Pub Date : 2025-12-18DOI: 10.1016/j.atherosclerosis.2025.120622
Stefano Manzini , Alice Colombo , Elsa Franchi, Giada Poletti, Marco Busnelli , Giulia Chiesa
Background and aims
With the aim of increasing our knowledge on the mutual interplay between miRNAs and lipids, which is still limited, a novel approach integrating miRNomic and lipidomic data gathered from mice with specific lipid traits was explored.
Methods
miRNomic and lipidomic analyses were previously performed in wild-type, Pcsk9 and Ldlr knockout mice fed normal laboratory diet or Western diet. miRNAs were high-throughput sequenced in liver, aorta, white adipose tissue, duodenum, jejunum, ileum and brain, whereas lipids were quantified by high-throughput mass-spectrometry in liver, aorta and plasma. miRNA expression levels were tested for correlation with each lipid measurement in different samples, and correlations were selected based on strict stringency criteria. In vitro experiments with miRNA mimics or inhibitors in mouse hepatoma cells were performed to validate correlations.
Results
Correlation analyses between miRNA expression levels and lipid concentrations in the different experimental conditions led to the selection of miRNAs potentially playing a major role in the regulation of lipid levels. Correlations mainly clustered in liver. Among selected miRNAs, some were already known to be related to lipid metabolism (miR-33, miR-210 and miR-21a) whereas others, including miR-431–5p, miR-434–3p, miR-434–5p and miR-677–5p had never been associated to lipidome perturbations before. In vitro experiments allowed to highlight a possible role of miR-431–5p andmiR-677–5p in the modulation of cholesterol and triglyceride concentrations.
Conclusions
This study bridged miRNomic and lipidomic data in relevant mouse models, allowing to highlight novel miRNAs potentially playing a role in the modulation of lipid levels.
{"title":"Integrated high-throughput miRNomics and lipidomics in mice with altered lipoprotein metabolism","authors":"Stefano Manzini , Alice Colombo , Elsa Franchi, Giada Poletti, Marco Busnelli , Giulia Chiesa","doi":"10.1016/j.atherosclerosis.2025.120622","DOIUrl":"10.1016/j.atherosclerosis.2025.120622","url":null,"abstract":"<div><h3>Background and aims</h3><div>With the aim of increasing our knowledge on the mutual interplay between miRNAs and lipids, which is still limited, a novel approach integrating miRNomic and lipidomic data gathered from mice with specific lipid traits was explored.</div></div><div><h3>Methods</h3><div>miRNomic and lipidomic analyses were previously performed in wild-type, Pcsk9 and Ldlr knockout mice fed normal laboratory diet or Western diet. miRNAs were high-throughput sequenced in liver, aorta, white adipose tissue, duodenum, jejunum, ileum and brain, whereas lipids were quantified by high-throughput mass-spectrometry in liver, aorta and plasma. miRNA expression levels were tested for correlation with each lipid measurement in different samples, and correlations were selected based on strict stringency criteria. <em>In vitro</em> experiments with miRNA mimics or inhibitors in mouse hepatoma cells were performed to validate correlations.</div></div><div><h3>Results</h3><div>Correlation analyses between miRNA expression levels and lipid concentrations in the different experimental conditions led to the selection of miRNAs potentially playing a major role in the regulation of lipid levels. Correlations mainly clustered in liver. Among selected miRNAs, some were already known to be related to lipid metabolism (miR-33, miR-210 and miR-21a) whereas others, including miR-431–5p, miR-434–3p, miR-434–5p and miR-677–5p had never been associated to lipidome perturbations before. <em>In vitro</em> experiments allowed to highlight a possible role of miR-431–5p andmiR-677–5p in the modulation of cholesterol and triglyceride concentrations.</div></div><div><h3>Conclusions</h3><div>This study bridged miRNomic and lipidomic data in relevant mouse models, allowing to highlight novel miRNAs potentially playing a role in the modulation of lipid levels.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120622"},"PeriodicalIF":5.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028201","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 : 2025-12-13DOI: 10.1016/j.atherosclerosis.2025.120574
