Pub Date : 2025-11-26DOI: 10.1016/j.atherosclerosis.2025.120603
Raymond Noordam , Wenyi Wang , Pavithra Nagarajan , Heming Wang , Michael R. Brown , Amy R. Bentley , Qin Hui , Aldi T. Kraja , John L. Morrison , Jeffrey R. O'Connel , Songmi Lee , Karen Schwander , Traci M. Bartz , Lisa de las Fuentes , Mary F. Feitosa , Xiuqing Guo , Xu Hanfei , Sarah E. Harris , Zhijie Huang , Mart Kals , Diana van Heemst
Background and aims
Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets.
Methods
We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels.
Results
The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature.
Conclusions
Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.
{"title":"Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants","authors":"Raymond Noordam , Wenyi Wang , Pavithra Nagarajan , Heming Wang , Michael R. Brown , Amy R. Bentley , Qin Hui , Aldi T. Kraja , John L. Morrison , Jeffrey R. O'Connel , Songmi Lee , Karen Schwander , Traci M. Bartz , Lisa de las Fuentes , Mary F. Feitosa , Xiuqing Guo , Xu Hanfei , Sarah E. Harris , Zhijie Huang , Mart Kals , Diana van Heemst","doi":"10.1016/j.atherosclerosis.2025.120603","DOIUrl":"10.1016/j.atherosclerosis.2025.120603","url":null,"abstract":"<div><h3>Background and aims</h3><div>Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets.</div></div><div><h3>Methods</h3><div>We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels.</div></div><div><h3>Results</h3><div>The one-degree of freedom variant-sleep interaction test identified 10 novel loci (P<sub>int</sub><5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (P<sub>joint</sub><5.0e-9 in combination with P<sub>int</sub><6.6e-6). Multiple loci, including those mapped to <em>APSH</em> (target for aspartic and succinic acid) and <em>SLC8A1</em> showed biological plausibility and druggability potential based on literature.</div></div><div><h3>Conclusions</h3><div>Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120603"},"PeriodicalIF":5.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653337","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 : 2025-11-26DOI: 10.1016/j.atherosclerosis.2025.120587
Gia V. Da Roza , Lubomira Cermakova , Jeanine Roeters van Lennep , Kirsten B. Holven , Iulia Iatan , Liam R. Brunham
Background and aims
Familial hypercholesterolemia (FH) is a common inherited dyslipidemia, affecting 1 in 311 individuals. In females, lipid profile changes occur during the menopausal transition period, but there is limited research on how menopause affects lipids in females with FH. The aim of this study was to investigate changes in lipid levels and lipid-lowering therapy (LLT) in females with FH before and after menopause.
Methods
We analyzed female patients with definite or probable FH (defined as Dutch Lipid Clinic Network score ≥6) from the British Columbia FH Registry with at least one lipid profile before and after self-reported age of menopause, or the age of 51 years if no self-reported date was available. We compared levels of low-density lipoprotein-cholesterol (LDL-C) and other lipids, as well as use of LLT at these two timepoints.
Results
A total of 93 females with FH were included in the analyses, of which 33 self-reported age at menopause and 60 were estimated at 51 years. LDL-C levels increased by 0.78 mmol/L from pre-to post-menopause (p < .001), representing a 12 % increase, and by 1.05 mmol/L (p = .04), a 17 % increase, in untreated females. The increase in LDL-C was significantly greater in those with a monogenic FH-causing genetic variant compared to those without (1.23 mmol/L vs. 0.39 mmol/L, p = .02). There were also significant increases in the proportion of females treated (10.8 %) and in treatment potency during the menopause transition period, as well as in other lipids including total cholesterol, triglycerides and non-high-density lipoprotein cholesterol.
Conclusion
LDL-C increases significantly during the menopausal transition period in females with FH, which contributes to an elevated cardiovascular risk post-menopause. These findings underscore the need for close monitoring and treatment of lipid levels during the menopausal transition in females with FH.
