Pub Date : 2025-12-01Epub Date: 2025-10-31DOI: 10.1016/j.atherosclerosis.2025.120557
Stephanie Wissel , Hubert Scharnagl , Marcus E. Kleber , Graciela Delgado , Angela Moissl , Bernhard Krämer , Winfried März
Background and aims
The Fatty Liver Index (FLI) has emerged as an indicator of metabolic dysfunction and has been related to cardiovascular outcomes. This study aims to investigate if the association between FLI and cardiovascular mortality is modified by systemic inflammation.
Methods
The study population consisted of 3316 participants (mean age 63 years, 30,3 % female) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The FLI was calculated using triglycerides, BMI, waist circumference, and gamma-glutamyl transferase (GGT). Systemic inflammatory markers (hsCRP and IL-6) were measured with immunoturbidimetric and ELISA assays. The outcome of interest was cardiovascular mortality. Cox proportional hazard analyses accounting for confounding variables were used for statistical analyses.
Results
During a median follow-up of 9.9 years, 603 cardiovascular deaths occurred. Individuals in the highest compared to the lowest FLI tertile were at an increased risk of cardiovascular death (HR 1.39, 95 % CI 1.02–1.89). This association was significantly modified by elevated hsCRP (≥2 mg/L, HR 1.58, 95 % CI 1.10–2.26) and IL-6 (≥3.2 ng/L, (HR 1.93, 95 %CI 1.36–2.74).
Conclusion
The Fatty Liver Index is not associated with cardiovascular mortality. However, this relationship is modified by systemic inflammation. These results indicate that liver steatosis is particularly relevant in presence of systemic inflammation which suggests that risk assessment in individuals with steatosis needs to consider both metabolic and inflammatory markers.
背景和目的：脂肪肝指数（FLI）已成为代谢功能障碍的指标，并与心血管结局相关。本研究旨在探讨FLI与心血管死亡率之间的关系是否会因全身性炎症而改变。方法：研究人群包括路德维希港风险和心血管健康（LURIC）研究的3316名参与者（平均年龄63岁，30.3%为女性）。FLI采用甘油三酯、BMI、腰围和γ -谷氨酰转移酶（GGT）计算。采用免疫比浊法和ELISA法检测全身炎症标志物（hsCRP和IL-6）。关注的结果是心血管死亡率。统计分析采用考虑混杂变量的Cox比例风险分析。结果：在平均9.9年的随访期间，发生了603例心血管死亡。与FLI指数最低的个体相比，FLI指数最高的个体心血管死亡风险增加（HR 1.39, 95% CI 1.02-1.89）。升高的hsCRP（≥2 mg/L, HR 1.58, 95% CI 1.10-2.26）和IL-6（≥3.2 ng/L, HR 1.93, 95% CI 1.36-2.74）显著改变了这种相关性。结论：脂肪肝指数与心血管疾病死亡率无相关性。然而，这种关系被全身性炎症所改变。这些结果表明肝脏脂肪变性与全身性炎症特别相关，这表明脂肪变性个体的风险评估需要考虑代谢和炎症标志物。
{"title":"Fatty liver-index, systemic inflammation and cardiovascular mortality. Results from the LURIC study","authors":"Stephanie Wissel , Hubert Scharnagl , Marcus E. Kleber , Graciela Delgado , Angela Moissl , Bernhard Krämer , Winfried März","doi":"10.1016/j.atherosclerosis.2025.120557","DOIUrl":"10.1016/j.atherosclerosis.2025.120557","url":null,"abstract":"<div><h3>Background and aims</h3><div>The Fatty Liver Index (FLI) has emerged as an indicator of metabolic dysfunction and has been related to cardiovascular outcomes. This study aims to investigate if the association between FLI and cardiovascular mortality is modified by systemic inflammation.</div></div><div><h3>Methods</h3><div>The study population consisted of 3316 participants (mean age 63 years, 30,3 % female) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The FLI was calculated using triglycerides, BMI, waist circumference, and gamma-glutamyl transferase (GGT). Systemic inflammatory markers (hsCRP and IL-6) were measured with immunoturbidimetric and ELISA assays. The outcome of interest was cardiovascular mortality. Cox proportional hazard analyses accounting for confounding variables were used for statistical analyses.</div></div><div><h3>Results</h3><div>During a median follow-up of 9.9 years, 603 cardiovascular deaths occurred. Individuals in the highest compared to the lowest FLI tertile were at an increased risk of cardiovascular death (HR 1.39, 95 % CI 1.02–1.89). This association was significantly modified by elevated hsCRP (≥2 mg/L, HR 1.58, 95 % CI 1.10–2.26) and IL-6 (≥3.2 ng/L, (HR 1.93, 95 %CI 1.36–2.74).</div></div><div><h3>Conclusion</h3><div>The Fatty Liver Index is not associated with cardiovascular mortality. However, this relationship is modified by systemic inflammation. These results indicate that liver steatosis is particularly relevant in presence of systemic inflammation which suggests that risk assessment in individuals with steatosis needs to consider both metabolic and inflammatory markers.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120557"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501939","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}
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.
