood counts, cardiovascular risk factors and life-style-related parameters. We also analysed protein associations with 13 subclinical cardiovascular traits comprising carotid intima media thickness, plaque burden, three modes of Vicorder-based pulse-wave velocities, ankle-brachial index and ECLIA-based N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

Results

Estimated glomerular filtration rate, triglycerides and sex where the most relevant covariables explaining more than 1 % variance of 49, 22 and 20 proteins, respectively. A total of 43 proteins were significantly associated with at least one of the analysed subclinical cardiovascular traits. NT-pro-BNP, brachial-ankle pulse-wave velocity (baPWV) and parameters of carotid plaque burden accounted for the largest number of associations. Association overlaps were relatively sparse. Only growth/differentiation factor 15, low density lipoprotein receptor and interleukin-1 receptor type 2 are associated with these three different cardiovascular traits. We confirmed several literature findings and found yet unreported associations for carotid plaque presence (von-Willebrand factor, galectin 4), carotid intima-media thickness (carboxypeptidase A1 andB1), baPWV (cathepsin D) and NT-proBNP (cathepsin Z, low density lipoprotein receptor, neurogenic locus homolog protein 3, trem-like transcript 2). Sex-interaction effects were observed, e.g. for spondin-1 and growth/differentiation factor 15 likely regulated by androgen response elements.

Conclusions

We extend the catalogue of proteome biomarkers possibly involved in early stages of cardiovascular disease pathologies providing targets for early risk prediction or intervention strategies.

背景和目的了解动脉粥样硬化性心血管疾病早期阶段的分子过程对于早期预测和干预措施至关重要。方法我们测量了基于人群的 LIFE-Adult 研究中 2024 名老年参与者的 92 种心血管疾病相关蛋白（Olink，心血管 III）。我们分析了 27 个协变量对这些蛋白质的影响，包括血细胞计数、心血管风险因素和生活方式相关参数。我们还分析了蛋白质与 13 种亚临床心血管特征的关系，包括颈动脉内膜厚度、斑块负荷、基于 Vicorder 的三种模式脉搏波速度、踝肱指数和基于 ECLIA 的脑钠肽 N 端前体（NT-proBNP）。共有 43 种蛋白质与所分析的亚临床心血管特征中的至少一种显著相关。NT-pro-BNP、肱踝脉搏波速度（baPWV）和颈动脉斑块负荷参数的相关性最大。关联重叠相对较少。只有生长/分化因子 15、低密度脂蛋白受体和白细胞介素-1 受体 2 型与这三种不同的心血管特征相关。我们证实了一些文献的研究结果，并发现颈动脉斑块的存在（von-Willebrand因子、galectin 4）、颈动脉内膜厚度（羧肽酶A1和B1）、baPWV（cathepsin D）和NT-proBNP（cathepsin Z、低密度脂蛋白受体、神经源性基因座同源蛋白3、trem-like转录本2）与之相关，但尚未报道。结论我们扩展了可能参与心血管疾病病理早期阶段的蛋白质组生物标志物目录，为早期风险预测或干预策略提供了目标。

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引用次数: 0

Lipids, lipoproteins, and apolipoproteins: Associations with cognition and dementia 血脂、脂蛋白和脂蛋白：与认知能力和痴呆症的关系

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-21 DOI: 10.1016/j.atherosclerosis.2024.118614

Ida Juul Rasmussen , Jiao Luo , Ruth Frikke-Schmidt

Due to increasing lifespan and aging populations globally there has been a steep rise in late-life dementia, which is now the second most common cause of death in high-income countries. In general, dementia can be divided into two major groups: Alzheimer's disease (AD) and vascular-related dementia (VD). AD is pathologically characterised by senile plaques containing amyloid-β and neurofibrillary tangles composed of hyperphosphorylated tau, whereas VD is dominated by vascular pathology such as cerebral small vessel disease, major strokes, and white matter lesions. Recently, the importance of vascular components in AD is increasingly recognized and it is estimated that up to 45 % of all dementia cases can be prevented by preventing or treating midlife cardiovascular risk factors such as physical inactivity, diabetes, and hypertension. Even though the brain contains approximately 25 % of the total body cholesterol pool, and several genetic variants related to the lipid metabolism have been identified in genome-wide associations studies of AD, the role of lipids, lipoproteins, and apolipoproteins in dementia risk is less well-known.