背景和目的家族性高胆固醇血症（FH）是一种常见的遗传性血脂异常，每311人中就有1人患病。在女性中，脂质谱变化发生在绝经过渡期，但关于绝经如何影响FH女性的脂质研究有限。本研究的目的是探讨女性FH患者绝经前后血脂水平的变化和降脂治疗（LLT）。方法：我们分析了不列颠哥伦比亚省FH登记处确诊或可能患有FH（定义为荷兰脂质临床网络评分≥6）的女性患者，这些患者在自我报告绝经年龄之前和之后至少有一种脂质谱，如果没有自我报告的日期，则年龄为51岁。我们比较了这两个时间点的低密度脂蛋白-胆固醇（LDL-C）和其他脂质的水平，以及LLT的使用。结果共有93例女性FH纳入分析，其中33例自报绝经年龄，60例估计为51岁。绝经前至绝经后LDL-C水平增加了0.78 mmol/L (p < .001)，增加了12%，未经治疗的女性LDL-C水平增加了1.05 mmol/L (p = .04)，增加了17%。携带单基因fh基因变异的患者LDL-C升高明显高于未携带单基因fh基因变异的患者（1.23 mmol/L vs. 0.39 mmol/L, p = 0.02）。接受治疗的女性比例（10.8%）和绝经过渡期的治疗效果也有显著增加，其他脂质包括总胆固醇、甘油三酯和非高密度脂蛋白胆固醇也有显著增加。结论FH患者ldl - c在绝经过渡期显著升高，与绝经后心血管风险升高有关。这些发现强调了在女性FH绝经过渡期间密切监测和治疗脂质水平的必要性。
{"title":"Lipid changes in females with familial hypercholesterolemia during the menopausal transition period","authors":"Gia V. Da Roza , Lubomira Cermakova , Jeanine Roeters van Lennep , Kirsten B. Holven , Iulia Iatan , Liam R. Brunham","doi":"10.1016/j.atherosclerosis.2025.120587","DOIUrl":"10.1016/j.atherosclerosis.2025.120587","url":null,"abstract":"<div><h3>Background and aims</h3><div>Familial hypercholesterolemia (FH) is a common inherited dyslipidemia, affecting 1 in 311 individuals. In females, lipid profile changes occur during the menopausal transition period, but there is limited research on how menopause affects lipids in females with FH. The aim of this study was to investigate changes in lipid levels and lipid-lowering therapy (LLT) in females with FH before and after menopause.</div></div><div><h3>Methods</h3><div>We analyzed female patients with definite or probable FH (defined as Dutch Lipid Clinic Network score ≥6) from the British Columbia FH Registry with at least one lipid profile before and after self-reported age of menopause, or the age of 51 years if no self-reported date was available. We compared levels of low-density lipoprotein-cholesterol (LDL-C) and other lipids, as well as use of LLT at these two timepoints.</div></div><div><h3>Results</h3><div>A total of 93 females with FH were included in the analyses, of which 33 self-reported age at menopause and 60 were estimated at 51 years. LDL-C levels increased by 0.78 mmol/L from pre-to post-menopause (<em>p</em> < .001), representing a 12 % increase, and by 1.05 mmol/L (<em>p</em> = .04), a 17 % increase, in untreated females. The increase in LDL-C was significantly greater in those with a monogenic FH-causing genetic variant compared to those without (1.23 mmol/L vs. 0.39 mmol/L, p = .02). There were also significant increases in the proportion of females treated (10.8 %) and in treatment potency during the menopause transition period, as well as in other lipids including total cholesterol, triglycerides and non-high-density lipoprotein cholesterol.</div></div><div><h3>Conclusion</h3><div>LDL-C increases significantly during the menopausal transition period in females with FH, which contributes to an elevated cardiovascular risk post-menopause. These findings underscore the need for close monitoring and treatment of lipid levels during the menopausal transition in females with FH.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120587"},"PeriodicalIF":5.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145697911","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 : 2025-11-26DOI: 10.1016/j.atherosclerosis.2025.120594
Yu Fu , Yu-Xin Hua , Ya-Li Zhang , Chen-Yang Zhang , Hai-Yun Li , Ivan Melnikov , Zufar A. Gabbasov , Yi Wu , En-Qi Liu , Shang-Rong Ji
Background and aims
C-reactive protein (CRP) is a liver-derived soluble marker of inflammation whose levels can predict the risk of atherosclerotic cardiovascular disease and therapeutic efficacy of statins. Intriguingly, however, CRP is not considered as a mediator of atherosclerosis based primarily on studies examining chow diet (CD)-fed mice. The aim of this study is to investigate the role of CRP in high-fat diet (HFD)-induced atherosclerosis, which models a more prevalent scenario in the real world, and to clarify its impact on Atorvastatin treatment.
Methods
Apoe-sufficient or -deficient mice with or without Crp knockout were fed with CD, HFD, or methionine- and choline-deficient diet, or subjected to carotid artery ligation or Atorvastatin treatment. Hepatic, vascular, and metabolic indexes were then analyzed. The effects of CRP on lipid droplet formation were examined by cellular assays.
Results
Knockout of Crp in Apoe-deficient mice does not affect the progression of atherosclerosis under CD feeding, but significantly reduces plaque burden under HFD feeding. The pro-atherosclerotic effects of Crp are not due to direct modulation of vascular inflammation, but appear to be the result of enhanced lipid accumulation in the liver and the ensuing aggravation of hyperlipidemia. Mechanistically, Crp enhances hepatic lipid accumulation by upregulating Cidea to promote the formation of enlarged lipid droplets in hepatocytes. We further show that the therapeutic efficacy of Atorvastatin on HFD-induced atherosclerosis in Apoe-deficient mice is largely dependent on Crp.
Conclusions
Our findings identify a previously unrecognized role of CRP in enhancing hepatic lipid accumulation under stresses induced by dietary or genetic factors, which underlies its secondary impact on atherosclerosis and determines the therapeutic efficacy of Atorvastatin.