{"title":"Metabolic dysfunction-associated steatotic liver disease, cardiometabolic risk factors, and cardiovascular disease","authors":"Lærke Kristine Kyhl , Børge Grønne Nordestgaard , Anne Tybjærg-Hansen , Sune Fallgaard Nielsen","doi":"10.1016/j.atherosclerosis.2025.120551","DOIUrl":"10.1016/j.atherosclerosis.2025.120551","url":null,"abstract":"<div><h3>Background and aims</h3><div>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.</div><div>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.</div></div><div><h3>Methods</h3><div>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.</div><div>We describe how MASLD associates with cardiovascular disease and suggest that fatty liver is associated with cardiovascular disease through very low-density lipoproteins.</div><div>Finally, we describe current guidelines and ongoing pharmaceutical approaches in the treatment of MASLD with the focus on cardiovascular risk factors.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>This review encompasses clinical aspects of MASLD from risk factors to outcome, including recommended clinical handling of these patients.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120551"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342851","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}
Pub Date : 2025-12-01Epub Date: 2025-11-17DOI: 10.1016/j.atherosclerosis.2025.120572
Tarek Harb MD , Gary Gerstenblith MD , Thorsten M. Leucker MD, PhD
{"title":"Lp(a) in Argentina: Regional data reinforce a global risk factor","authors":"Tarek Harb MD , Gary Gerstenblith MD , Thorsten M. Leucker MD, PhD","doi":"10.1016/j.atherosclerosis.2025.120572","DOIUrl":"10.1016/j.atherosclerosis.2025.120572","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120572"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614803","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}
Pub Date : 2025-12-01Epub Date: 2025-11-17DOI: 10.1016/j.atherosclerosis.2025.120517
Philipp Scherrer , Timoteo Marchini , Xiaowei Li , Abed Al Hadi El Rabih , Jan Pennig , Lucia Sol Mitre , Juana Dominguez , Mark Colin Gissler , Guido Pisani , Nathaly Anto Michel , Timothy Mwinyella , Tijani Abogunloko , Natalie Hoppe , Lisa Spiga , Daniela Stallmann , Hauke Horstmann , Patrick Malcolm Siegel , Sophie Hansen , Ingo Hilgendorf , Esther Lutgens , Dennis Wolf
Background and aims
The repertoire of adhesion receptors and ligands is supported by molecules, which are primarily recognized for their roles in immunity. We have recently shown that the co-stimulatory molecule CD40 ligand (CD154/CD40L) is pro-atherogenic and serves as an adhesive ligand for cells expressing the integrin Mac-1 (CD11b/CD18). Here, we studied the role of endothelial CD40L in several models of cardiovascular inflammation.
Methods and results
We generated mice with an endothelial cell-specific deficiency of CD40L, Bmx-CreERT2+Cd40lgfl/flApoe−/− (EC-CD40L-KO), and Cd40lgfl/flApoe−/− as controls. In a model of atherosclerosis, EC-CD40L-KO mice developed on average 39.4 ± 14.7 % smaller atherosclerotic plaques after 10 weeks of the conditional genetic deficiency compared to controls. Plaques from EC-CD40L-KO mice contained less macrophages, lipids and more collagen. In intravital microscopy of inflamed mesenteric venules, leukocyte adhesion was reduced 3.1-fold in EC-CD40L-KO mice with a similar effect on slow rolling. In a model of thioglycolate-induced peritonitis, leukocyte migration into the peritoneal cavity was reduced by 38.2 ± 16.2 % in EC-CD40L-KO mice compared to controls after 72 h. Furthermore, 7 days after a permanent surgical ligation of the Left Anterior Descending (LAD) coronary artery, significantly fewer Mac-1-expressing neutrophils and macrophages were detected in the infarcted myocardium in the absence of endothelial CD40L.
