Pub Date : 2025-11-19DOI: 10.1016/j.atherosclerosis.2025.120589
Mathilde Mura , Amandine Thomas , Michèle Weiss-Gayet , Laurie Josset , Chantal L. Rytz , Emeraude Rivoire , Marie Chambion-Diaz , Nellie Della-Schiava , Matthieu Arsicot , Anne Long , Bénédicte Chazaud , Antoine Millon , Vincent Pialoux
Background and aims
Up to 25 % of ischemic strokes are the consequence of a ruptured vulnerable carotid atherosclerotic plaque. Circulating pro-inflammatory classical and intermediate monocytes are known predictors of ischemic events and cardiovascular death. Interestingly, chronic physical activity can decrease inflammation, and is thereby associated with a reduction in pro-inflammatory monocytes.
Methods
In a randomized, controlled and monocentric trial, we recruited 56 patients (71 ± 8 years old) with asymptomatic carotid stenosis of ≥50 % who were ineligible for carotid endarterectomy. Blood analyses were completed to assess the phenotype of monocytes, as well as a multiplex assay and colorimetric assay for cytokines concentration and redox status, respectively.
Results
Classical monocyte count was increased in the control arm, while it remained stable in response to the physical activity intervention (−5215 ± 2307, [95 %CI -9878 to −551], p = 0.03). Moreover, the expression of most of pro-inflammatory cytokines was down-regulated in response to the physical activity intervention, while it was increased in the control arm.
Conclusions
The stabilization of classical monocytes and down-regulation of the expression of pro-inflammatory cytokines in response to the physical activity intervention suggest that chronic physical activity alleviate the pro-inflammatory state, and might thereby reduce carotid plaque vulnerability and the subsequent risk of ischemic events. These results highlight that home-based physical activity intervention is an efficient clinical care that induce biological changes in carotid atherosclerotic patients.
背景和目的高达25%的缺血性中风是易损性颈动脉粥样硬化斑块破裂的结果。循环促炎经典单核细胞和中间单核细胞是已知的缺血性事件和心血管死亡的预测因子。有趣的是，慢性体育活动可以减少炎症，因此与促炎单核细胞的减少有关。方法在一项随机、对照、单中心试验中，我们招募了56例（71±8岁）无症状颈动脉狭窄≥50%且不适合行颈动脉内膜切除术的患者。完成血液分析以评估单核细胞的表型，以及细胞因子浓度和氧化还原状态的多重测定和比色测定。结果对照组的经典单核细胞计数增加，而体力活动干预组的经典单核细胞计数保持稳定（- 5215±2307,[95% CI -9878 ~ - 551], p = 0.03）。此外，大多数促炎细胞因子的表达在体育活动干预下下调，而在对照组中则升高。结论运动干预对颈动脉经典单核细胞的稳定和促炎细胞因子表达的下调表明，慢性运动可以缓解颈动脉促炎状态，从而降低颈动脉斑块易损性和随后发生缺血事件的风险。这些结果强调，以家庭为基础的身体活动干预是一种有效的临床护理，可诱导颈动脉粥样硬化患者的生物学变化。
{"title":"Physical activity in carotid atherosclerotic patients blunts monocyte pro-inflammatory processes: a randomised controlled trial","authors":"Mathilde Mura , Amandine Thomas , Michèle Weiss-Gayet , Laurie Josset , Chantal L. Rytz , Emeraude Rivoire , Marie Chambion-Diaz , Nellie Della-Schiava , Matthieu Arsicot , Anne Long , Bénédicte Chazaud , Antoine Millon , Vincent Pialoux","doi":"10.1016/j.atherosclerosis.2025.120589","DOIUrl":"10.1016/j.atherosclerosis.2025.120589","url":null,"abstract":"<div><h3>Background and aims</h3><div>Up to 25 % of ischemic strokes are the consequence of a ruptured vulnerable carotid atherosclerotic plaque. Circulating pro-inflammatory classical and intermediate monocytes are known predictors of ischemic events and cardiovascular death. Interestingly, chronic physical activity can decrease inflammation, and is thereby associated with a reduction in pro-inflammatory monocytes.