{"title":"C-reactive protein exacerbates high-fat diet-induced atherosclerosis via a liver-to-vessel axis that determines therapeutic efficacy of atorvastatin","authors":"Yu Fu , Yu-Xin Hua , Ya-Li Zhang , Chen-Yang Zhang , Hai-Yun Li , Ivan Melnikov , Zufar A. Gabbasov , Yi Wu , En-Qi Liu , Shang-Rong Ji","doi":"10.1016/j.atherosclerosis.2025.120594","DOIUrl":"10.1016/j.atherosclerosis.2025.120594","url":null,"abstract":"<div><h3>Background and aims</h3><div>C-reactive protein (CRP) is a liver-derived soluble marker of inflammation whose levels can predict the risk of atherosclerotic cardiovascular disease and therapeutic efficacy of statins. Intriguingly, however, CRP is not considered as a mediator of atherosclerosis based primarily on studies examining chow diet (CD)-fed mice. The aim of this study is to investigate the role of CRP in high-fat diet (HFD)-induced atherosclerosis, which models a more prevalent scenario in the real world, and to clarify its impact on Atorvastatin treatment.</div></div><div><h3>Methods</h3><div><em>Apoe</em>-sufficient or -deficient mice with or without <em>Crp</em> knockout were fed with CD, HFD, or methionine- and choline-deficient diet, or subjected to carotid artery ligation or Atorvastatin treatment. Hepatic, vascular, and metabolic indexes were then analyzed. The effects of CRP on lipid droplet formation were examined by cellular assays.</div></div><div><h3>Results</h3><div>Knockout of <em>Crp</em> in <em>Apoe</em>-deficient mice does not affect the progression of atherosclerosis under CD feeding, but significantly reduces plaque burden under HFD feeding. The pro-atherosclerotic effects of Crp are not due to direct modulation of vascular inflammation, but appear to be the result of enhanced lipid accumulation in the liver and the ensuing aggravation of hyperlipidemia. Mechanistically, Crp enhances hepatic lipid accumulation by upregulating Cidea to promote the formation of enlarged lipid droplets in hepatocytes. We further show that the therapeutic efficacy of Atorvastatin on HFD-induced atherosclerosis in <em>Apoe</em>-deficient mice is largely dependent on Crp.</div></div><div><h3>Conclusions</h3><div>Our findings identify a previously unrecognized role of CRP in enhancing hepatic lipid accumulation under stresses induced by dietary or genetic factors, which underlies its secondary impact on atherosclerosis and determines the therapeutic efficacy of Atorvastatin.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120594"},"PeriodicalIF":5.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145646924","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 : 2025-11-25DOI: 10.1016/j.atherosclerosis.2025.120605
Mia Ø. Johansen , Signe Vedel-Krogh , Sune F. Nielsen , Shoaib Afzal , George Davey Smith , Børge G. Nordestgaard
Emerging evidence from large observational studies and causal genetic studies suggest that elevated very-low-density lipoproteins (VLDL) are important and independent risk factors for atherosclerosis, myocardial infarction, and coronary artery disease. The cholesterol content of VLDL particles is often combined as overall remnant cholesterol; however, VLDL particles encompasses a heterogeneous group of lipoproteins that vary significantly in size, density, and structural composition, contributing to metabolic heterogeneity of VLDL particles. This heterogeneity has been suggested important for understanding the atherogenicity of VLDL particles. Nevertheless, remnant cholesterol lack precision to capture metabolic heterogeneity of VLDL subfractions; in contrast, advanced techniques such as nuclear magnetic resonance (NMR) spectroscopy provide more accurate estimates of VLDL particle number and cholesterol content across subfractions. This review aims at summarizing current evidence of the association between remnant cholesterol and particle number of VLDL subfractions as risk factors for myocardial infarction and coronary artery disease including pros and cons for using easily accessible remnant cholesterol versus using more advanced measurement methods for estimation of particle number of VLDL subfractions.
{"title":"Remnant cholesterol and particle number of VLDL subfractions in coronary artery disease: Pros and cons","authors":"Mia Ø. Johansen , Signe Vedel-Krogh , Sune F. Nielsen , Shoaib Afzal , George Davey Smith , Børge G. Nordestgaard","doi":"10.1016/j.atherosclerosis.2025.120605","DOIUrl":"10.1016/j.atherosclerosis.2025.120605","url":null,"abstract":"<div><div>Emerging evidence from large observational studies and causal genetic studies suggest that elevated very-low-density lipoproteins (VLDL) are important and independent risk factors for atherosclerosis, myocardial infarction, and coronary artery disease. The cholesterol content of VLDL particles is often combined as overall remnant cholesterol; however, VLDL particles encompasses a heterogeneous group of lipoproteins that vary significantly in size, density, and structural composition, contributing to metabolic heterogeneity of VLDL particles. This heterogeneity has been suggested important for understanding the atherogenicity of VLDL particles. Nevertheless, remnant cholesterol lack precision to capture metabolic heterogeneity of VLDL subfractions; in contrast, advanced techniques such as nuclear magnetic resonance (NMR) spectroscopy provide more accurate estimates of VLDL particle number and cholesterol content across subfractions. This review aims at summarizing current evidence of the association between remnant cholesterol and particle number of VLDL subfractions as risk factors for myocardial infarction and coronary artery disease including pros and cons for using easily accessible remnant cholesterol versus using more advanced measurement methods for estimation of particle number of VLDL subfractions.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120605"},"PeriodicalIF":5.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653297","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 : 2025-11-24DOI: 10.1016/j.atherosclerosis.2025.120588
Yasushi Ueki , Ryota Kakizaki , Tatsuhiko Otsuka , Tadashi Itagaki , Sylvain Losdat , Hiroki Shibutani , Jonas Häner , Sarah Bär , Juan F. Iglesias , Robert-Jan van Geuns , David Spirk , Joost Daemen , Thomas Engstrøm , Irene Lang , Konstantinos C. Koskinas , Lorenz Räber
Background and aims
Previous clinical studies have demonstrated the enhanced cardiovascular benefit of proprotein convertase subtilisin/kexin type 9 inhibition in high-risk patient subsets; however, the mechanisms underlying the greater benefit among patients at high atherothrombotic risk remain largely unknown. We aimed to investigate the effect of alirocumab on coronary plaque regression stratified according to AHA/ACC guideline-defined risk categories among patients with acute myocardial infarction (AMI).
