Atherosclerosis最新文献_第4页

Is colchicine on its way to a place in the polypill for cardiovascular prevention? 秋水仙碱是否即将成为预防心血管疾病的多用途药物？

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-05 DOI: 10.1016/j.atherosclerosis.2024.118594

引用次数: 0

Silencing ARL11 relieved atherosclerotic inflammation and lipid deposition via retraining JAK2/STAT1 pathway 沉默ARL11可通过重新训练JAK2/STAT1通路缓解动脉粥样硬化炎症和脂质沉积。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-05 DOI: 10.1016/j.atherosclerosis.2024.118564

Background and aims

Atherosclerosis (AS), an arterial vasculature disease, is characterized by abnormal lipid accumulation and inflammatory response. ADP ribosylation factor like GTPase 11 (ARL11) is linked to multifarious processes in cells. This study aims to clarify the underlying mechanism of ARL11 in AS.

Methods

ApoE^−/− mice fed with high-fat diet were used as mouse model of AS. Gene expression in AS was determined by mRNA-sequencing. ARL11 expression was detected by real-time PCR, Western blot and immunofluorescence. M1 polarization of macrophages was indicated by TNF-α and IL-6 levels as detected with ELISA, and iNOS expression determined by real-time PCR and Western blot. The role of ARL11 during AS was explored through loss-of-function analysis.

Results

There were 1301 upregulated and 1110 downregulated genes during AS. These differentially expressed genes (DEGs) were mainly enriched in pathways and terms which are involved in inflammation. Moreover, Arl11 was highly expressed in AS models. Downregulation of Arl11 decreased lipid deposition and atherosclerotic plaques in the aortas of AS mice, and declined inflammatory cytokines and M1 polarization of macrophages induced by IFN-γ. Furthermore, ARL11 interacted with JAK2 and p-JAK2 and modulated their degradation, thus inhibiting the activation of JAK2/STAT1 pathway.

Conclusions

ARL11 promoted the development of AS via interacting with JAK2 and activating JAK2/STAT1 pathway. Thus, silencing ARL11 may prevent the process of AS and be a novel way to treat AS.

背景和目的：动脉粥样硬化（AS）是一种动脉血管疾病，以脂质异常积累和炎症反应为特征。ADP 核糖基化因子类 GTPase 11（ARL11）与细胞中的多种过程有关。本研究旨在阐明ARL11在强直性脊柱炎中的潜在机制：方法：以高脂饮食喂养的载脂蛋白E-/-小鼠作为强直性脊柱炎小鼠模型。通过 mRNA 序列测定 AS 中的基因表达。通过实时 PCR、Western 印迹和免疫荧光检测 ARL11 的表达。巨噬细胞的M1极化通过ELISA检测的TNF-α和IL-6水平以及实时PCR和Western印迹检测的iNOS表达来显示。通过功能缺失分析探讨了ARL11在强直性脊柱炎中的作用：结果：强直性脊柱炎期间有1301个基因上调，1110个基因下调。这些差异表达基因（DEGs）主要富集在与炎症有关的通路和术语中。此外，Arl11在强直性脊柱炎模型中高度表达。下调Arl11可减少AS小鼠主动脉中的脂质沉积和动脉粥样硬化斑块，并降低炎性细胞因子和IFN-γ诱导的巨噬细胞M1极化。此外，ARL11与JAK2和p-JAK2相互作用并调节其降解，从而抑制了JAK2/STAT1通路的激活：结论：ARL11通过与JAK2相互作用并激活JAK2/STAT1通路，促进了强直性脊柱炎的发展。结论：ARL11通过与JAK2相互作用并激活JAK2/STAT1通路，促进了强直性脊柱炎的发展。

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引用次数: 0

Endothelial epoxyeicosatrienoic acid release is intact in aldosterone excess 内皮环氧二十碳三烯酸的释放在醛固酮过量时保持不变

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-05 DOI: 10.1016/j.atherosclerosis.2024.118591

Background and aims

Endothelial dysfunction (ED) is considered to be a major driver of the increased incidence of cardiovascular disease in primary aldosteronism (PA). The functionality of the epoxyeicosatrienoic acid (EET) pathway, involving the release of beneficial endothelium-derived lipid mediators, in PA is unknown. Evidence suggests this pathway to be disturbed in various models of experimental hypertension.

We therefore assessed EET production in primary human coronary artery endothelial cells exposed to aldosterone excess and measured circulating EET in patients with PA.