</div></div><div><h3>Methods</h3><div>In a randomized, controlled and monocentric trial, we recruited 56 patients (71 ± 8 years old) with asymptomatic carotid stenosis of ≥50 % who were ineligible for carotid endarterectomy. Blood analyses were completed to assess the phenotype of monocytes, as well as a multiplex assay and colorimetric assay for cytokines concentration and redox status, respectively.</div></div><div><h3>Results</h3><div>Classical monocyte count was increased in the control arm, while it remained stable in response to the physical activity intervention (−5215 ± 2307, [95 %CI -9878 to −551], p = 0.03). Moreover, the expression of most of pro-inflammatory cytokines was down-regulated in response to the physical activity intervention, while it was increased in the control arm.</div></div><div><h3>Conclusions</h3><div>The stabilization of classical monocytes and down-regulation of the expression of pro-inflammatory cytokines in response to the physical activity intervention suggest that chronic physical activity alleviate the pro-inflammatory state, and might thereby reduce carotid plaque vulnerability and the subsequent risk of ischemic events. These results highlight that home-based physical activity intervention is an efficient clinical care that induce biological changes in carotid atherosclerotic patients.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120589"},"PeriodicalIF":5.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555130","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 : 2025-11-19DOI: 10.1016/j.atherosclerosis.2025.120584
Elizabeth M. Semler , Danielle L. Michell , Philip J. Kingsley , Marisol A. Ramirez , Clark Massick , Mark Castleberry , Amanda C. Doran , John J. Carr , Lawrence Marnett , Quanhu Sheng , MacRae F. Linton , Kasey C. Vickers
Background and aims
Epitranscriptomic RNA modifications play a crucial role in RNA processing, stability, and function. Small non-coding RNAs (sRNAs), such as tRNA-derived fragments (tDRs), likely inherit modifications from parent transcripts. Evidence supports that cell-free sRNA modifications regulate gene expression, modulate immune responses, and are closely linked to the pathogenesis of immune related diseases. Given that high-density lipoproteins (HDL) transport sRNAs from parent transcripts with extensive modifications, we predicted that many HDL-sRNAs harbor immune regulatory modifications that contribute to HDL functionality.
Methods
To assess HDL-sRNA modifications in atherosclerotic cardiovascular disease (ASCVD), total RNAs were isolated from HDL of healthy subjects and those with advanced ASCVD. HDL-sRNA modifications were quantified using liquid chromatography-tandem mass-spectrometry (LC-MS/MS), AlkB-facilitated RNA (de)Methylation Sequencing (ARM-seq), and qPCR.
Results
LC-MS/MS revealed a significant increase in the relative levels of modified nucleosides on HDL in ASCVD and healthy individuals. ARM-seq identified candidate tDR-ArgACG fragments harboring 1-methyladenosine (m1A) modifications that were enriched in ASCVD subjects compared to controls. Bulk mRNA sequencing showed significant macrophage gene expression changes in response to ASCVD-HDL-sRNA uptake, including TMEM123, a transmembrane protein linked to immune cell migration and adhesion. Reconstituted HDL loaded with m1A-tDR-ArgACG were also found to significantly increase TMEM123 expression in primary macrophages, and blocking m1A using an anti-m1A neutralizing antibody attenuated this effect.
Conclusions
Results support a model in which HDL-delivered m1A-HDL-tDRs regulate immune signaling, macrophage activation, and pro-inflammatory sub-phenotypes within the atherosclerotic lesion.