Raffaele Piccolo , Angelo Laino , Antonio Pio Vitale , Anna Franzone , Daniele Giacoppo , Eduardo Bossone , Davide Capodanno , Giovanni Esposito
<div><h3>Background and aims</h3><div>C-reactive protein (CRP) has been associated with an increased risk of cardiovascular events in the setting of primary prevention; however, its risk association in secondary cardiovascular prevention remains unclear. We evaluated the prognostic role of CRP across the spectrum of patients with established atherosclerotic cardiovascular disease (ASCVD).</div></div><div><h3>Methods</h3><div>We performed a systematic review and meta-analysis by screening Embase and MEDLINE databases from inception through November 2024. We included studies reporting adjusted risk associations between CRP and cardiovascular events among patients with ASCVD. Two reviewers extracted data and assessed the risk of bias. Data were extracted using an adaption of the Checklist for Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies (CHARMS-PF). The primary analysis was conducted using a random-effects model within a Bayesian framework. Risk of bias was assessed using the Quality in Prognosis Studies tool. The GRADE (grading of recommendations assessment, development, and evaluation) approach was used to rate the certainty in the prognostic yield of CRP. The principal outcome was major adverse cardiovascular events. Additional outcomes included: all-cause death, myocardial infarction, cardiovascular death, and cerebrovascular events.</div></div><div><h3>Results</h3><div>We included 27 studies, published from 2002 to 2024, and involving 193,761 participants (65,204 or 34 % females). Higher CRP levels were defined accordingly to the included studies and ranged from 0.5 to 5.0 mg/L 26 studies adjusted for conventional cardiovascular risk factors (age, sex, smoking, diabetes, dyslipidemia, hypertension); one omitted smoking status but included the others. Higher CRP levels were associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR, 1.55, 95 % credible intervals, CrI, 1.39 to 1.73; tau = 0.24, 95 %CrI 0.14 to 0.34; high certainty), all-cause death (aHR 1.92, 95 %CrI 1.52 to 2.41; tau = 0.30, 95 %CrI 0.14 to 0.51; moderate certainty), myocardial infarction (aHR 1.40, 95 %CrI 1.22 to 1.63; tau = 0.066, 95 %CrI 0.001 to 0.28; moderate certainty), and cardiovascular death (aHR 1.35, 95 %CrI 0.98 to 1.84; tau = 0.20, 95 %CrI 0.001 to 0.54; low certainty) after adjustment for traditional risk factors. The association between CRP and the risk of cerebrovascular events was inconclusive (aHR 1.52, 95 %CrI 0.69 to 3.32; tau = 0.33 95 %CrI 0.001 to 0.85; very low certainty). Dose-response Bayesian meta-analysis showed a non-linear association between CRP and major cardiovascular events, with levels between 2 and 4 mg/L being associated with clinically relevant higher risk. A similar dose-response relationship was observed also for all-cause death.</div></div><div><h3>Conclusions</h3><div>Among patients with ASCVD, elevated levels of CRP are associated with an increase
{"title":"Association between C-reactive protein and adverse events in secondary cardiovascular prevention: A systematic review and meta-analysis of prognostic factor studies","authors":"Raffaele Piccolo , Angelo Laino , Antonio Pio Vitale , Anna Franzone , Daniele Giacoppo , Eduardo Bossone , Davide Capodanno , Giovanni Esposito","doi":"10.1016/j.atherosclerosis.2025.120574","DOIUrl":"10.1016/j.atherosclerosis.2025.120574","url":null,"abstract":"<div><h3>Background and aims</h3><div>C-reactive protein (CRP) has been associated with an increased risk of cardiovascular events in the setting of primary prevention; however, its risk association in secondary cardiovascular prevention remains unclear. We evaluated the prognostic role of CRP across the spectrum of patients with established atherosclerotic cardiovascular disease (ASCVD).