Methods

We used qPCR to investigate changes in the expression levels of essential genes for the synthesis and degradation of EET, calcium imaging to address the functional impact on overall endothelial function, as well as mass spectrometry to determine endothelial synthetic capacity to release EET upon stimulation. RNA-seq was performed to gain further mechanistic insights. Eicosanoid concentrations in patient's plasma were also determined by mass spectrometry.

Results

Aldosterone, while eliciting proinflammatory VCAM1 expression and disturbed calcium response to acetylcholine, did not negatively affect stimulated release of endothelial EET. Likewise, no differences were observed in eicosanoid concentrations in plasma from patients with PA when compared to essential hypertensive controls.

However, an inhibitor of soluble epoxide hydrolase abrogated aldosterone-mediated VCAM1 induction and led to a normalized endothelial calcium response probably by restoring expression of CHRNE.

Conclusion

EET release appears intact despite aldosterone excess. Epoxide hydrolase inhibition may revert aldosterone-induced functional changes in endothelial cells. These findings indicate a potential new therapeutic principle to address ED, which should be explored in future preclinical and clinical trials.

背景和目的内皮功能障碍（ED）被认为是原发性醛固酮增多症（PA）心血管疾病发病率增加的主要原因。环二十碳三烯酸（EET）途径涉及释放有益的内皮衍生脂质介质，但其在 PA 中的功能尚不清楚。因此，我们评估了暴露于醛固酮过量的原代人类冠状动脉内皮细胞的 EET 生成情况，并测量了 PA 患者的循环 EET。方法：我们使用 qPCR 来研究 EET 合成和降解的重要基因表达水平的变化，使用钙成像来研究对整体内皮功能的影响，并使用质谱法来确定内皮在受到刺激时释放 EET 的合成能力。为了进一步了解机理，还进行了 RNA-seq 分析。结果醛固酮虽然会引起促炎性 VCAM1 表达和对乙酰胆碱的钙反应紊乱，但不会对内皮 EET 的刺激释放产生负面影响。然而，可溶性环氧化物水解酶抑制剂可减轻醛固酮介导的 VCAM1 诱导，并可能通过恢复 CHRNE 的表达而导致内皮钙反应正常化。环氧化物水解酶抑制可恢复醛固酮诱导的内皮细胞功能变化。这些发现揭示了一种潜在的新治疗原理，可用于治疗 ED，应在未来的临床前和临床试验中加以探索。

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引用次数: 0

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-05 DOI: 10.1016/j.atherosclerosis.2024.118592

Background and aims

Arterial stiffness, a known cardiovascular risk factor, is associated with increasing age and arteriosclerosis. This study examines age-related annual changes in arterial stiffness in a large cohort of healthy individuals without cardiovascular disease, hypertension, or diabetes mellitus.

Methods

The study included 195,405 Korean adults aged 30–79 years who attended a health check-up between 2006 and 2019. Arterial stiffness was assessed using brachial-ankle pulse wave velocity (baPWV), and the final cohort for the baPWV annual change analysis comprised 147,313 participants.

Results

The study found that baPWV values increase progressively with age in both sexes, with the most notable changes occurring in the 70–79 age group. The spread in baPWV measurements, as indicated by the interquartile ranges, generally increases with age but was particularly pronounced in women in the 50s and 60s age groups, with men showing a greater spread in the 70–79 age group. The average annual change in baPWV (ΔbaPWV) values increased from 1.48 cm/s (95 % CI: 0.80–2.16) in the 30–39 age group to 23.72 cm/s (95 % CI: 16.25–31.19) in the 70–79 age group in men. Similarly, for women, the average ΔbaPWV values increased from 1.80 cm/s (95 % CI: 0.93–2.68) to 18.51 cm/s (95 % CI: 7.18–29.85) in the 30–39 and 70–79 age groups, respectively. The study observed that arterial stiffness in men consistently increases across all age groups, whereas in women, it does not significantly increase annually before age 50 but shows a steeper rise after this age.

Conclusions

This study emphasizes the progressive nature of arterial stiffness with aging in a healthy population. It highlights notable differences in the rate of progression and the distribution of baPWV between men and women, with men exhibiting a greater spread in the oldest age group.