Conclusions
In this functional validation study, we demonstrate that endothelial cell-expressed CD40L serves as an adhesion molecule in different models of acute inflammation in the aortic, peritoneal, mesenteric, and coronary vasculature. CD40L may therefore represent a promising therapeutic target at the interface of adaptive immunity and myeloid inflammation.
{"title":"Endothelial CD40L serves as a pro-atherogenic adhesion receptor in the inflamed vasculature","authors":"Philipp Scherrer , Timoteo Marchini , Xiaowei Li , Abed Al Hadi El Rabih , Jan Pennig , Lucia Sol Mitre , Juana Dominguez , Mark Colin Gissler , Guido Pisani , Nathaly Anto Michel , Timothy Mwinyella , Tijani Abogunloko , Natalie Hoppe , Lisa Spiga , Daniela Stallmann , Hauke Horstmann , Patrick Malcolm Siegel , Sophie Hansen , Ingo Hilgendorf , Esther Lutgens , Dennis Wolf","doi":"10.1016/j.atherosclerosis.2025.120517","DOIUrl":"10.1016/j.atherosclerosis.2025.120517","url":null,"abstract":"<div><h3>Background and aims</h3><div>The repertoire of adhesion receptors and ligands is supported by molecules, which are primarily recognized for their roles in immunity. We have recently shown that the co-stimulatory molecule CD40 ligand (CD154/CD40L) is pro-atherogenic and serves as an adhesive ligand for cells expressing the integrin Mac-1 (CD11b/CD18). Here, we studied the role of endothelial CD40L in several models of cardiovascular inflammation.</div></div><div><h3>Methods and results</h3><div>We generated mice with an endothelial cell-specific deficiency of CD40L, <em>Bmx-Cre</em><sup>ERT2+</sup><em>Cd4</em>0lg<sup>fl/fl</sup><em>Apoe</em><sup>−/−</sup> (EC-CD40L-KO), and <em>Cd4</em>0lg<sup>fl/fl</sup><em>Apoe</em><sup>−/−</sup> as controls. In a model of atherosclerosis, EC-CD40L-KO mice developed on average 39.4 ± 14.7 % smaller atherosclerotic plaques after 10 weeks of the conditional genetic deficiency compared to controls. Plaques from EC-CD40L-KO mice contained less macrophages, lipids and more collagen. In intravital microscopy of inflamed mesenteric venules, leukocyte adhesion was reduced 3.1-fold in EC-CD40L-KO mice with a similar effect on slow rolling. In a model of thioglycolate-induced peritonitis, leukocyte migration into the peritoneal cavity was reduced by 38.2 ± 16.2 % in EC-CD40L-KO mice compared to controls after 72 h. Furthermore, 7 days after a permanent surgical ligation of the Left Anterior Descending (LAD) coronary artery, significantly fewer Mac-1-expressing neutrophils and macrophages were detected in the infarcted myocardium in the absence of endothelial CD40L.</div></div><div><h3>Conclusions</h3><div>In this functional validation study, we demonstrate that endothelial cell-expressed CD40L serves as an adhesion molecule in different models of acute inflammation in the aortic, peritoneal, mesenteric, and coronary vasculature. CD40L may therefore represent a promising therapeutic target at the interface of adaptive immunity and myeloid inflammation.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120517"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614804","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}
Pub Date : 2025-12-01Epub Date: 2025-10-31DOI: 10.1016/j.atherosclerosis.2025.120559
Sae Young Jae , Dong-Hyuk Cho , Setor K. Kunutsor , Jimi Choi , Barry A. Franklin , Jun Gyo Gwon
Background and aims
Sex differences have been suggested in the association between baseline physical activity (PA) and cardiovascular outcomes, with women potentially benefiting more. This study evaluated sex differences in survival benefits of changes in moderate-to-vigorous physical activity (MVPA) before and after acute coronary syndrome (ACS).
Methods
We analyzed 30,840 patients with an ACS diagnosis (mean age 60 years; men: 25,069, women: 5771) from the National Health Insurance Service. Changes in MVPA before and after ACS were self-reported and categorized as persistently inactive, MVPA initiation, MVPA cessation, or MVPA continuation. Outcomes included all-cause and cardiovascular disease (CVD) mortality.