{"title":"Post-transcriptional modifications on tRNA fragments confer functional changes to high-density lipoproteins in atherosclerosis","authors":"Elizabeth M. Semler , Danielle L. Michell , Philip J. Kingsley , Marisol A. Ramirez , Clark Massick , Mark Castleberry , Amanda C. Doran , John J. Carr , Lawrence Marnett , Quanhu Sheng , MacRae F. Linton , Kasey C. Vickers","doi":"10.1016/j.atherosclerosis.2025.120584","DOIUrl":"10.1016/j.atherosclerosis.2025.120584","url":null,"abstract":"<div><h3>Background and aims</h3><div>Epitranscriptomic RNA modifications play a crucial role in RNA processing, stability, and function. Small non-coding RNAs (sRNAs), such as tRNA-derived fragments (tDRs), likely inherit modifications from parent transcripts. Evidence supports that cell-free sRNA modifications regulate gene expression, modulate immune responses, and are closely linked to the pathogenesis of immune related diseases. Given that high-density lipoproteins (HDL) transport sRNAs from parent transcripts with extensive modifications, we predicted that many HDL-sRNAs harbor immune regulatory modifications that contribute to HDL functionality.</div></div><div><h3>Methods</h3><div>To assess HDL-sRNA modifications in atherosclerotic cardiovascular disease (ASCVD), total RNAs were isolated from HDL of healthy subjects and those with advanced ASCVD. HDL-sRNA modifications were quantified using liquid chromatography-tandem mass-spectrometry (LC-MS/MS), AlkB-facilitated RNA (de)Methylation Sequencing (ARM-seq), and qPCR.</div></div><div><h3>Results</h3><div>LC-MS/MS revealed a significant increase in the relative levels of modified nucleosides on HDL in ASCVD and healthy individuals. ARM-seq identified candidate tDR-ArgACG fragments harboring 1-methyladenosine (m<sup>1</sup>A) modifications that were enriched in ASCVD subjects compared to controls. Bulk mRNA sequencing showed significant macrophage gene expression changes in response to ASCVD-HDL-sRNA uptake, including <em>TMEM123</em>, a transmembrane protein linked to immune cell migration and adhesion. Reconstituted HDL loaded with m<sup>1</sup>A-tDR-ArgACG were also found to significantly increase <em>TMEM123</em> expression in primary macrophages, and blocking m<sup>1</sup>A using an anti-m<sup>1</sup>A neutralizing antibody attenuated this effect.</div></div><div><h3>Conclusions</h3><div>Results support a model in which HDL-delivered m<sup>1</sup>A-HDL-tDRs regulate immune signaling, macrophage activation, and pro-inflammatory sub-phenotypes within the atherosclerotic lesion.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120584"},"PeriodicalIF":5.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733055","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 : 2025-11-19DOI: 10.1016/j.atherosclerosis.2025.120590
G.B. John Mancini , Arnold Ryomoto , Isabelle Ruel , Iulia Iatan , Frederick J. Raal , Raul D. Santos , Ana Paula Marte , Robert A. Hegele , Brooke A. Kennedy , Liam R. Brunham , Daniel Gaudet , Miriam Larouche , Diane Brisson , Willemijn Schonck , Laurens F. Reeskamp , Jacques Genest , Canadian Homozygous Familial Hypercholesterolemia Registry and the Homozygous Familial Hypercholesterolemia International Clinical Collaboration
Background and aims
Diagnosis of Homozygous Familial Hypercholesterolaemia (HoFH) relies on untreated low-density lipoprotein-cholesterol (LDL-C) which is often unknown. We determine whether untreated LDL-C can be imputed from treated LDL-C in HoFH.
Methods
Two groups with HoFH were identified: Group 1 (n = 193) from Canada, Brazil and South Africa; Group 2 (n = 206) from the HoFH International Clinical Collaboration. Pre- and post-treatment LDL-C and lipid lowering therapy (LLT) intensity from Group 1 were used to develop a regression model and applied to treated LDL-C in Group 2 to impute pre-treatment LDL-C. The same process was performed in reverse. A final imputation model was created from combining both groups.
Results
There was a curvilinear relationship between the expected and observed % lowering of LDL-C on LLT (r = 0.3923, p < 0.0001, Standard Error [SE] = 23 %). Using this relationship, LDL-C was imputed from treated values and showed significant correlation with pre-treatment LDL-C (r = 0.71, p < 0.001; mean values 13.4 ± 4.7 [Standard Deviation] and 13.6 ± 7.3 mmol/L, respectively, ns). Concordance between actual and imputed values ≥ 10 or <10 mmol/L was 80 %. Whereas 36 % of patients had treated LDL-C ≥ 10 mmol/L, 64 % had treated or imputed pre-treatment LDL-C ≥ 10 mmol/L.
Conclusions
In HoFH, the response to LLT can be quantified and used to impute untreated LDL-C from treated LDL-C. Imputation may augment awareness of possible HoFH in treated subjects lacking records of untreated LDL-C.