Methods
This was a substudy of the PACMAN-AMI trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in addition to high-intensity statin in AMI patients undergoing percutaneous coronary intervention. Patients underwent serial intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) in the non-infarct-related arteries at baseline and after 52 weeks. Patients were categorized as very-high risk (VHR) if they had at least 1 prior cardiovascular event or at least 2 high-risk conditions. The key outcome measures were percent atheroma volume (PAV) by IVUS, maximum lipid core burden index within 4 mm (maxLCBI4mm) by NIRS, minimum fibrous cap thickness (FCT) and macrophage angle by OCT.
Results
Among 263 patients available for serial IVUS data, 111 (42.2 %) were classified as VHR. A greater reduction in PAV by alirocumab was observed in the non-VHR group compared with the VHR group (difference in change: 1.8 % [-2.5 to −1.0], P < 0.001 vs. −0.8 % [-1.7 to −0.1], P = 0.068, Pfor interaction = 0.109). Similarly, greater reduction in maxLCBI4mm and macrophage angle was observed in non-VHR vs. VHR patients (−72.8 [-109.3 to −36.4], P < 0.001 vs. −10.1 [-53.4 to 33.2], P = 0.647, Pfor interaction = 0.030, and +21.2 μm [-1.4 to +43.8], P = 0.066 vs. +35.0 μm [+8.3 to +61.8], P = 0.011, Pfor interaction = 0.031, respectively). In contrast, the increase in minimum FCT was more pronounced in the VHR group than the non-VHR group (difference in change: +21.2 μm [-1.4 to +43.8], P = 0.066 vs. +35.0 μm [+8.3 to +61.8], P = 0.011, Pfor interaction = 0.440).
Conclusions
Among AMI patients, the addition of alirocumab to high-intensity statin therapy resulted in greater coronary plaque regression and lipid burden reduction in patients not at VHR. Further investigation is needed to clarify the impact of atherothrombotic risks on plaque regression and subsequent risk reduction in different patient subsets.
{"title":"Effect of alirocumab on coronary plaque stratified by atherothrombotic risk","authors":"Yasushi Ueki , Ryota Kakizaki , Tatsuhiko Otsuka , Tadashi Itagaki , Sylvain Losdat , Hiroki Shibutani , Jonas Häner , Sarah Bär , Juan F. Iglesias , Robert-Jan van Geuns , David Spirk , Joost Daemen , Thomas Engstrøm , Irene Lang , Konstantinos C. Koskinas , Lorenz Räber","doi":"10.1016/j.atherosclerosis.2025.120588","DOIUrl":"10.1016/j.atherosclerosis.2025.120588","url":null,"abstract":"<div><h3>Background and aims</h3><div>Previous clinical studies have demonstrated the enhanced cardiovascular benefit of proprotein convertase subtilisin/kexin type 9 inhibition in high-risk patient subsets; however, the mechanisms underlying the greater benefit among patients at high atherothrombotic risk remain largely unknown. We aimed to investigate the effect of alirocumab on coronary plaque regression stratified according to AHA/ACC guideline-defined risk categories among patients with acute myocardial infarction (AMI).</div></div><div><h3>Methods</h3><div>This was a substudy of the PACMAN-AMI trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in addition to high-intensity statin in AMI patients undergoing percutaneous coronary intervention. Patients underwent serial intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) in the non-infarct-related arteries at baseline and after 52 weeks. Patients were categorized as very-high risk (VHR) if they had at least 1 prior cardiovascular event or at least 2 high-risk conditions. The key outcome measures were percent atheroma volume (PAV) by IVUS, maximum lipid core burden index within 4 mm (maxLCBI<sub>4mm</sub>) by NIRS, minimum fibrous cap thickness (FCT) and macrophage angle by OCT.</div></div><div><h3>Results</h3><div>Among 263 patients available for serial IVUS data, 111 (42.2 %) were classified as VHR. A greater reduction in PAV by alirocumab was observed in the non-VHR group compared with the VHR group (difference in change: 1.8 % [-2.5 to −1.0], P < 0.001 vs. −0.8 % [-1.7 to −0.1], P = 0.068, P<sub>for interaction</sub> = 0.109). Similarly, greater reduction in maxLCBI<sub>4mm</sub> and macrophage angle was observed in non-VHR vs. VHR patients (−72.8 [-109.3 to −36.4], P < 0.001 vs. −10.1 [-53.4 to 33.2], P = 0.647, P<sub>for interaction</sub> = 0.030, and +21.2 μm [-1.4 to +43.8], P = 0.066 vs. +35.0 μm [+8.3 to +61.8], P = 0.011, P<sub>for interaction</sub> = 0.031, respectively). In contrast, the increase in minimum FCT was more pronounced in the VHR group than the non-VHR group (difference in change: +21.2 μm [-1.4 to +43.8], P = 0.066 vs. +35.0 μm [+8.3 to +61.8], P = 0.011, P<sub>for interaction</sub> = 0.440).</div></div><div><h3>Conclusions</h3><div>Among AMI patients, the addition of alirocumab to high-intensity statin therapy resulted in greater coronary plaque regression and lipid burden reduction in patients not at VHR. Further investigation is needed to clarify the impact of atherothrombotic risks on plaque regression and subsequent risk reduction in different patient subsets.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120588"},"PeriodicalIF":5.7,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622638","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 : 2025-11-22DOI: 10.1016/j.atherosclerosis.2025.120604
Boao Liu , Huiping Ma , Yunxuan Guo , Hao Luo , Jie Ma , Shengqi Fu , Lin Xu , Xiwen Xiong
Background and aims
Vascular smooth muscle cells (VSMCs) contribute to atherosclerotic foam cell formation, but mechanisms regulating their phenotypic switching and programmed cell death remain unclear. O-GlcNAcylation, a nutrient-sensitive post-translational modification implicated in vascular calcification, lacks defined roles in VSMC foam cell biology.