</div></div><div><h3>Methods</h3><div>We performed a systematic review and meta-analysis by screening Embase and MEDLINE databases from inception through November 2024. We included studies reporting adjusted risk associations between CRP and cardiovascular events among patients with ASCVD. Two reviewers extracted data and assessed the risk of bias. Data were extracted using an adaption of the Checklist for Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies (CHARMS-PF). The primary analysis was conducted using a random-effects model within a Bayesian framework. Risk of bias was assessed using the Quality in Prognosis Studies tool. The GRADE (grading of recommendations assessment, development, and evaluation) approach was used to rate the certainty in the prognostic yield of CRP. The principal outcome was major adverse cardiovascular events. Additional outcomes included: all-cause death, myocardial infarction, cardiovascular death, and cerebrovascular events.</div></div><div><h3>Results</h3><div>We included 27 studies, published from 2002 to 2024, and involving 193,761 participants (65,204 or 34 % females). Higher CRP levels were defined accordingly to the included studies and ranged from 0.5 to 5.0 mg/L 26 studies adjusted for conventional cardiovascular risk factors (age, sex, smoking, diabetes, dyslipidemia, hypertension); one omitted smoking status but included the others. Higher CRP levels were associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR, 1.55, 95 % credible intervals, CrI, 1.39 to 1.73; tau = 0.24, 95 %CrI 0.14 to 0.34; high certainty), all-cause death (aHR 1.92, 95 %CrI 1.52 to 2.41; tau = 0.30, 95 %CrI 0.14 to 0.51; moderate certainty), myocardial infarction (aHR 1.40, 95 %CrI 1.22 to 1.63; tau = 0.066, 95 %CrI 0.001 to 0.28; moderate certainty), and cardiovascular death (aHR 1.35, 95 %CrI 0.98 to 1.84; tau = 0.20, 95 %CrI 0.001 to 0.54; low certainty) after adjustment for traditional risk factors. The association between CRP and the risk of cerebrovascular events was inconclusive (aHR 1.52, 95 %CrI 0.69 to 3.32; tau = 0.33 95 %CrI 0.001 to 0.85; very low certainty). Dose-response Bayesian meta-analysis showed a non-linear association between CRP and major cardiovascular events, with levels between 2 and 4 mg/L being associated with clinically relevant higher risk. A similar dose-response relationship was observed also for all-cause death.</div></div><div><h3>Conclusions</h3><div>Among patients with ASCVD, elevated levels of CRP are associated with an increase","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120574"},"PeriodicalIF":5.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761933","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 : 2025-12-04DOI: 10.1016/j.atherosclerosis.2025.120608
Ya Li , Julian Leberzammer , Xavier Blanchet , Rundan Duan , Michael Lacy , Vasiliki Triantafyllidou , Veit Eckardt , Eva Briem , Anna Simone Jung , Rui Su , Joel Guerra , Yvonne Jansen , Michael Hristov , Wolfgang Enard , Jürgen Bernhagen , Christian Weber , Dorothee Atzler , Alexander Bartelt , Yvonne Döring , Donato Santovito , Philipp von Hundelshausen
Background and aims
Atherosclerosis is a chronic immunometabolic disease driven by lipid accumulation and immune cell infiltration. Macrophages and T cells play key roles throughout plaque development. Galectin-1 (Gal-1), a glycan-binding protein, modulates immune functions in these cells and has been reported to attenuate atherosclerosis, though its mechanisms remain incompletely understood. Here, we investigated the effects of Gal-1 on macrophages and T cells during plaque formation.
Methods
Effects of Gal-1 on atherosclerosis, macrophages and T cells during lesion formation were studied in Apoe−/− mice treated with recombinant Gal-1. Complementary mouse peritoneal foam cell and in vitro macrophage and T cell culture experiments were performed to study T cell differentiation, macrophage function, polarization and energy metabolism. The impact of Gal-1 on human macrophages was further evaluated in endarterectomy specimens.
Results
Gal-1 treatment reduced lesion size and increased circulating IL-10 levels, inversely correlating with plaque burden. Unexpectedly, IL-10 neutralization also mitigated atherosclerosis, indicating that its action is at least partially IL-10–independent. In plaques, Gal-1 promoted anti-inflammatory macrophage phenotypes, mirrored by a quiescent metabolic and anti-inflammatory profile in foamy macrophages ex vivo. The use of the Gal-1E71Q variant revealed that these effects were only partly dependent on glycan binding. Beyond IL-10, Gal-1 reshaped cytokine profiles by increasing IL-17, IL-22, and IL-23, consistent with a macrophage-driven regulatory Th17 response, alongside higher frequencies of IL-10–producing and regulatory T cells.