背景和目的：动脉僵化是一种已知的心血管风险因素，与年龄增长和动脉硬化有关。本研究调查了一大批无心血管疾病、高血压或糖尿病的健康人动脉僵化与年龄有关的年度变化：研究对象包括 2006 年至 2019 年期间参加健康体检的 195,405 名年龄在 30-79 岁之间的韩国成年人。动脉僵硬度通过肱踝关节脉搏波速度（baPWV）进行评估，baPWV年度变化分析的最终队列包括147313名参与者：研究发现，随着年龄的增长，男女参与者的 baPWV 值都会逐渐增加，其中 70-79 岁年龄组的变化最为显著。baPWV测量值的分布（如四分位间范围所示）一般随年龄的增长而增加，但在50和60岁年龄组中，女性的分布尤为明显，而在70-79岁年龄组中，男性的分布更大。男性 baPWV 的年均变化值（ΔbaPWV）从 30-39 岁年龄组的 1.48 厘米/秒（95 % CI：0.80-2.16）增加到 70-79 岁年龄组的 23.72 厘米/秒（95 % CI：16.25-31.19）。同样，在女性中，30-39 岁年龄组和 70-79 岁年龄组的平均 ΔbaPWV 值分别从 1.80 厘米/秒（95 % CI：0.93-2.68）增至 18.51 厘米/秒（95 % CI：7.18-29.85）。研究观察到，男性的动脉僵化在所有年龄组中都会持续增加，而女性的动脉僵化在 50 岁之前每年都不会显著增加，但在 50 岁之后会急剧增加：这项研究强调了在健康人群中，动脉僵化会随着年龄的增长而逐渐加重。结论：这项研究强调了健康人群中动脉僵化随年龄增长而逐渐加重的特性，并突出了男女之间动脉僵化的进展速度和分布的明显差异，其中男性在最年长的年龄组中表现出更大的差异。

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引用次数: 0

Recurrent cardiovascular and limb events in 294,428 patients with coronary or peripheral artery disease or ischemic stroke on antiplatelet monotherapy: The RESRISK cohort study 294,428 名接受抗血小板单药治疗的冠状动脉或外周动脉疾病或缺血性中风患者的复发性心血管和肢体事件：RESRISK队列研究

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-04 DOI: 10.1016/j.atherosclerosis.2024.118589

Background and aims

Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT).

Methods

Retrospective cohort study using data (2010–2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD.

Results

266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%–47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3–272.0) than CAD (92.9; 95%CI 92.5–93.4) or PAD cohorts (97.2; 95%CI 94.6–99.8). MALE incidence rate was 195.9 (95%CI 192.2–199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate.

Conclusions

Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population.

背景和目的我们利用真实世界的数据，量化了接受指南推荐的抗血小板单药治疗（APMT）的冠状动脉疾病（CAD）或外周动脉疾病（PAD）或缺血性中风（IS）患者的心血管风险因素负担和动脉粥样硬化血栓事件的长期残余风险。方法利用英国临床实践研究数据链（CPRD）和医院病例统计（Hospital Episode Statistics）中的数据（2010-2020 年）进行回顾性队列研究，研究对象包括首次接受 APMT（CAD/IS：阿司匹林；PAD：氯吡格雷）治疗的患有 CAD、PAD 或 IS 的成人。主要结果（复发事件）：CAD/PAD/IS队列的主要不良心血管事件（MACE），PAD的主要不良肢体事件（MALE）。结果共纳入266,478例CAD、13,162例PAD和14,788例IS患者（平均年龄：71岁；女性占37.7%-47.5%）。风险因素负担较重，达到建议目标的比例较低。在 CAD、PAD 和 IS 患者中，分别有 73,691 人、3,121 人和 7,137 人发生 MACE（中位随访时间分别为 89.9 个月、42.4 个月和 75.9 个月），在 PAD 患者中，有 4,767 人发生 MALE。IS患者每1000人年的MACE发病率（268.7；95%CI 265.3-272.0）高于CAD患者（92.9；95%CI 92.5-93.4）或PAD患者（97.2；95%CI 94.6-99.8）。男性发病率为每千人年 195.9 例（95%CI 192.2-199.6 例）。IS患者的住院率较低，首次住院时间较长，但一旦住院，住院时间也较长。结论在接受 APMT 治疗的当代心血管疾病患者中，尽管接受了 APMT 治疗，但长期残留的动脉粥样硬化血栓风险仍然很高。需要更加重视风险因素控制和使用适当的循证疗法，以降低这一高风险人群的残余风险。