Methods
Inducible smooth muscle-specific Ogt knockout mice on an Apoe−/− background were subjected to streptozotocin-induced hyperglycemia and a 12-week high-fat/high-cholesterol diet. Immunostaining of aortic sections was performed to evaluate the expression and localization of OGT, O-GlcNAc, and α-SMA in VSMCs and their derived foam cells. Primary VSMCs were treated with oxidized LDL to induce foam cell formation, and OGT inhibition was achieved either pharmacologically using OSMI-1 or genetically via shOgt adenovirus infection. Lipid accumulation was assessed by BODIPY/Oil Red O staining, and cell death was evaluated via TUNEL assay, flow cytometry, and Western blot.
Results
OGT expression and global O-GlcNAcylation were reduced in VSMCs during atherogenic progression. Ogt deletion in VSMCs promoted foam cell formation with enhanced lipid accumulation but paradoxically reduced atherosclerotic lesion area concurrent with increased intraplaque cell death. Both genetic and pharmacological OGT inhibition recapitulated this duality in vitro, simultaneously accelerating lipid accumulation while triggering PANoptosis, as evidenced by concurrent activation of cleaved caspase-3, phosphorylated MLKL, and cleaved GSDMD. Individual inhibition of apoptosis, necroptosis, or pyroptosis provided only partial rescue.
Conclusions
OGT acts as a dual regulator of VSMC fate, attenuating plaque burden through PANoptosis induction while promoting foam cell formation, revealing its complex role in atherosclerosis pathogenesis and suggesting context-dependent therapeutic implications.
背景和目的血管平滑肌细胞（VSMCs）参与动脉粥样硬化泡沫细胞的形成，但调节其表型转换和程序性细胞死亡的机制尚不清楚。o - glcn酰化是一种与血管钙化有关的营养敏感的翻译后修饰，在VSMC泡沫细胞生物学中缺乏明确的作用。方法在Apoe−/−背景下诱导平滑肌特异性Ogt基因敲除小鼠进行链脲佐菌素诱导的高血糖和12周的高脂肪/高胆固醇饮食。采用主动脉切片免疫染色法评价OGT、O-GlcNAc和α-SMA在VSMCs及其衍生泡沫细胞中的表达和定位。用氧化LDL处理原代VSMCs诱导泡沫细胞形成，通过OSMI-1或通过shOgt腺病毒感染实现OGT抑制。脂质积累采用BODIPY/Oil Red O染色法，细胞死亡采用TUNEL法、流式细胞术和Western blot法。结果在动脉粥样硬化过程中，VSMCs中sogt表达和o - glcn酰化水平降低。VSMCs中Ogt的缺失促进了泡沫细胞的形成，增加了脂质积累，但矛盾的是，减少了动脉粥样硬化病变面积，同时增加了斑块内细胞死亡。在体外实验中，基因和药理学上的OGT抑制都再现了这一双重特性，在加速脂质积累的同时引发PANoptosis，这一点可以通过裂解caspase-3、磷酸化MLKL和裂解GSDMD的同时激活得到证明。单独抑制细胞凋亡、坏死或焦亡只提供部分拯救。结论sogt作为VSMC命运的双重调节因子，通过诱导PANoptosis减轻斑块负担，同时促进泡沫细胞的形成，揭示了其在动脉粥样硬化发病中的复杂作用，并提示其治疗意义与环境相关。
{"title":"OGT deficiency in vascular smooth muscle orchestrates foam cell formation and PANoptosis during atherosclerotic progression","authors":"Boao Liu , Huiping Ma , Yunxuan Guo , Hao Luo , Jie Ma , Shengqi Fu , Lin Xu , Xiwen Xiong","doi":"10.1016/j.atherosclerosis.2025.120604","DOIUrl":"10.1016/j.atherosclerosis.2025.120604","url":null,"abstract":"<div><h3>Background and aims</h3><div>Vascular smooth muscle cells (VSMCs) contribute to atherosclerotic foam cell formation, but mechanisms regulating their phenotypic switching and programmed cell death remain unclear. O-GlcNAcylation, a nutrient-sensitive post-translational modification implicated in vascular calcification, lacks defined roles in VSMC foam cell biology.</div></div><div><h3>Methods</h3><div>Inducible smooth muscle-specific <em>Ogt</em> knockout mice on an <em>Apoe</em><sup><em>−/−</em></sup> background were subjected to streptozotocin-induced hyperglycemia and a 12-week high-fat/high-cholesterol diet. Immunostaining of aortic sections was performed to evaluate the expression and localization of OGT, O-GlcNAc, and α-SMA in VSMCs and their derived foam cells. Primary VSMCs were treated with oxidized LDL to induce foam cell formation, and OGT inhibition was achieved either pharmacologically using OSMI-1 or genetically via shOgt adenovirus infection. Lipid accumulation was assessed by BODIPY/Oil Red O staining, and cell death was evaluated via TUNEL assay, flow cytometry, and Western blot.</div></div><div><h3>Results</h3><div>OGT expression and global O-GlcNAcylation were reduced in VSMCs during atherogenic progression. <em>Ogt</em> deletion in VSMCs promoted foam cell formation with enhanced lipid accumulation but paradoxically reduced atherosclerotic lesion area concurrent with increased intraplaque cell death. Both genetic and pharmacological OGT inhibition recapitulated this duality in vitro, simultaneously accelerating lipid accumulation while triggering PANoptosis, as evidenced by concurrent activation of cleaved caspase-3, phosphorylated MLKL, and cleaved GSDMD. Individual inhibition of apoptosis, necroptosis, or pyroptosis provided only partial rescue.</div></div><div><h3>Conclusions</h3><div>OGT acts as a dual regulator of VSMC fate, attenuating plaque burden through PANoptosis induction while promoting foam cell formation, revealing its complex role in atherosclerosis pathogenesis and suggesting context-dependent therapeutic implications.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120604"},"PeriodicalIF":5.7,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622528","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 : 2025-11-22DOI: 10.1016/j.atherosclerosis.2025.120593
Yi Qin , Yu Jiang , Mirjam von Lucadou , Markus Geissen , Justus M. Grewe , Lea Wegmann , Elke Oetjen , E. Sebastian Debus , Rainer Böger , Günter Daum , Axel Larena-Avellaneda , Edzard Schwedhelm