Results
Over a median follow-up of 5.8 years, 1349 CVD deaths and 4379 all-cause deaths occurred. MVPA initiation was associated with reduced all-cause mortality in men (Hazard Ratio [HR] = 0.77, 95 % Confidence Interval [CI] 0.64–0.93) and women (HR = 0.57, 95 % CI 0.42–0.79). MVPA continuation was associated with reduced all-cause mortality in men and women: (HR = 0.74, 95 % CI 0.63–0.88) and (HR = 0.58, 95 % CI 0.44–0.77). For CVD mortality, MVPA initiation yielded HRs of 0.84 (95 % CI 0.59–1.19) in men and 0.53 (95 % CI 0.31–0.91) in women; MVPA continuation rendered HRs of 0.71 (95 % CI 0.51–0.99) in men and 0.46 (95 % CI 0.29–0.75) in women. Interaction analyses did not suggest significant sex differences in these associations.
Conclusions
Initiating or continuing MVPA post-ACS diagnosis is associated with a lower risk of all-cause and CVD mortality, with comparable benefits in men and women; this challenging the notion that women derive greater PA-induced mortality reductions than their male counterparts.
背景和目的基线体力活动（PA）与心血管结果之间存在性别差异，女性可能受益更多。本研究评估了急性冠脉综合征（ACS）前后中高强度体力活动（MVPA）变化对生存益处的性别差异。方法我们分析了来自国民健康保险服务的30840例ACS诊断患者（平均年龄60岁，男性：25,069，女性：5771）。ACS前后MVPA的变化是自我报告的，并分类为持续不活跃、MVPA启动、MVPA停止或MVPA持续。结果包括全因和心血管疾病（CVD）死亡率。结果在中位5.8年的随访中，发生了1349例心血管疾病死亡和4379例全因死亡。MVPA启动与男性和女性全因死亡率降低相关（风险比[HR] = 0.77, 95%可信区间[CI] 0.64-0.93） （HR = 0.57, 95%可信区间[CI] 0.42-0.79）。MVPA的延续与男性和女性全因死亡率降低相关：（HR = 0.74, 95% CI 0.63-0.88）和（HR = 0.58, 95% CI 0.44-0.77）。对于心血管疾病死亡率，MVPA启动的男性hr为0.84 (95% CI 0.59-1.19)，女性hr为0.53 (95% CI 0.31-0.91)；MVPA的延续使得男性的hr为0.71 (95% CI 0.51-0.99)，女性的hr为0.46 （95% CI 0.29-0.75）。相互作用分析并未显示这些关联存在显著的性别差异。结论：acs诊断后开始或继续MVPA与全因和CVD死亡风险较低相关，男性和女性的获益相当；这挑战了女性比男性更能降低pa导致的死亡率的观念。
{"title":"Sex differences in mortality associated with physical activity before and after acute coronary syndrome","authors":"Sae Young Jae , Dong-Hyuk Cho , Setor K. Kunutsor , Jimi Choi , Barry A. Franklin , Jun Gyo Gwon","doi":"10.1016/j.atherosclerosis.2025.120559","DOIUrl":"10.1016/j.atherosclerosis.2025.120559","url":null,"abstract":"<div><h3>Background and aims</h3><div>Sex differences have been suggested in the association between baseline physical activity (PA) and cardiovascular outcomes, with women potentially benefiting more. This study evaluated sex differences in survival benefits of changes in moderate-to-vigorous physical activity (MVPA) before and after acute coronary syndrome (ACS).</div></div><div><h3>Methods</h3><div>We analyzed 30,840 patients with an ACS diagnosis (mean age 60 years; men: 25,069, women: 5771) from the National Health Insurance Service. Changes in MVPA before and after ACS were self-reported and categorized as persistently inactive, MVPA initiation, MVPA cessation, or MVPA continuation. Outcomes included all-cause and cardiovascular disease (CVD) mortality.</div></div><div><h3>Results</h3><div>Over a median follow-up of 5.8 years, 1349 CVD deaths and 4379 all-cause deaths occurred. MVPA initiation was associated with reduced all-cause mortality in men (Hazard Ratio [HR] = 0.77, 95 % Confidence Interval [CI] 0.64–0.93) and women (HR = 0.57, 95 % CI 0.42–0.79). MVPA continuation was associated with reduced all-cause mortality in men and women: (HR = 0.74, 95 % CI 0.63–0.88) and (HR = 0.58, 95 % CI 0.44–0.77). For CVD mortality, MVPA initiation yielded HRs of 0.84 (95 % CI 0.59–1.19) in men and 0.53 (95 % CI 0.31–0.91) in women; MVPA continuation rendered HRs of 0.71 (95 % CI 0.51–0.99) in men and 0.46 (95 % CI 0.29–0.75) in women. Interaction analyses did not suggest significant sex differences in these associations.</div></div><div><h3>Conclusions</h3><div>Initiating or continuing MVPA post-ACS diagnosis is associated with a lower risk of all-cause and CVD mortality, with comparable benefits in men and women; this challenging the notion that women derive greater PA-induced mortality reductions than their male counterparts.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120559"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463693","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}
Pub Date : 2025-12-01Epub Date: 2025-10-31DOI: 10.1016/j.atherosclerosis.2025.120558