In this review, we go through the current literature on lipids, lipoproteins, and apolipoproteins and risk of dementia. We conclude that the evidence is primarily insufficient or conflicting, possibly due to nonoptimal study designs. The future calls for large, prospective studies of midlife measurements of lipids, lipoproteins, and apolipoproteins and one-sample, individual level data Mendelian randomization studies to overcome survival bias. However, the current literature suggests that it is safe to say that what is good for the heart is good for the brain.

由于全球寿命延长和人口老龄化，晚年痴呆症的发病率急剧上升，目前已成为高收入国家的第二大常见死因。一般来说，痴呆症可分为两大类：阿尔茨海默病（AD）和血管相关性痴呆（VD）。阿尔茨海默病的病理特征是含有淀粉样蛋白-β的老年斑和由高磷酸化 tau 组成的神经纤维缠结，而血管性痴呆则以血管病变为主，如脑小血管疾病、重大中风和白质病变。最近，血管病变在老年痴呆症中的重要性日益得到认可，据估计，通过预防或治疗中年期心血管风险因素（如缺乏运动、糖尿病和高血压），可预防高达 45% 的痴呆症病例。尽管大脑中的胆固醇约占人体胆固醇总量的 25%，而且在注意力缺失症的全基因组关联研究中发现了一些与脂质代谢有关的基因变异，但脂质、脂蛋白和载脂蛋白在痴呆症风险中的作用却鲜为人知。我们得出的结论是，证据主要不足或相互矛盾，这可能是由于非最佳研究设计造成的。未来需要对血脂、脂蛋白和脂蛋白的中年测量进行大型前瞻性研究，并进行单样本、个体水平数据的孟德尔随机研究，以克服生存偏倚。不过，目前的文献表明，可以肯定地说，对心脏有益的东西就是对大脑有益的东西。

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引用次数: 0

The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report 德国脂蛋白分离登记处--第十一次年度报告摘要

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-19 DOI: 10.1016/j.atherosclerosis.2024.118601

V.J.J. Schettler , N. Selke , S. Jenke , T. Zimmermann , G. Schlieper , W. Bernhardt , F. Heigl , P. Grützmacher , I. Löhlein , R. Klingel , B. Hohenstein , W. Ramlow , A. Vogt , U. Julius , Scientific Board of GLAR for the German Apheresis Working Group

Background

In 2012, the German Lipoprotein Apheresis Registry (GLAR) was launched. Real-world data on lipoprotein apheresis (LA) treatment are now available for a time period of 11 years. All patients received the maximally tolerated lipid-lowering therapy, which included statins, ezetimibe, bempedoic acid, and either proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies or antisense therapy.

Methods and Results

During the time period from 2012 to 2022, 92 German apheresis centers collected retrospective and prospective observational data of a total of 2,301 patients undergoing regular lipoprotein apheresis (LA) treatment of hypercholesterolemia or/and Lp(a)-hyperlipoproteinemia suffering from progressive atherosclerotic cardiovascular disease (ASCVD), with complete data sets of 1.125 patients, who were the subject of this analysis. More than 61,500 LA sessions are documented in the database. In 2022, all patients treated with LA demonstrated a significant immediate median reduction rate of LDL-C (68.8 %) and Lp(a) (72.9 %). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to eleven years on LA treatment (y+1 to y+11). During the first two years of LA treatment (y+1 and y+2), a MACE reduction of 73 % was observed and continued to be low during y+3 to y+11, when all LA patients were analyzed. LA patients with only increased Lp(a) levels (Lp(a) ≥ 60 mg/dl (≥120 nmol/l) and an LDL-C < 100 mg/dl (<2.6 mmol/l)) had a higher MACE reduction (85 %; n = 443) in the first two years of LA treatment compared to LA patients with only increased LDL-C-levels (LDL-C ≥ 100 mg/dl (≥2.6 mmol/l); Lp(a) < 60 mg/dl (<120 nmol/l)) (53 %; n = 171). Adverse events of LA remained low (about 5 %) over the eleven years and mainly represented puncture problems (1.0 %). No side effects resulted in termination of LA therapy.

Conclusions

The current analysis of GLAR data indicates that regular LA leads to very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid-lowering medication, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Additionally, LA was safe with a low rate of adverse effects over an 11-year period. The number of enrolled patients and the duration of observation establish GLAR as the largest LA registry worldwide.