{"title":"Imputation of untreated LDL-C in treated subjects with homozygous familial hypercholesterolaemia: An international collaboration","authors":"G.B. John Mancini , Arnold Ryomoto , Isabelle Ruel , Iulia Iatan , Frederick J. Raal , Raul D. Santos , Ana Paula Marte , Robert A. Hegele , Brooke A. Kennedy , Liam R. Brunham , Daniel Gaudet , Miriam Larouche , Diane Brisson , Willemijn Schonck , Laurens F. Reeskamp , Jacques Genest , Canadian Homozygous Familial Hypercholesterolemia Registry and the Homozygous Familial Hypercholesterolemia International Clinical Collaboration","doi":"10.1016/j.atherosclerosis.2025.120590","DOIUrl":"10.1016/j.atherosclerosis.2025.120590","url":null,"abstract":"<div><h3>Background and aims</h3><div>Diagnosis of Homozygous Familial Hypercholesterolaemia (HoFH) relies on untreated low-density lipoprotein-cholesterol (LDL-C) which is often unknown. We determine whether untreated LDL-C can be imputed from treated LDL-C in HoFH.</div></div><div><h3>Methods</h3><div>Two groups with HoFH were identified: Group 1 (n = 193) from Canada, Brazil and South Africa; Group 2 (n = 206) from the HoFH International Clinical Collaboration. Pre- and post-treatment LDL-C and lipid lowering therapy (LLT) intensity from Group 1 were used to develop a regression model and applied to treated LDL-C in Group 2 to impute pre-treatment LDL-C. The same process was performed in reverse. A final imputation model was created from combining both groups.</div></div><div><h3>Results</h3><div>There was a curvilinear relationship between the expected and observed % lowering of LDL-C on LLT (r = 0.3923, p < 0.0001, Standard Error [SE] = 23 %). Using this relationship, LDL-C was imputed from treated values and showed significant correlation with pre-treatment LDL-C (r = 0.71, p < 0.001; mean values 13.4 ± 4.7 [Standard Deviation] and 13.6 ± 7.3 mmol/L, respectively, ns). Concordance between actual and imputed values ≥ 10 or <10 mmol/L was 80 %. Whereas 36 % of patients had treated LDL-C ≥ 10 mmol/L, 64 % had treated or imputed pre-treatment LDL-C ≥ 10 mmol/L.</div></div><div><h3>Conclusions</h3><div>In HoFH, the response to LLT can be quantified and used to impute untreated LDL-C from treated LDL-C. Imputation may augment awareness of possible HoFH in treated subjects lacking records of untreated LDL-C.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120590"},"PeriodicalIF":5.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578372","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 : 2025-11-09DOI: 10.1016/j.atherosclerosis.2025.120563
Jaime Mazón-Ruiz , David Arroyo , Marina de Cos , María Riestra , Emilio Sánchez-Alvarez , Paula González Bores , Jose Luis Hernández , Pablo Corral
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death among patients with chronic kidney disease (CKD), who face significantly higher rates of cardiovascular events compared to the general population. Despite this increased risk, CKD patients are still undertreated with lipid-lowering therapies (LLT) for both primary and secondary prevention. This systematic review highlights the ongoing underrepresentation of CKD patients in past and current randomized clinical trials (RCTs) evaluating LLT, pointing to evidence gaps in managing dyslipidemia for this high-risk group. Due to the limited inclusion of CKD populations in clinical studies, current treatment approaches often rely on extrapolated data from the general population, raising concerns about their relevance and effectiveness in this subgroup. The results underscore the importance of conducting dedicated trials focused on specific lipid management strategies to reduce cardiovascular risk in this vulnerable population better.