Guoxia Shi , Ziquan Jiang , Zhuo Du , Sibo Sun , Dongxu Huang , Pingping Wan , Shuang Li , Manyu Du , Qiuying Yan , Bo Yu , Caiying Tang , Ping Sun , Jiannan Dai
Background and aims
Cigarette smoking is a well-established risk factor for vascular injury. However, the effects of nicotine alone remain poorly understood. This study aimed to investigate whether nicotine regulates endothelial nitric oxide synthase (eNOS) expression, thereby contributing to vascular endothelial injury, and to elucidate the critical involvement of N6-Methyladenosine (m6A) modification in this process.
Methods
Mice were exposed to 12 weeks of nicotine exposure, to examine its impact on vascular endothelial injury. Human coronary artery endothelial cells were stimulated with nicotine in vitro, and qRT-PCR and MeRIP-qPCR were performed to measure eNOS expression and its m6A modification levels, respectively. RNA pull-down assays were used to identify eNOS mRNA-interacting proteins, and an endothelial-specific methyltransferase-like protein 3 (Mettl3) knockout model and eNOS recombinant adenovirus were utilized to validate the role of eNOS m6A modification in nicotine-induced endothelial injury.
Results
Nicotine stimulation induced vascular endothelial injury by activating endothelial cells, thereby increasing their permeability and migration capacity through suppressing eNOS expression. These pathological changes were alleviated in both eNOS-overexpressing and endothelial-specific Mettl3 knockout mice. Mechanistically, nicotine increased the m6A modification of eNOS through METTL3. METTL3 then interacted with the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which led to mRNA degradation and reduced protein levels via the m6A-dependent pathway.
Conclusions
We propose a novel mechanism by which nicotine promotes vascular endothelial injury via METTL3/YTHDF2-mediated m6A modification of eNOS in endothelial cells. This study offers a new insights for the formation of vascular endothelial injury.
{"title":"Nicotine induces m6A-modified eNOS dysregulation to aggravate endothelial injury in male mice","authors":"Guoxia Shi , Ziquan Jiang , Zhuo Du , Sibo Sun , Dongxu Huang , Pingping Wan , Shuang Li , Manyu Du , Qiuying Yan , Bo Yu , Caiying Tang , Ping Sun , Jiannan Dai","doi":"10.1016/j.atherosclerosis.2025.120558","DOIUrl":"10.1016/j.atherosclerosis.2025.120558","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cigarette smoking is a well-established risk factor for vascular injury. However, the effects of nicotine alone remain poorly understood. This study aimed to investigate whether nicotine regulates endothelial nitric oxide synthase (<em>eNOS</em>) expression, thereby contributing to vascular endothelial injury, and to elucidate the critical involvement of N6-Methyladenosine (m6A) modification in this process.</div></div><div><h3>Methods</h3><div>Mice were exposed to 12 weeks of nicotine exposure, to examine its impact on vascular endothelial injury. Human coronary artery endothelial cells were stimulated with nicotine in vitro, and qRT-PCR and MeRIP-qPCR were performed to measure eNOS expression and its m6A modification levels, respectively. RNA pull-down assays were used to identify eNOS mRNA-interacting proteins, and an endothelial-specific methyltransferase-like protein 3 (Mettl3) knockout model and eNOS recombinant adenovirus were utilized to validate the role of eNOS m6A modification in nicotine-induced endothelial injury.</div></div><div><h3>Results</h3><div>Nicotine stimulation induced vascular endothelial injury by activating endothelial cells, thereby increasing their permeability and migration capacity through suppressing <em>eNOS</em> expression. These pathological changes were alleviated in both <em>eNOS</em>-overexpressing and endothelial-specific <em>Mettl3</em> knockout mice. Mechanistically, nicotine increased the m6A modification of <em>eNOS</em> through METTL3. METTL3 then interacted with the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which led to mRNA degradation and reduced protein levels via the m6A-dependent pathway.</div></div><div><h3>Conclusions</h3><div>We propose a novel mechanism by which nicotine promotes vascular endothelial injury via METTL3/YTHDF2-mediated m6A modification of <em>eNOS</em> in endothelial cells. This study offers a new insights for the formation of vascular endothelial injury.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120558"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450718","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}