{"title":"Recurrent cardiovascular and limb events in 294,428 patients with coronary or peripheral artery disease or ischemic stroke on antiplatelet monotherapy: The RESRISK cohort study","authors":"","doi":"10.1016/j.atherosclerosis.2024.118589","DOIUrl":"10.1016/j.atherosclerosis.2024.118589","url":null,"abstract":"<div><h3>Background and aims</h3><p>Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT).</p></div><div><h3>Methods</h3><p>Retrospective cohort study using data (2010–2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD.</p></div><div><h3>Results</h3><p>266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%–47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3–272.0) than CAD (92.9; 95%CI 92.5–93.4) or PAD cohorts (97.2; 95%CI 94.6–99.8). MALE incidence rate was 195.9 (95%CI 192.2–199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate.</p></div><div><h3>Conclusions</h3><p>Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population.</p></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0021915024011614/pdfft?md5=440a262c1a70c0869990fbc2ed7b1642&pid=1-s2.0-S0021915024011614-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232171","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}

引用次数: 0

Very short-term effects of a single dose of a proprotein convertase subtilisin/kexin 9 inhibitor before percutaneous coronary intervention: A single-arm study 经皮冠状动脉介入治疗前单次服用蛋白转化酶枯草酶/kexin 9抑制剂的短期效果：单臂研究

IF 5.3 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-09-02 DOI: 10.1016/j.atherosclerosis.2024.118581

Tatsuhiro Kataoka, Tetsuji Morishita, Hiroyasu Uzui, Yusuke Sato, Tomohiro Shimizu, Machiko Miyoshi, Junya Yamaguchi, Yuichiro Shiomi, Hiroyuki Ikeda, Naoto Tama, Kanae Hasegawa, Kentaro Ishida, Hiroshi Tada

The short-term (within 6 weeks) effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on lipid plaques have not been adequately evaluated. We aimed to investigate whether a single dose of a PCSK9 inhibitor before percutaneous coronary intervention (PCI) could reduce the abundance of lipid-core plaques identified via near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) at target lesions within a very short period. This prospective, single-arm, single-center interventional study enrolled 27 consecutive patients with coronary artery disease. These patients underwent NIRS-IVUS during coronary angiography and repeat NIRS-IVUS during PCI performed between 2 and 6 weeks after the single-dose administration of 420 mg evolocumab. Changes in lesion lipid-core burden index (LCBI) and maximal LCBI over any 4-mm segment (max-LCBI) were assessed using NIRS at the target lesions, along with lipid profile. The max-LCBI significantly decreased from 387 before PCSK9 inhibitor administration to 315 after its administration (interquartile range [IQR]: 268–572 and 221–488, respectively; = 0.02) within a very short period. The lesion LCBI also decreased from 161 to 117 (IQR: 105–263 and 65–226, respectively; = 0.02). No significant changes were observed in the minimum lumen area and diameter. After PCSK9 inhibitor administration, low-density lipoprotein (LDL) cholesterol ( < 0.001), lipoprotein(a) ( = 0.001), and malondialdehyde-modified LDL ( < 0.001) levels decreased compared with those before its administration. A single dose of the PCSK9 inhibitor administered before PCI reduced the abundance of lipid-core plaques identified via NIRS-IVUS at target lesions within a very short period of 2–6 weeks.

目前尚未充分评估丙蛋白转化酶亚基酶/kexin 9（PCSK9）抑制剂对脂质斑块的短期（6周内）影响。我们的目的是研究在经皮冠状动脉介入治疗（PCI）前使用单剂量 PCSK9 抑制剂是否能在短期内减少通过近红外光谱血管内超声（NIRS-IVUS）在靶病变处发现的脂质核心斑块的数量。这项前瞻性、单臂、单中心介入研究连续招募了 27 名冠心病患者。这些患者在冠状动脉造影期间接受了 NIRS-IVUS 检查，并在单剂量服用 420 毫克 evolocumab 2 至 6 周后进行 PCI 时再次接受了 NIRS-IVUS 检查。在目标病变处使用 NIRS 评估了病变脂质核心负荷指数（LCBI）和任意 4 mm 区段最大 LCBI（max-LCBI）的变化，同时还评估了脂质概况。在很短的时间内，最大 LCBI 从 PCSK9 抑制剂用药前的 387 显著下降到用药后的 315（四分位数间距 [IQR]：分别为 268-572 和 221-488；= 0.02）。病变 LCBI 也从 161 降至 117（IQR 分别为 105-263 和 65-226；= 0.02）。最小管腔面积和直径没有明显变化。服用 PCSK9 抑制剂后，低密度脂蛋白胆固醇（< 0.001）、脂蛋白（a）（= 0.001）和丙二醛修饰的低密度脂蛋白（< 0.001）水平与服用前相比均有所下降。在PCI术前服用单剂量的PCSK9抑制剂可在2-6周的极短时间内减少通过NIRS-IVUS在目标病变处发现的脂质核心斑块的数量。