{"title":"Lipid lowering therapies in chronic kidney disease: A call to action","authors":"Jaime Mazón-Ruiz , David Arroyo , Marina de Cos , María Riestra , Emilio Sánchez-Alvarez , Paula González Bores , Jose Luis Hernández , Pablo Corral","doi":"10.1016/j.atherosclerosis.2025.120563","DOIUrl":"10.1016/j.atherosclerosis.2025.120563","url":null,"abstract":"<div><div>Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death among patients with chronic kidney disease (CKD), who face significantly higher rates of cardiovascular events compared to the general population. Despite this increased risk, CKD patients are still undertreated with lipid-lowering therapies (LLT) for both primary and secondary prevention. This systematic review highlights the ongoing underrepresentation of CKD patients in past and current randomized clinical trials (RCTs) evaluating LLT, pointing to evidence gaps in managing dyslipidemia for this high-risk group. Due to the limited inclusion of CKD populations in clinical studies, current treatment approaches often rely on extrapolated data from the general population, raising concerns about their relevance and effectiveness in this subgroup. The results underscore the importance of conducting dedicated trials focused on specific lipid management strategies to reduce cardiovascular risk in this vulnerable population better.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120563"},"PeriodicalIF":5.7,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568859","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 : 2025-11-08DOI: 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":"2025-11-08","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 : 2025-11-06DOI: 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":"2025-11-06","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}
Pub Date : 2025-11-04DOI: 10.1016/j.atherosclerosis.2025.120569
Manon Levy , Alexandre Janin , Oriane Marmontel , Anthony Fourier , Séverine Nony , Antoine Rimbert , Bertrand Cariou , Sylvie Villar-Fimbel , Sybil Charrière , Philippe Moulin , Mathilde Di Filippo
Background and aims
Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family.
Methods
Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRSLDL-C). The effect of the variant was investigated by assessing the ANGPTL3 protein secretion in vitro. A replication study was performed in the UK-biobank.
Results
All 8 HBL subjects had PRSLDL-C below the first decile, supporting a polygenic HBL. Six family members also carrying the p.H343R variant (n = 6) had a significantly lower LDL-C than the polygenic members non-carriers of the p.H343R (n = 2) (p=0.012). In vitro, p.H343R variant significantly decreased ANGPTL3 concentration in the medium (−82 %, p=0.029) and the ratio of secretion (0.28 ± 0.06 vs. 1.00 ± 0.30 p=0.029, n = 3) compared to the wild-type. The synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition was confirmed in the UK biobank.
Conclusions
This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition.
背景和目的原发性低脂蛋白血症（HBL）主要是由于多基因起源或单基因疾病，包括APOB的功能丧失（LOF）变异，更不常见的是血管生成素样3基因（ANGPTL3）。一个新的不确定意义杂合变异（VUS）， p.H343R错义变异ANGPTL3与HBL共分离。本研究的目的是在体外评估这种变异的功能，并确定其在该家族中的因果关系。方法采用ldl - c专用多基因风险评分（PRSLDL-C），对先证进行定向新一代测序，评估单基因和多基因起源。通过测定体外ANGPTL3蛋白分泌来研究该变异的影响。在UK-biobank中进行了重复研究。结果8例HBL患者PRSLDL-C均低于前十分位数，支持多基因HBL。6名携带p.H343R变异的家庭成员（n = 6）的LDL-C显著低于非p.H343R变异的多基因成员（n = 2） （p=0.012）。与野生型相比，p.H343R变异显著降低了ANGPTL3在体外的浓度（- 82%,p=0.029）和分泌量（0.28±0.06 vs. 1.00±0.30 p=0.029, n = 3）。p.H343R ANGPTL3变异与多基因HBL易感性的协同组合在英国生物银行得到证实。结论本研究表明新型ANGPTL3-p。H343R变异体在体外减少ANGPTL3分泌，现在可以认为是LOF变异体。该家族的脂质表型是p.H343R ANGPTL3变异和多基因HBL易感性的协同组合的结果。
{"title":"Synergic combination of the monogenic ANGPTL3 p.H343R variant and a polygenic predisposition in a family with hypobetalipoproteinemia","authors":"Manon Levy , Alexandre Janin , Oriane Marmontel , Anthony Fourier , Séverine Nony , Antoine Rimbert , Bertrand Cariou , Sylvie Villar-Fimbel , Sybil Charrière , Philippe Moulin , Mathilde Di Filippo","doi":"10.1016/j.atherosclerosis.2025.120569","DOIUrl":"10.1016/j.atherosclerosis.2025.120569","url":null,"abstract":"<div><h3>Background and aims</h3><div>Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in <em>APOB</em>, much less frequently <em>Angiopoietin-like 3</em> gene (<em>ANGPTL3</em>). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in <em>ANGPTL3</em> cosegregated with HBL in a family. The aim of the present study was to assess <em>in vitro</em> the functionality of this variant and to establish its causality in this family.