Pub Date : 2025-12-01Epub Date: 2025-11-08DOI: 10.1016/j.atherosclerosis.2025.120571
Giuseppina Novo , Luca Arcari , Cristina Madaudo , Antonio Greco , Ilaria Ragnatela , Damiano D'Alessandro , Daniela Di Lisi , Beatrice Musumeci , Giulia Manguso , Luca Cacciotti , Emanuele Barbato , Alfredo Ruggero Galassi , Thomas Stiermaier , Ingo Eitel , Natale Daniele Brunetti , Ivan Nunez Gil , Francesco Santoro
Background and aims
Takotsubo Syndrome (TTS) is a transient left ventricular systolic dysfunction that mimics acute coronary syndrome (ACS) with unclear pathophysiology. This study aims to evaluate blood cell subtypes in TTS and ACS on admission and their impact on outcome.
Methods
Admission hemograms of 466 consecutive TTS patients from the German Italian Spanish (GEIST) registry were recorded and, after propensity matching, compared with admission hemograms of 280 ACS patients. Hemogram parameters, including neutrophil lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR), were recorded. The primary endpoint was long-term all-cause mortality; the secondary endpoint was in-hospital complications (hemodynamic or electrical instability).
Results
Higher monocyte levels and lower LMR were found in TTS compared with ACS patients (0.63 ± 0.3 vs 0.51 ± 0.24 103/μL, p < 0.001; 2.7 (IQR 1.8–3.9) vs 3.2 (IQR 2.2–4.4), p < 0.01). One hundred thirty-three out of 466 (28.5 %) TTS patients experienced in-hospital complications. In multivariate analysis, LVEF (OR 0.92, 95 %CI 0.90–0.95, p < 0.001), physical triggers (OR 2.59, 95 %CI 1.47–4.55, p < 0.01), and NLR (OR 1.06, 95 %CI 1.03–1.09, p < 0.001) were independently associated with in-hospital complications. At multivariate analysis, including age, gender, physical trigger, admission LVEF, hemoglobin levels and NLR (model 1) or LMR (model 2), NLR (OR 1.02, 95 %CI 1.01–1.03, p < 0.01) or LMR (OR = 0.89, 95 %CI 0.81–0.99, p < 0.04) were independent predictors of long-term mortality. NLR levels above the median value and LMR levels below the median value were associated with poor survival in TTS patients (log-rank p < 0.01).
Conclusions
TTS is featured by higher levels of monocytes and lower LMR than ACS during hospital admission. NLR and LMR are independent predictors of long-term mortality in TTS.
背景和目的：Takotsubo综合征（TTS）是一种类似急性冠状动脉综合征（ACS）的短暂性左心室收缩功能障碍，病理生理不明确。本研究旨在评估TTS和ACS患者入院时的血细胞亚型及其对预后的影响。方法：记录来自德国、意大利、西班牙（GEIST）注册中心的466例连续TTS患者的入院血象，并与280例ACS患者的入院血象进行倾向匹配比较。记录血象参数，包括中性粒细胞淋巴细胞比率（NLR）和淋巴细胞单核细胞比率（LMR）。主要终点是长期全因死亡率；次要终点是院内并发症（血流动力学或电不稳定）。结果：TTS患者单核细胞水平高于ACS(0.63±0.3 vs 0.51±0.24 103/μL, p)， LMR低于ACS（0.51±0.24 103/μL, p）。结论：TTS患者入院时单核细胞水平高于ACS， LMR低于ACS。NLR和LMR是TTS患者长期死亡率的独立预测因子。
{"title":"Blood Cell Subtype patterns in Takotsubo Syndrome and acute coronary syndrome: analysis from the GEIST registry","authors":"Giuseppina Novo , Luca Arcari , Cristina Madaudo , Antonio Greco , Ilaria Ragnatela , Damiano D'Alessandro , Daniela Di Lisi , Beatrice Musumeci , Giulia Manguso , Luca Cacciotti , Emanuele Barbato , Alfredo Ruggero Galassi , Thomas Stiermaier , Ingo Eitel , Natale Daniele Brunetti , Ivan Nunez Gil , Francesco Santoro","doi":"10.1016/j.atherosclerosis.2025.120571","DOIUrl":"10.1016/j.atherosclerosis.2025.120571","url":null,"abstract":"<div><h3>Background and aims</h3><div>Takotsubo Syndrome (TTS) is a transient left ventricular systolic dysfunction that mimics acute coronary syndrome (ACS) with unclear pathophysiology. This study aims to evaluate blood cell subtypes in TTS and ACS on admission and their impact on outcome.</div></div><div><h3>Methods</h3><div>Admission hemograms of 466 consecutive TTS patients from the German Italian Spanish (GEIST) registry were recorded and, after propensity matching, compared with admission hemograms of 280 ACS patients. Hemogram parameters, including neutrophil lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR), were recorded. The primary endpoint was long-term all-cause mortality; the secondary endpoint was in-hospital complications (hemodynamic or electrical instability).