Conclusion
Gal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways.
{"title":"Galectin-1 induces macrophage immunometabolic reprogramming, modulates T cell immunity and attenuates atherosclerotic plaque formation","authors":"Ya Li , Julian Leberzammer , Xavier Blanchet , Rundan Duan , Michael Lacy , Vasiliki Triantafyllidou , Veit Eckardt , Eva Briem , Anna Simone Jung , Rui Su , Joel Guerra , Yvonne Jansen , Michael Hristov , Wolfgang Enard , Jürgen Bernhagen , Christian Weber , Dorothee Atzler , Alexander Bartelt , Yvonne Döring , Donato Santovito , Philipp von Hundelshausen","doi":"10.1016/j.atherosclerosis.2025.120608","DOIUrl":"10.1016/j.atherosclerosis.2025.120608","url":null,"abstract":"<div><h3>Background and aims</h3><div>Atherosclerosis is a chronic immunometabolic disease driven by lipid accumulation and immune cell infiltration. Macrophages and T cells play key roles throughout plaque development. Galectin-1 (Gal-1), a glycan-binding protein, modulates immune functions in these cells and has been reported to attenuate atherosclerosis, though its mechanisms remain incompletely understood. Here, we investigated the effects of Gal-1 on macrophages and T cells during plaque formation.</div></div><div><h3>Methods</h3><div>Effects of Gal-1 on atherosclerosis, macrophages and T cells during lesion formation were studied in <em>Apoe</em><sup>−/−</sup> mice treated with recombinant Gal-1. Complementary mouse peritoneal foam cell and in vitro macrophage and T cell culture experiments were performed to study T cell differentiation, macrophage function, polarization and energy metabolism. The impact of Gal-1 on human macrophages was further evaluated in endarterectomy specimens.</div></div><div><h3>Results</h3><div>Gal-1 treatment reduced lesion size and increased circulating IL-10 levels, inversely correlating with plaque burden. Unexpectedly, IL-10 neutralization also mitigated atherosclerosis, indicating that its action is at least partially IL-10–independent. In plaques, Gal-1 promoted anti-inflammatory macrophage phenotypes, mirrored by a quiescent metabolic and anti-inflammatory profile in foamy macrophages ex vivo. The use of the Gal-1<sup>E71Q</sup> variant revealed that these effects were only partly dependent on glycan binding. Beyond IL-10, Gal-1 reshaped cytokine profiles by increasing IL-17, IL-22, and IL-23, consistent with a macrophage-driven regulatory Th17 response, alongside higher frequencies of IL-10–producing and regulatory T cells.</div></div><div><h3>Conclusion</h3><div>Gal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120608"},"PeriodicalIF":5.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749705","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 : 2025-12-01DOI: 10.1016/j.atherosclerosis.2025.120541
Jaka Šikonja , Kaja Kobale , Jan Kafol , Barbara Čugalj Kern , Matej Mlinarič , Ana Drole Torkar , Jernej Kovač , Matija Cevc , Zlatko Fras , Tadej Battelino , Urh Grošelj
Background and aims
Cascade familial hypercholesterolemia (FH) screening of parents could reduce the burden cardiovascular disease (CVD) in relatives of index cases by enabling timely diagnosis of FH. Here, we present the positive outcomes of the pilot child-parent cascade screening program in Slovenia.
Methods
One hundred and thirty-eight parents from 123 families of an index child with genetically confirmed FH were randomly included in the pilot child-parent cascade screening program. Index children were identified through the universal FH screening program in preschool children. Genetic testing using Sanger sequencing was performed for cascade screening to detect (likely) pathogenic variants, previously confirmed in the index child.
Results
The success rate of confirming a (likely) pathogenic variant was 77.2 % when the first parent, preferably with higher total cholesterol levels, was tested, and reached 99.1 % when the variant was identified in the first tested parent or when both parents were tested. In the minority of cases (13.8 %), parents had had a clinical diagnosis of FH prior to their child and these had somewhat higher prevalence of CVD compared to parents that were diagnosed after their index child through the pilot program (12.5 % vs. 4.3 %; p = 0.382).