</div></div><div><h3>Methods</h3><div>Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRS<sub>LDL-C</sub>). The effect of the variant was investigated by assessing the ANGPTL3 protein secretion <em>in vitro</em>. A replication study was performed in the UK-biobank.</div></div><div><h3>Results</h3><div>All 8 HBL subjects had PRS<sub>LDL-C</sub> below the first decile, supporting a polygenic HBL. Six family members also carrying the p.H343R variant (n = 6) had a significantly lower LDL-C than the polygenic members non-carriers of the p.H343R (n = 2) (<em>p=0.012</em>). <em>In vitro,</em> p.H343R variant significantly decreased ANGPTL3 concentration in the medium (−82 %, <em>p=0.029</em>) and the ratio of secretion (0.28 ± 0.06 vs. 1.00 ± 0.30 <em>p=0.029</em>, n = 3) compared to the wild-type. The synergistic combination of the p.H343R <em>ANGPTL3</em> variant and a polygenic HBL predisposition was confirmed in the UK biobank.</div></div><div><h3>Conclusions</h3><div>This study shows that the novel <em>ANGPTL3</em>-p.H343R variant decreases ANGPTL3 secretion <em>in vitro</em> and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R <em>ANGPTL3</em> variant and a polygenic HBL predisposition.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120569"},"PeriodicalIF":5.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463694","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 : 2025-11-02DOI: 10.1016/j.atherosclerosis.2025.120561
DuJiang Yang, GuoYou Wang
This letter provides a critical perspective on the recent study by Laukkanen et al. examining the association between high-density lipoprotein cholesterol (HDL-C) levels and coronary atherosclerosis. While the authors' demonstration of a nonlinear, inverse relationship is noteworthy, our analysis highlights fundamental limitations in interpreting HDL-C as a causal risk factor. We emphasize that the observed plateau effect at higher HDL-C levels aligns with evidence from Mendelian randomization studies and failed trials of HDL-C-raising therapies, which collectively question the “more is better” paradigm. Substantial methodological limitations are addressed, including the reliance on static HDL-C measurements that fail to capture HDL's functional heterogeneity. Furthermore, we discuss how residual confounding by metabolic syndrome components may partly explain the association at low HDL-C levels. We conclude that the field must transition from quantifying HDL cholesterol to assessing its functionality, as this shift is essential for advancing our understanding of HDL's role in cardiovascular disease.
{"title":"Beyond quantity: The nonlinear association between HDL cholesterol and coronary atherosclerosis","authors":"DuJiang Yang, GuoYou Wang","doi":"10.1016/j.atherosclerosis.2025.120561","DOIUrl":"10.1016/j.atherosclerosis.2025.120561","url":null,"abstract":"<div><div>This letter provides a critical perspective on the recent study by Laukkanen et al. examining the association between high-density lipoprotein cholesterol (HDL-C) levels and coronary atherosclerosis. While the authors' demonstration of a nonlinear, inverse relationship is noteworthy, our analysis highlights fundamental limitations in interpreting HDL-C as a causal risk factor. We emphasize that the observed plateau effect at higher HDL-C levels aligns with evidence from Mendelian randomization studies and failed trials of HDL-C-raising therapies, which collectively question the “more is better” paradigm. Substantial methodological limitations are addressed, including the reliance on static HDL-C measurements that fail to capture HDL's functional heterogeneity. Furthermore, we discuss how residual confounding by metabolic syndrome components may partly explain the association at low HDL-C levels. We conclude that the field must transition from quantifying HDL cholesterol to assessing its functionality, as this shift is essential for advancing our understanding of HDL's role in cardiovascular disease.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120561"},"PeriodicalIF":5.7,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450737","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}
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, risk stratification remains an unmet need. In 2025, the European Atherosclerosis Society (EAS) introduced a novel metabolic disorder staging system. This study aimed at assessing the prevalence and prognostic value of metabolic disorders as defined by the EAS 2025 consensus statement in a cohort of SLE patients.