</div></div><div><h3>Results</h3><div>Higher monocyte levels and lower LMR were found in TTS compared with ACS patients (0.63 ± 0.3 vs 0.51 ± 0.24 10<strong><sup>3</sup></strong>/μL, p < 0.001; 2.7 (IQR 1.8–3.9) vs 3.2 (IQR 2.2–4.4), p < 0.01). One hundred thirty-three out of 466 (28.5 %) TTS patients experienced in-hospital complications. In multivariate analysis, LVEF (OR 0.92, 95 %CI 0.90–0.95, p < 0.001), physical triggers (OR 2.59, 95 %CI 1.47–4.55, p < 0.01), and NLR (OR 1.06, 95 %CI 1.03–1.09, p < 0.001) were independently associated with in-hospital complications. At multivariate analysis, including age, gender, physical trigger, admission LVEF, hemoglobin levels and NLR (model 1) or LMR (model 2), NLR (OR 1.02, 95 %CI 1.01–1.03, p < 0.01) or LMR (OR = 0.89, 95 %CI 0.81–0.99, p < 0.04) were independent predictors of long-term mortality. NLR levels above the median value and LMR levels below the median value were associated with poor survival in TTS patients (log-rank p < 0.01).</div></div><div><h3>Conclusions</h3><div>TTS is featured by higher levels of monocytes and lower LMR than ACS during hospital admission. NLR and LMR are independent predictors of long-term mortality in TTS.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120571"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511505","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}
Pub Date : 2025-12-01Epub Date: 2025-10-17DOI: 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.
{"title":"Metabolomics of aortic valve stenosis: Are aortic valve stenosis and sclerosis different diseases?","authors":"Elisa Koljonen , Olli Kärkkäinen , Retu Haikonen , Anu Turpeinen , Juha Hartikainen , Jaana Rysä","doi":"10.1016/j.atherosclerosis.2025.120549","DOIUrl":"10.1016/j.atherosclerosis.2025.120549","url":null,"abstract":"<div><h3>Background and aims</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120549"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360499","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}
Pub Date : 2025-12-01Epub Date: 2025-10-15DOI: 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.
{"title":"Alamandine suppresses vascular calcification through inhibition of ferroptosis","authors":"Zhanpeng Wen , Jingbin Guo , Keyang Li , Xingchen Zhou , Zirong Lan , An Chen , Li Feng , Jianyun Yan","doi":"10.1016/j.atherosclerosis.2025.120548","DOIUrl":"10.1016/j.atherosclerosis.2025.120548","url":null,"abstract":"<div><h3>Background and aims</h3><div>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.</div></div><div><h3>Methods</h3><div>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 D<sub>3</sub>. Alizarin red staining and calcium content assay were used to assess calcification. Western blot analysis was used to examine the protein expression levels.</div></div><div><h3>Results</h3><div>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 <em>ex vivo</em>, and inhibited mouse aortic calcification <em>in vivo</em>. 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.</div></div><div><h3>Conclusions</h3><div>our study for the first time revealed that ALA/MrgD suppressed VSMC calcification under osteogenic condition and aortic calcification in VitD<sub>3</sub>-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.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120548"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145323126","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}
Pub Date : 2025-12-01Epub Date: 2025-11-06DOI: 10.1016/j.atherosclerosis.2025.120573
Stine Gunnersen , Julián Albarrán-Juárez , Lise Filt Jensen , Laura Alonso-Herranz , Jeong Tangkjær Shim , Charlotte B. Sørensen , Jacob F. Bentzon
Background and aims
Recruitment of fibrous cap smooth muscle cells (SMCs) is critical for stabilizing atherosclerotic plaques and preventing rupture. This study investigated the importance of the myeloid differentiation primary response protein 88 (Myd88) gene, encoding an adaptor protein essential for cytokine and pattern-recognition receptor signalling, for cap SMC recruitment during murine atherosclerosis.