Conclusions
In conclusion, the presented pilot child–parent cascade screening program is feasible in clinical practice and shows a high success rate in identifying parents with FH. Parents diagnosed through the program appeared to have a lower prevalence of CVD. However, larger cohorts are needed to confirm these findings.
{"title":"Child-parent cascade screening for familial hypercholesterolemia in Slovenia: Insights from the pilot program","authors":"Jaka Šikonja , Kaja Kobale , Jan Kafol , Barbara Čugalj Kern , Matej Mlinarič , Ana Drole Torkar , Jernej Kovač , Matija Cevc , Zlatko Fras , Tadej Battelino , Urh Grošelj","doi":"10.1016/j.atherosclerosis.2025.120541","DOIUrl":"10.1016/j.atherosclerosis.2025.120541","url":null,"abstract":"<div><h3>Background and aims</h3><div>Cascade familial hypercholesterolemia (FH) screening of parents could reduce the burden cardiovascular disease (CVD) in relatives of index cases by enabling timely diagnosis of FH. Here, we present the positive outcomes of the pilot child-parent cascade screening program in Slovenia.</div></div><div><h3>Methods</h3><div>One hundred and thirty-eight parents from 123 families of an index child with genetically confirmed FH were randomly included in the pilot child-parent cascade screening program. Index children were identified through the universal FH screening program in preschool children. Genetic testing using Sanger sequencing was performed for cascade screening to detect (likely) pathogenic variants, previously confirmed in the index child.</div></div><div><h3>Results</h3><div>The success rate of confirming a (likely) pathogenic variant was 77.2 % when the first parent, preferably with higher total cholesterol levels, was tested, and reached 99.1 % when the variant was identified in the first tested parent or when both parents were tested. In the minority of cases (13.8 %), parents had had a clinical diagnosis of FH prior to their child and these had somewhat higher prevalence of CVD compared to parents that were diagnosed after their index child through the pilot program (12.5 % vs. 4.3 %; <em>p</em> = 0.382).</div></div><div><h3>Conclusions</h3><div>In conclusion, the presented pilot child–parent cascade screening program is feasible in clinical practice and shows a high success rate in identifying parents with FH. Parents diagnosed through the program appeared to have a lower prevalence of CVD. However, larger cohorts are needed to confirm these findings.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120541"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614637","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 : 2025-12-01DOI: 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 : 2025-12-01DOI: 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 : 2025-12-01DOI: 10.1016/j.atherosclerosis.2025.120547
Fahimeh Varzideh , Pasquale Mone , Urna Kansakar , Stanislovas S. Jankauskas , Gaetano Santulli
{"title":"Cardiac rehab has no gender: The universal power of physical exercise post acute coronary syndrome","authors":"Fahimeh Varzideh , Pasquale Mone , Urna Kansakar , Stanislovas S. Jankauskas , Gaetano Santulli","doi":"10.1016/j.atherosclerosis.2025.120547","DOIUrl":"10.1016/j.atherosclerosis.2025.120547","url":null,"abstract":"","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120547"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614805","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 : 2025-12-01DOI: 10.1016/j.atherosclerosis.2025.120546
Pablo Corral , Maria Gabriela Matta , Nicolás F. Renna , Matias F. Arrupe , Sergio Gimenez , Juan Bautista Soumoulou , Ezequiel Forte , Federico Salazar , Santiago Lynch , Walter Masson , Flavia Salati , Gabriel Waisman , Ezequiel Lerech , Fiorella Tartaglione , Florencia Aranguren , Emiliano Salmeri , Eduardo R. Perna , Aldo Prado , Natalia Nardelli , Gustavo Lavenia , Laura Schreier
Background and aims
Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor. Despite its clinical relevance, data on Lp(a) prevalence and impact in Latin America are limited. We aimed to assess the prevalence of elevated Lp(a) and its association with cardiovascular outcomes in a large, multicenter Argentine registry.