Background and aims
Sphingosine-1-phosphate (S1P) is crucial for cardiovascular homeostasis and pathophysiology. We aimed to explore i) whether the associations between blood components and circulating S1P change in patients with atherosclerosis undergoing invasive vascular procedures and ii) whether in a mice model of vascular injury heparin treatment regulates circulatory S1P levels and intimal hyperplasia.
Methods
In a group of patients with vascular diseases, S1P blood concentrations and laboratory parameters were measured before and shortly after vascular procedures (n = 330) as well as 3-month later (n = 167). We further investigated in C57/Bl6J mice the effect of heparin treatment on serum S1P and intimal hyperplasia after clamping of the abdominal aorta.
Results
In patients, perioperative circulating S1P serum concentrations correlated with counts of thrombocytes, leukocytes, neutrophils and lymphocytes, while postoperative S1P concentrations were increasingly linked to erythrocytes counts as well as cholesterol, fibrinogen and calcium levels. Median serum S1P levels dropped by 23 % (p < 0.0001) after interventions and recovered to the initial levels within 3 months. However, patients under 3-month low molecular weight heparin medication presented with lower S1P concentrations than patients without (p < 0.001). In mice, a single heparin injection (1000 IU/kg) decreased circulatory S1P to 50 % within 4 h (p < 0.0001). Continuous heparin application reduced the intima to media ratio by 74 % compared to controls without heparin (p < 0.001).
Conclusions
Circulating S1P concentrations in patients with atherosclerosis are associated to different blood components before and after interventions. Reduced postoperative serum S1P levels in patients are most likely attributed to heparin treatment. The causalities between heparin treatment, reduced serum S1P and reduced intimal hyperplasia deserve further investigations.
{"title":"Heparin decreases serum sphingosine-1-phosphate levels in patients with vascular diseases","authors":"Yi Qin , Yu Jiang , Mirjam von Lucadou , Markus Geissen , Justus M. Grewe , Lea Wegmann , Elke Oetjen , E. Sebastian Debus , Rainer Böger , Günter Daum , Axel Larena-Avellaneda , Edzard Schwedhelm","doi":"10.1016/j.atherosclerosis.2025.120593","DOIUrl":"10.1016/j.atherosclerosis.2025.120593","url":null,"abstract":"<div><h3>Background and aims</h3><div>Sphingosine-1-phosphate (S1P) is crucial for cardiovascular homeostasis and pathophysiology. We aimed to explore i) whether the associations between blood components and circulating S1P change in patients with atherosclerosis undergoing invasive vascular procedures and ii) whether in a mice model of vascular injury heparin treatment regulates circulatory S1P levels and intimal hyperplasia.</div></div><div><h3>Methods</h3><div>In a group of patients with vascular diseases, S1P blood concentrations and laboratory parameters were measured before and shortly after vascular procedures (n = 330) as well as 3-month later (n = 167). We further investigated in C57/Bl6J mice the effect of heparin treatment on serum S1P and intimal hyperplasia after clamping of the abdominal aorta.</div></div><div><h3>Results</h3><div>In patients, perioperative circulating S1P serum concentrations correlated with counts of thrombocytes, leukocytes, neutrophils and lymphocytes, while postoperative S1P concentrations were increasingly linked to erythrocytes counts as well as cholesterol, fibrinogen and calcium levels. Median serum S1P levels dropped by 23 % (<em>p</em> < 0.0001) after interventions and recovered to the initial levels within 3 months. However, patients under 3-month low molecular weight heparin medication presented with lower S1P concentrations than patients without (<em>p</em> < 0.001). In mice, a single heparin injection (1000 IU/kg) decreased circulatory S1P to 50 % within 4 h (<em>p</em> < 0.0001). Continuous heparin application reduced the intima to media ratio by 74 % compared to controls without heparin (<em>p</em> < 0.001).</div></div><div><h3>Conclusions</h3><div>Circulating S1P concentrations in patients with atherosclerosis are associated to different blood components before and after interventions. Reduced postoperative serum S1P levels in patients are most likely attributed to heparin treatment. The causalities between heparin treatment, reduced serum S1P and reduced intimal hyperplasia deserve further investigations.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120593"},"PeriodicalIF":5.7,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622639","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 : 2025-11-21DOI: 10.1016/j.atherosclerosis.2025.120592
D. Pavluk , M. Schreinlechner , S. Proell , F. Theurl , P. Marschang , M. Noflatscher , F. Hofer , C. Dlaska , A. Bauer
Background and aims
AI derived biological age from surface ECGs (AI ECG age) has shown prognostic value beyond chronological age. We hypothesized that AI ECG age reflects atherosclerotic burden as indicated by carotid plaque volume (PV).