Methods
Myd88 knockdown was performed in cultured rat aortic SMCs, and the effects of inflammatory stimulation were assessed. SMC-specific Myd88 knockout mice were generated using Cre/lox recombination, and atherosclerosis was induced by proprotein convertase subtilisin/kexin type 9 (PCSK9) gene transfer followed by a high-fat diet for 12 or 20 weeks. Plaque size, composition, and fibrous cap SMC accumulation were analysed by immunofluorescence and in situ hybridization.
Results
Myd88 knockdown preserved contractile gene expression under inflammatory stimulation, reduced SMC proliferation and migration, and enhanced contraction of SMC-infiltrated collagen gels. In hypercholesterolemic mice, SMC-specific Myd88 deficiency did not significantly alter plaque size in the aortic root but reduced the number of cap SMCs in advanced lesions at 20 weeks and in the most atherosclerosis-susceptible aortic sinus at 12 weeks. Other plaque features, including macrophages, necrotic core size, and collagen content, were not significantly affected. Notably, Myd88 deletion preserved the contractile phenotype of medial SMCs beneath plaques, suggesting that impaired phenotypic modulation contributed to reduced cap SMC recruitment.
Conclusions
MyD88-dependent signalling promotes medial SMC phenotypic modulation and the recruitment of cap SMCs, linking inflammatory signalling to protective fibrous cap formation in murine atherosclerosis.
{"title":"MyD88-dependent signalling promotes the recruitment of fibrous cap smooth muscle cells in murine atherosclerosis","authors":"Stine Gunnersen , Julián Albarrán-Juárez , Lise Filt Jensen , Laura Alonso-Herranz , Jeong Tangkjær Shim , Charlotte B. Sørensen , Jacob F. Bentzon","doi":"10.1016/j.atherosclerosis.2025.120573","DOIUrl":"10.1016/j.atherosclerosis.2025.120573","url":null,"abstract":"<div><h3>Background and aims</h3><div>Recruitment of fibrous cap smooth muscle cells (SMCs) is critical for stabilizing atherosclerotic plaques and preventing rupture. This study investigated the importance of the myeloid differentiation primary response protein 88 (<em>Myd88</em>) gene, encoding an adaptor protein essential for cytokine and pattern-recognition receptor signalling, for cap SMC recruitment during murine atherosclerosis.</div></div><div><h3>Methods</h3><div><em>Myd88</em> knockdown was performed in cultured rat aortic SMCs, and the effects of inflammatory stimulation were assessed. SMC-specific <em>Myd88</em> knockout mice were generated using Cre/lox recombination, and atherosclerosis was induced by proprotein convertase subtilisin/kexin type 9 (PCSK9) gene transfer followed by a high-fat diet for 12 or 20 weeks. Plaque size, composition, and fibrous cap SMC accumulation were analysed by immunofluorescence and in situ hybridization.</div></div><div><h3>Results</h3><div><em>Myd88</em> knockdown preserved contractile gene expression under inflammatory stimulation, reduced SMC proliferation and migration, and enhanced contraction of SMC-infiltrated collagen gels. In hypercholesterolemic mice, SMC-specific <em>Myd88</em> deficiency did not significantly alter plaque size in the aortic root but reduced the number of cap SMCs in advanced lesions at 20 weeks and in the most atherosclerosis-susceptible aortic sinus at 12 weeks. Other plaque features, including macrophages, necrotic core size, and collagen content, were not significantly affected. Notably, <em>Myd88</em> deletion preserved the contractile phenotype of medial SMCs beneath plaques, suggesting that impaired phenotypic modulation contributed to reduced cap SMC recruitment.</div></div><div><h3>Conclusions</h3><div>MyD88-dependent signalling promotes medial SMC phenotypic modulation and the recruitment of cap SMCs, linking inflammatory signalling to protective fibrous cap formation in murine atherosclerosis.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120573"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501892","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}
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