Methods
Consecutive SLE patients who underwent a comprehensive cardiovascular risk assessment between January 2014 and January 2024 at our center were retrospectively included. Data were leveraged to classify patients at baseline according to the EAS 2025 clinical staging system (metabolically healthy, stage 1, stage 2). The risk of incident ASCVD event was compared across these subgroups using log-rank tests and bivariate cox proportional hazard ratio models.
Results
A total of 214 SLE patients were included (91 % females, age 44 ± 13 years, SLE duration 13 ± 9 years). Patients were grouped as follows: metabolically healthy (N = 121, 56 %), stage 1 (N = 53, 25 %), stage 2 (N = 40, 19 %). After a median follow-up of 8 [3–10] years, 10 patients (5 %) had an incident ASCVD event. On survival analysis, EAS-based metabolic stages were significantly associated with incident ASCVD events (Log-rank p = 0.001) and remained so after adjustment on age, sex, SLE duration, disease activity index and damage index.
Conclusions
The 2025 EAS clinical staging system has independent prognostic value in predicting incident cardiovascular events in SLE.
{"title":"Assessment of the 2025 EAS clinical staging system for cardiometabolic disorders in systemic lupus erythematosus","authors":"Lévi-Dan Azoulay , Nadjia Kachenoura , Samia Boussouar , Etienne Charpentier , Nicoletta Pasi , Lan-Anh Nguyen , Nassim Ait Abdallah , Micheline Pha , Miguel Hié , Alexis Mathian , Matthias Papo , Fleur Cohen-Aubart , Julien Haroche , Zahir Amoura , Alban Redheuil","doi":"10.1016/j.atherosclerosis.2025.120562","DOIUrl":"10.1016/j.atherosclerosis.2025.120562","url":null,"abstract":"<div><h3>Background and aims</h3><div>Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, risk stratification remains an unmet need. In 2025, the European Atherosclerosis Society (EAS) introduced a novel metabolic disorder staging system. This study aimed at assessing the prevalence and prognostic value of metabolic disorders as defined by the EAS 2025 consensus statement in a cohort of SLE patients.</div></div><div><h3>Methods</h3><div>Consecutive SLE patients who underwent a comprehensive cardiovascular risk assessment between January 2014 and January 2024 at our center were retrospectively included. Data were leveraged to classify patients at baseline according to the EAS 2025 clinical staging system (metabolically healthy, stage 1, stage 2). The risk of incident ASCVD event was compared across these subgroups using log-rank tests and bivariate cox proportional hazard ratio models.</div></div><div><h3>Results</h3><div>A total of 214 SLE patients were included (91 % females, age 44 ± 13 years, SLE duration 13 ± 9 years). Patients were grouped as follows: metabolically healthy (N = 121, 56 %), stage 1 (N = 53, 25 %), stage 2 (N = 40, 19 %). After a median follow-up of 8 [3–10] years, 10 patients (5 %) had an incident ASCVD event. On survival analysis, EAS-based metabolic stages were significantly associated with incident ASCVD events (Log-rank <em>p</em> = 0.001) and remained so after adjustment on age, sex, SLE duration, disease activity index and damage index.</div></div><div><h3>Conclusions</h3><div>The 2025 EAS clinical staging system has independent prognostic value in predicting incident cardiovascular events in SLE.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"411 ","pages":"Article 120562"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457479","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 : 2025-11-01DOI: 10.1016/j.atherosclerosis.2025.120459
Xiaoqian Li , Wentao Wang , Shizhong Wang , Xiaolu Li , Bei Zhang , Beulah Evangelin Stephen , Tao Yu , Jianxun Wang , Yanyan Yang
The diagnosis and management of aortic dissection (AD), a critical cardiovascular disease (CVD), remains significant challenges in clinical practice. PIWI-interacting RNAs (piRNAs), a newly discovered class of non-coding small RNAs, play key regulatory role in various CVDs. However, the mechanism of their action in AD remains unclear. Through sequencing of aortic clinical samples from AD patients, we identified piRNA-0228 (piR-0228) as the most significantly downregulated piRNA in AD patients compared with healthy populations. Overexpression and knockdown of piR-0228 in mouse monocyte macrophage leukemia cells (RAW264.7) and aortic vascular smooth muscle cells (VSMCs) revealed that piR-0228 regulates key cytopathic processes, primarily involving inflammatory response and necrosis, driven by stimulator of interferon genes (STING) pathway. Bioinformatics analysis and validation demonstrated that receptor-interacting protein kinase 1 (RIPK1) was a direct target gene of piR-0228, confirmed by both in vivo and in vitro studies. Finally, in an AD animal model, we observed that piR-0228 agomir significantly reduced mortality, morbidity, inflammation and vascular remodeling, demonstrating the effective therapy of piR-0228 agomir in reversing the disease's pathological progression. Therefore, our findings establish piR-0228 as a promising therapeutic target for AD and provide valuable insights for the future development of clinical treatment strategies for this condition.