Methods
We retrospectively analyzed 101 patients with cardiovascular disease or ≥1 risk factor from a prospective single-center cohort (NCT01895725) on carotid atherosclerosis progression. Carotid plaque volume (PV) was measured by standardized 3D ultrasound at baseline and at ∼12-month intervals (median follow-up 1091 days). AI ECG age was derived from standard 10-s 12-lead ECGs using a validated deep neural network. Associations between AI ECG age, Δage (AI ECG age – chronological age), and PV were assessed by correlation, regression, and ROC analyses. At baseline, 101 patients had both ECG and 3D ultrasound; follow-up PV was available for 95, 88, and 80 patients at 1, 2 and 3 years, respectively.
Results
AI ECG age and chronological age correlated with PV (r = 0.54 and r = 0.48, both p < 0.001). In multivariable linear regression, AI ECG age was independently associated with PV (β = 6.95, 95 %CI: 2.88–11.01, p = 0.001), whereas chronological age was not (p = 0.120). Adding Δ age to a model with age, sex, lipid and inflammatory markers improved AUC from 0.77 to 0.82 and enhanced net reclassification (NRI = 0.48, p = 0.017). AI-ECG age predicted PV progression over time (β = 1.83, 95 %CI: 0.42 to 4.09, p = 0.042), independent of chronological age.
Conclusion
AI ECG age correlates more closely with carotid plaque burden than chronological age. Its divergence from chronological age independently predicts plaque progression, supporting AI ECG age as an accessible adjunct for vascular risk assessment.
{"title":"AI-ECG age predicts carotid atherosclerotic plaque volume and progression","authors":"D. Pavluk , M. Schreinlechner , S. Proell , F. Theurl , P. Marschang , M. Noflatscher , F. Hofer , C. Dlaska , A. Bauer","doi":"10.1016/j.atherosclerosis.2025.120592","DOIUrl":"10.1016/j.atherosclerosis.2025.120592","url":null,"abstract":"<div><h3>Background and aims</h3><div>AI derived biological age from surface ECGs (AI ECG age) has shown prognostic value beyond chronological age. We hypothesized that AI ECG age reflects atherosclerotic burden as indicated by carotid plaque volume (PV).</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 101 patients with cardiovascular disease or ≥1 risk factor from a prospective single-center cohort (NCT01895725) on carotid atherosclerosis progression. Carotid plaque volume (PV) was measured by standardized 3D ultrasound at baseline and at ∼12-month intervals (median follow-up 1091 days). AI ECG age was derived from standard 10-s 12-lead ECGs using a validated deep neural network. Associations between AI ECG age, Δage (AI ECG age – chronological age), and PV were assessed by correlation, regression, and ROC analyses. At baseline, 101 patients had both ECG and 3D ultrasound; follow-up PV was available for 95, 88, and 80 patients at 1, 2 and 3 years, respectively.</div></div><div><h3>Results</h3><div>AI ECG age and chronological age correlated with PV (r = 0.54 and r = 0.48, both p < 0.001). In multivariable linear regression, AI ECG age was independently associated with PV (β = 6.95, 95 %CI: 2.88–11.01, p = 0.001), whereas chronological age was not (p = 0.120). Adding Δ age to a model with age, sex, lipid and inflammatory markers improved AUC from 0.77 to 0.82 and enhanced net reclassification (NRI = 0.48, p = 0.017). AI-ECG age predicted PV progression over time (β = 1.83, 95 %CI: 0.42 to 4.09, p = 0.042), independent of chronological age.</div></div><div><h3>Conclusion</h3><div>AI ECG age correlates more closely with carotid plaque burden than chronological age. Its divergence from chronological age independently predicts plaque progression, supporting AI ECG age as an accessible adjunct for vascular risk assessment.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120592"},"PeriodicalIF":5.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622637","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 : 2025-11-20DOI: 10.1016/j.atherosclerosis.2025.120595
Oskari Repo , Markus Juonala , Harri Niinikoski , Suvi Rovio , Juha Mykkänen , Carol Y. Cheung , Mika Ala-Korpela , Hanna Vaahtoranta-Lehtonen , Jaakko Nevalainen , Antti Jula , Mika Kähönen , Terho Lehtimäki , Tomi P. Laitinen , Tapani Rönnemaa , Jorma Viikari , Olli Raitakari , Robyn Tapp , Katja Pahkala
Backgroung and aims
Inflammation is associated with cardiovascular disease development and microvascular dysfunction. The aim of the present study is to test the hypothesis that long-term exposure to chronic inflammation in childhood and adulthood is associated with adverse retinal microvascular structure in young and mid-adulthood.