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引用次数: 0

Gene inactivation of lysyl oxidase in smooth muscle cells reduces atherosclerosis burden and plaque calcification in hyperlipidemic mice 平滑肌细胞中的赖氨酰氧化酶基因失活可减少高脂血症小鼠的动脉粥样硬化负担和斑块钙化

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-08-31 DOI: 10.1016/j.atherosclerosis.2024.118582

Background and aims

Lysyl oxidase (LOX) catalyzes the crosslinking of collagen and elastin to maintain tensile strength and structural integrity of the vasculature. Excessive LOX activity increases vascular stiffness and the severity of occlusive diseases. Herein, we investigated the mechanisms by which LOX controls atherogenesis and osteogenic differentiation of vascular smooth muscle cells (SMC) in hyperlipidemic mice.

Methods

Gene inactivation of Lox in SMC was achieved in conditional knockout mice after tamoxifen injections. Atherosclerosis burden and vascular calcification were assessed in hyperlipidemic conditional [Lox^f/f Myh11-CreER^T2 ApoE^−/−] and sibling control mice [Lox^wt/wt Myh11-CreER^T2 ApoE^−/−]. Mechanistic studies were performed with primary aortic SMC from Lox mutant and wild type mice.

Results

Inactivation of Lox in SMCs decreased > 70 % its RNA expression and protein level in the aortic wall and significantly reduced LOX activity without compromising vascular structure and function. Moreover, LOX deficiency protected mice against atherosclerotic burden (13 ± 2 versus 23 ± 1 %, p < 0.01) and plaque calcification (5 ± 0.4 versus 11.8 ± 3 %, p < 0.05) compared to sibling controls. Interestingly, gene inactivation of Lox in SMCs preserved the contractile phenotype of vascular SMC under hyperlipidemic conditions as demonstrated by single-cell RNA sequencing and immunofluorescence. Mechanistically, the absence of LOX in SMC prevented excessive collagen crosslinking and the subsequent activation of the pro-osteogenic FAK/β-catenin signaling axis.

Conclusions

Lox inactivation in SMC protects mice against atherosclerosis and plaque calcification by reducing SMC modulation and FAK/β-catenin signaling.

背景和目的赖氨酰氧化酶（LOX）催化胶原蛋白和弹性蛋白的交联，以保持血管的抗张强度和结构完整性。过高的 LOX 活性会增加血管僵硬度和闭塞性疾病的严重性。在此，我们研究了 LOX 控制高脂血症小鼠动脉粥样硬化发生和血管平滑肌细胞（SMC）成骨分化的机制。评估了高脂血症条件性小鼠[Loxf/f Myh11-CreERT2 ApoE-/-]和同胞对照小鼠[Loxwt/wt Myh11-CreERT2 ApoE-/-]的动脉粥样硬化负担和血管钙化情况。结果活化 SMC 中的 Lox，可使其在主动脉壁中的 RNA 表达和蛋白水平降低 70%，并显著降低 LOX 活性，而不会损害血管结构和功能。此外，与同胞对照组相比，LOX 缺乏可保护小鼠免受动脉粥样硬化负担（13 ± 2 对 23 ± 1 %，p < 0.01）和斑块钙化（5 ± 0.4 对 11.8 ± 3 %，p < 0.05）的影响。有趣的是，单细胞 RNA 测序和免疫荧光显示，在高脂血症条件下，SMC 中的 Lox 基因失活保留了血管 SMC 的收缩表型。从机理上讲，SMC 中 LOX 的缺失可防止胶原过度交联以及随后的促骨质生成 FAK/β-catenin 信号轴的激活。

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引用次数: 0

Association between different stages of cardiovascular-kidney-metabolic syndrome and the risk of all-cause mortality 心血管-肾脏-代谢综合征不同阶段与全因死亡风险之间的关系

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-08-30 DOI: 10.1016/j.atherosclerosis.2024.118585

Background and aims

Poor cardiovascular-kidney-metabolic (CKM) health is a major determinant of all-cause mortality, which poses a significant burden on global public health systems and socio-economics. However, the association between different stages of CKM syndrome and the risk of all-cause mortality remains unclear. This study aimed to evaluate the association between different stages of CKM syndrome and risk of all-cause mortality.