主动脉夹层（aortic夹层，AD）是一种严重的心血管疾病（CVD），其诊断和治疗在临床实践中仍然是一个重大挑战。piwi相互作用rna （pirna）是一类新发现的非编码小rna，在多种心血管疾病中起着关键的调控作用。然而，它们在AD中的作用机制尚不清楚。通过对AD患者主动脉临床样本的测序，我们发现与健康人群相比，AD患者中piRNA-0228 （piRNA-0228）是下调最显著的piRNA。piR-0228在小鼠单核巨噬细胞白血病细胞（RAW264.7）和主动脉血管平滑肌细胞（VSMCs）中的过表达和敲低表明，piR-0228在干扰素刺激因子（STING）通路驱动下调节关键的细胞病变过程，主要涉及炎症反应和坏死。生物信息学分析和验证表明，受体相互作用蛋白激酶1 （receptor-interacting protein kinase 1, RIPK1）是piR-0228的直接靶基因，体内和体外研究均证实了这一点。最后，在AD动物模型中，我们观察到piR-0228 agomir显著降低了死亡率、发病率、炎症和血管重构，证明了piR-0228 agomir在逆转疾病病理进展方面的有效治疗。因此，我们的研究结果确定了piR-0228是一个有希望的AD治疗靶点，并为该疾病的临床治疗策略的未来发展提供了有价值的见解。
{"title":"Role and mechanism of piR-0228 targeting RIPK1 to regulate vascular remodeling and aortic dissection","authors":"Xiaoqian Li , Wentao Wang , Shizhong Wang , Xiaolu Li , Bei Zhang , Beulah Evangelin Stephen , Tao Yu , Jianxun Wang , Yanyan Yang","doi":"10.1016/j.atherosclerosis.2025.120459","DOIUrl":"10.1016/j.atherosclerosis.2025.120459","url":null,"abstract":"<div><div>The diagnosis and management of aortic dissection (AD), a critical cardiovascular disease (CVD), remains significant challenges in clinical practice. PIWI-interacting RNAs (piRNAs), a newly discovered class of non-coding small RNAs, play key regulatory role in various CVDs. However, the mechanism of their action in AD remains unclear. Through sequencing of aortic clinical samples from AD patients, we identified piRNA-0228 (piR-0228) as the most significantly downregulated piRNA in AD patients compared with healthy populations. Overexpression and knockdown of piR-0228 in mouse monocyte macrophage leukemia cells (RAW264.7) and aortic vascular smooth muscle cells (VSMCs) revealed that piR-0228 regulates key cytopathic processes, primarily involving inflammatory response and necrosis, driven by stimulator of interferon genes (STING) pathway. Bioinformatics analysis and validation demonstrated that receptor-interacting protein kinase 1 (RIPK1) was a direct target gene of piR-0228, confirmed by both <em>in vivo</em> and <em>in vitro</em> studies. Finally, in an AD animal model, we observed that piR-0228 agomir significantly reduced mortality, morbidity, inflammation and vascular remodeling, demonstrating the effective therapy of piR-0228 agomir in reversing the disease's pathological progression. Therefore, our findings establish piR-0228 as a promising therapeutic target for AD and provide valuable insights for the future development of clinical treatment strategies for this condition.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"410 ","pages":"Article 120459"},"PeriodicalIF":5.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697501","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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