Methods
The GAELp(a) registry included 3000 adults from six Argentine regions. Lp(a) levels were measured using standardized assays; elevated Lp(a) was defined as >50 mg/dL or >125 nmol/L. Clinical, biochemical, and imaging data were collected retrospectively and prospectively. Associations between Lp(a) and major adverse cardiovascular events (MACE) were evaluated with logistic regression in the overall population and stratified by statin use.
Results
Elevated Lp(a) was present in 31.4 % of participants, with no sex difference. It was associated with family history of cardiovascular disease, subclinical atherosclerosis, and familial hypercholesterolemia. Patients with elevated Lp(a) had a higher prevalence of coronary artery disease (18.4 % vs. 12.5 %, p < 0.001), peripheral artery disease (4.8 % vs. 2.5 %, p = 0.001), and MACE (21.3 % vs. 14.8 %, p < 0.001). Elevated Lp(a) independently predicted MACE (OR 1.53, 95 % CI: 1.24–1.90, p < 0.001), with stronger associations in statin-naïve individuals (OR 2.18, 95 % CI: 1.17–4.07). ROC analysis showed modest discrimination (AUC 0.57 in nmol/L, 0.59 in mg/dL).
Conclusions
Elevated Lp(a) is frequent in Argentina and strongly linked to cardiovascular disease and events. Its predictive value appears greater in statin-naïve patients, highlighting its role as a marker of residual risk. These findings support routine Lp(a) measurement in cardiovascular risk assessment, particularly in regions with high ASCVD burden.
{"title":"Lp(a) in Argentina: A multicenter study on prevalence and clinical outcomes","authors":"Pablo Corral , Maria Gabriela Matta , Nicolás F. Renna , Matias F. Arrupe , Sergio Gimenez , Juan Bautista Soumoulou , Ezequiel Forte , Federico Salazar , Santiago Lynch , Walter Masson , Flavia Salati , Gabriel Waisman , Ezequiel Lerech , Fiorella Tartaglione , Florencia Aranguren , Emiliano Salmeri , Eduardo R. Perna , Aldo Prado , Natalia Nardelli , Gustavo Lavenia , Laura Schreier","doi":"10.1016/j.atherosclerosis.2025.120546","DOIUrl":"10.1016/j.atherosclerosis.2025.120546","url":null,"abstract":"<div><h3>Background and aims</h3><div>Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor. Despite its clinical relevance, data on Lp(a) prevalence and impact in Latin America are limited. We aimed to assess the prevalence of elevated Lp(a) and its association with cardiovascular outcomes in a large, multicenter Argentine registry.</div></div><div><h3>Methods</h3><div>The GAELp(a) registry included 3000 adults from six Argentine regions. Lp(a) levels were measured using standardized assays; elevated Lp(a) was defined as >50 mg/dL or >125 nmol/L. Clinical, biochemical, and imaging data were collected retrospectively and prospectively. Associations between Lp(a) and major adverse cardiovascular events (MACE) were evaluated with logistic regression in the overall population and stratified by statin use.</div></div><div><h3>Results</h3><div>Elevated Lp(a) was present in 31.4 % of participants, with no sex difference. It was associated with family history of cardiovascular disease, subclinical atherosclerosis, and familial hypercholesterolemia. Patients with elevated Lp(a) had a higher prevalence of coronary artery disease (18.4 % vs. 12.5 %, p < 0.001), peripheral artery disease (4.8 % vs. 2.5 %, p = 0.001), and MACE (21.3 % vs. 14.8 %, p < 0.001). Elevated Lp(a) independently predicted MACE (OR 1.53, 95 % CI: 1.24–1.90, p < 0.001), with stronger associations in statin-naïve individuals (OR 2.18, 95 % CI: 1.17–4.07). ROC analysis showed modest discrimination (AUC 0.57 in nmol/L, 0.59 in mg/dL).</div></div><div><h3>Conclusions</h3><div>Elevated Lp(a) is frequent in Argentina and strongly linked to cardiovascular disease and events. Its predictive value appears greater in statin-naïve patients, highlighting its role as a marker of residual risk. These findings support routine Lp(a) measurement in cardiovascular risk assessment, particularly in regions with high ASCVD burden.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120546"},"PeriodicalIF":5.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614807","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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