Methods

A total of 97,777 adults from the Kailuan Study were included. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) of all-cause mortality according to different stages of CKM syndrome.

Results

Over a median follow-up of 15.0 (14.7–15.2) years, we identified 14,805 all-cause mortality cases. The stage of CKM syndrome was positively associated with the risk of all-cause mortality (p-trend <0.001). Compared with Stage 0, the multivariable-adjusted HRs (95 % CIs) of all-cause mortality were 1.24 (1.06–1.45) for Stage 1, 1.72 (1.48–2.00) for Stage 2, 2.58 (2.22–3.01) for Stage 3 and 3.73 (3.19–4.37) for Stage 4. Moreover, the observed associations were more pronounced in younger adults (aged <60 years) compared with older adults (p for interaction <0.001).

Conclusions

Our data showed that a higher stage of CKM syndrome was associated with a higher risk of all-cause mortality, with a particularly pronounced association observed in younger adults. The study emphasized the need for targeted public health strategies and clinical management tailored to the stages of CKM syndrome, aiming to alleviate its burden on individuals and healthcare systems.

背景和目的不良的心血管-肾脏-代谢（CKM）健康状况是全因死亡率的主要决定因素，给全球公共卫生系统和社会经济造成了沉重负担。然而，不同阶段的 CKM 综合征与全因死亡风险之间的关系仍不清楚。本研究旨在评估不同阶段的 CKM 综合征与全因死亡风险之间的关系。结果在中位随访 15.0 (14.7-15.2) 年期间，我们共发现了 14 805 例全因死亡病例。CKM综合征的分期与全因死亡风险呈正相关（p-trend <0.001）。与 0 期相比，经多变量调整的全因死亡率 HRs（95 % CIs）分别为：1 期 1.24（1.06-1.45），2 期 1.72（1.48-2.00），3 期 2.58（2.22-3.01），4 期 3.73（3.19-4.37）。结论我们的数据显示，CKM 综合征的分期越高，全因死亡的风险越高，年轻成人的相关性尤其明显。该研究强调，有必要根据 CKM 综合征的不同阶段制定有针对性的公共卫生策略和临床管理，以减轻其对个人和医疗系统造成的负担。

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引用次数: 0

Correspondence on: "Subclinical atherosclerosis: More data - More insights into prevention". 通讯："亚临床动脉粥样硬化：更多数据 - 更多预防见解"。

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-08-29 DOI: 10.1016/j.atherosclerosis.2024.118571

J David Spence

引用次数: 0

Polygenic risk of high LDL cholesterol and ischemic heart disease in the general population 普通人群高低密度脂蛋白胆固醇和缺血性心脏病的多基因风险

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis

Pub Date : 2024-08-28 DOI: 10.1016/j.atherosclerosis.2024.118574

Background and aims

We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population.

Methods

We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH).

Results

Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43–3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20–80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38–0.88) and 1.83 (95 % CI, 1.33–2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41–0.92) and 2.06 (95 % CI, 1.49–2.85).

Conclusions

The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically.

背景和目的我们测试了丹麦普通人群中低密度脂蛋白胆固醇（LDL-C）和冠状动脉疾病（CAD）的多基因风险评分（PRS）与 LDL-C 和缺血性心脏病（IHD）风险的关联。每个人的低密度脂蛋白-PRS和中密度脂蛋白-CAD-PRS都是基于400,000个变体计算得出的。我们还对已知会导致家族性高胆固醇血症（FH）的 LDLR 或 APOB 中的四个罕见变体进行了基因分型。结果 APOB 或 LDLR 中导致 FH 的变体的杂合子携带者的平均 LDL-C 分别为 5.40 和 6.09 mmol/L，与非携带者相比，IHD 的几率比为 2.27（95 % CI 1.43-3.51）。LDL-PRS 解释了队列中 LDL-C 总变化的 13.8%。LDL-PRS 最低和最高 1% 的个体的平均 LDL-C 分别为 2.49 和 4.75 mmol/L。与中间 20-80% 的人群相比，LDL-PRS 最低和最高 1% 的人群患 IHD 的几率比分别为 0.58（95% CI，0.38-0.88）和 1.83（95% CI，1.33-2.53）。结论 LDL-PRS 和 CAD-PRS 的前 1% 对 LDL-C 和 IHD 风险的影响与 APOB 或 LDLR 中罕见的 FH 致病变异携带者的影响相当。这些结果凸显了在临床上实施此类PRS的潜在价值。

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