背景2012年，德国脂蛋白分离注册中心（GLAR）成立。目前已有11年来的脂蛋白分离（LA）治疗的真实数据。所有患者都接受了最大耐受性降脂治疗，包括他汀类药物、依折麦布、贝美多酸和9型丙蛋白转换酶亚基酶/kexin（PCSK9）抗体或反义疗法。方法和结果在2012年至2022年期间，德国的92个无细胞疗法中心共收集了2301名接受常规脂蛋白无细胞疗法（LA）治疗的高胆固醇血症或/和Lp（a）-高脂蛋白血症的进展性动脉粥样硬化性心血管疾病（ASCVD）患者的回顾性和前瞻性观察数据，其中有1125名患者的完整数据集是本次分析的对象。数据库中记录了 61,500 多次 LA 治疗。2022 年，所有接受 LA 治疗的患者的低密度脂蛋白胆固醇（LDL-C）（68.8%）和脂蛋白（a）（72.9%）的即时中位数下降率都非常显著。对患者数据进行了分析，以了解LA治疗开始前1年和2年（y-2和y-1）以及LA治疗11年（y+1至y+11）的主要冠状动脉事件（MACE）发生率。在 LA 治疗的前两年（y+1 和 y+2），观察到 MACE 减少了 73%，在 y+3 至 y+11 期间，对所有 LA 患者进行分析时，MACE 减少率仍然很低。仅 Lp(a) 水平升高（Lp(a) ≥ 60 mg/dl (≥120 nmol/l)和 LDL-C < 100 mg/dl (< 2.6毫摩尔/升））的LA患者相比，LDL-C水平仅升高（LDL-C ≥ 100 mg/dl (≥2.6 mmol/l)；Lp(a) < 60 mg/dl (<120 nmol/l)）的LA患者在LA治疗的头两年中MACE减少率更高（85%；n = 443）（53%；n = 171）。十一年来，LA 的不良反应仍然很少（约 5%），主要是穿刺问题（1.0%）。结论目前对 GLAR 数据的分析表明，对于低密度脂蛋白胆固醇（LDL-C）和/或脂蛋白（a）水平较高、有进行性 ASCVD 和最大耐受性降脂药物（包括 9 型丙蛋白转换酶亚基酶/kexin (PCSK9) 抑制剂）的患者，定期服用 LA 可降低心血管事件的发生率。此外，在长达11年的时间里，LA安全性高，不良反应发生率低。GLAR登记的患者人数和观察时间使其成为全球最大的LA登记机构。

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引用次数: 0

The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse. 过氧化物酶体增殖激活受体α基因敲除小鼠心脏代谢异常的发展与年龄有关。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-17 DOI: 10.1016/j.atherosclerosis.2024.118599

Michael S Dodd, Lucy Ambrose, Vicky Ball, Kieran Clarke, Carolyn A Carr, Damian J Tyler

Background and aims: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.

Methods: Hyperpolarized [1-¹³C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression.

Results: PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation.

Conclusions: Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis.

背景和目的：过氧化物酶体增殖激活受体α（PPARα）是调节心脏、肝脏和肾脏中心脏β氧化作用的关键。衰老可诱发心脏代谢改变，但 PPARα 的作用尚未得到广泛表征。研究方法：使用超极化[1-13C]丙酮酸评估幼年（3 个月）和老年（20-22 个月）PPARα 基因敲除（KO）小鼠与对照组的体内心脏碳水化合物代谢。显像核磁共振成像评估了心脏结构和功能的变化。心脏组织分析包括 Pparα、中链酰基-CoA 脱氢酶（MCAD）、解偶联蛋白（UCP）3、葡萄糖转运体（GLUT）4 和 PDH 激酶（PDK）1、2 和 4 表达的 qRT-PCR 和 Western 印迹检测：结果：与对照组相比，年轻和年老小鼠的 PPARα-KO 心脏的 Pparα mRNA 显著减少，MCAD 蛋白水平下降了 58-59%。年轻对照组和 PPARα-KO 小鼠的心脏 PDH 通量相似，但老年 PPARα-KO 小鼠的 PDH 通量比对照组高 96%。基因型之间的差异在进食和禁食状态下是一致的，禁食时 PDH 通量降低。PDH 通量增加的同时，心肌 GLUT4 蛋白也增加了 179%。喂养组之间的 PDK 1、2 或 4 蛋白水平没有差异，这表明老龄 PPARα-KO 小鼠 PDH 通量的增加不是由于 PDH 磷酸化的变化：结论：与对照组相比，老年 PPARα-KO 小鼠表现出更高的心脏 PDH 通量，心肌 GLUT4 蛋白水平的增加促进了 PDH 通量的增加，从而导致葡萄糖摄取和糖酵解的增强。

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引用次数: 0