Methods
We analyzed data derived from the Special Turku Coronary Risk Factor Intervention Project (STRIP) and longitudinal Cardiovascular Risk in Young Finns Study (YFS). In STRIP, fundus photos were taken in young adulthood (aged 26 years), and in YFS in mid-adulthood (aged 34–49 years). Retinal microvascular measures were derived in both cohorts (arteriolar and venular diameters and tortuosity; additionally, fractal dimensions in STRIP). Cumulative exposure as the area under the curve for high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls (GlycA), and other conventional cardiovascular risk factors was determined over a 15- and 17-year period in STRIP, and a 10-year period in YFS. Overall, retinal microvascular and cumulative hsCRP and/or GlycA were available for 344 STRIP and 1211 YFS participants, thus forming the cohort of the present study.
Results
In both cohorts, cumulative hsCRP was associated with wider venules when adjusted for sex (and age in YFS), and further for related cardiovascular risk factors. In young adulthood (STRIP), higher exposure to cumulative hsCRP was associated with decreased venular tortuosity, whereas in mid-adulthood (YFS), the association was inverse. Cumulative hsCRP was not associated with arteriolar measures whereas cumulative GlycA showed no significant association with any retinal microvascular measures.
Conclusions
Long-term cumulative hsCRP exposure was associated with wider venules in young and mid-adulthood, whereas the associations with venular tortuosity were inconsistent. Wider retinal venules might act as a marker for cumulative inflammatory burden.
{"title":"Associations of long-term cumulative C-reactive protein and glycoprotein acetyls concentrations in childhood, adolescence and adulthood with adulthood retinal microvascular structure","authors":"Oskari Repo , Markus Juonala , Harri Niinikoski , Suvi Rovio , Juha Mykkänen , Carol Y. Cheung , Mika Ala-Korpela , Hanna Vaahtoranta-Lehtonen , Jaakko Nevalainen , Antti Jula , Mika Kähönen , Terho Lehtimäki , Tomi P. Laitinen , Tapani Rönnemaa , Jorma Viikari , Olli Raitakari , Robyn Tapp , Katja Pahkala","doi":"10.1016/j.atherosclerosis.2025.120595","DOIUrl":"10.1016/j.atherosclerosis.2025.120595","url":null,"abstract":"<div><h3>Backgroung and aims</h3><div>Inflammation is associated with cardiovascular disease development and microvascular dysfunction. The aim of the present study is to test the hypothesis that long-term exposure to chronic inflammation in childhood and adulthood is associated with adverse retinal microvascular structure in young and mid-adulthood.</div></div><div><h3>Methods</h3><div>We analyzed data derived from the Special Turku Coronary Risk Factor Intervention Project (STRIP) and longitudinal Cardiovascular Risk in Young Finns Study (YFS). In STRIP, fundus photos were taken in young adulthood (aged 26 years), and in YFS in mid-adulthood (aged 34–49 years). Retinal microvascular measures were derived in both cohorts (arteriolar and venular diameters and tortuosity; additionally, fractal dimensions in STRIP). Cumulative exposure as the area under the curve for high-sensitivity <em>C</em>-reactive protein (hsCRP) and glycoprotein acetyls (GlycA), and other conventional cardiovascular risk factors was determined over a 15- and 17-year period in STRIP, and a 10-year period in YFS. Overall, retinal microvascular and cumulative hsCRP and/or GlycA were available for 344 STRIP and 1211 YFS participants, thus forming the cohort of the present study.</div></div><div><h3>Results</h3><div>In both cohorts, cumulative hsCRP was associated with wider venules when adjusted for sex (and age in YFS), and further for related cardiovascular risk factors. In young adulthood (STRIP), higher exposure to cumulative hsCRP was associated with decreased venular tortuosity, whereas in mid-adulthood (YFS), the association was inverse. Cumulative hsCRP was not associated with arteriolar measures whereas cumulative GlycA showed no significant association with any retinal microvascular measures.</div></div><div><h3>Conclusions</h3><div>Long-term cumulative hsCRP exposure was associated with wider venules in young and mid-adulthood, whereas the associations with venular tortuosity were inconsistent. Wider retinal venules might act as a marker for cumulative inflammatory burden.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120595"},"PeriodicalIF":5.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578373","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 : 2025-11-20DOI: 10.1016/j.atherosclerosis.2025.120591
Xiaotong Yao , Lina Liu , Lifen Zhao , Nianzhu Zhang
Background
The single-point insulin sensitivity estimator (SPISE) index is a surrogate marker for insulin resistance. However, its association with cardiovascular disease (CVD) risk remains unclear.
Methods
The study included 5755 participants from the Chinese Longitudinal Healthy Longevity Survey (CHARLS) and 2598 from the English Longitudinal Study of Ageing (ELSA). Cox proportional hazards models were used to examine the association between the SPISE index and CVD incidence, reporting hazard ratios (HR) and 95 % confidence intervals (CI). Within the Cox proportional hazards model framework, restricted cubic splines were applied to evaluate non-linear associations, and cumulative hazard curves were generated to illustrate the dynamics of risk over time. Subgroup analyses were conducted to assess effect heterogeneity, and a mediation analysis was performed to explore potential underlying mechanisms.
Results
During the follow-up period (2004–2018 for ELSA and 2011–2018 for CHARLS), 935 (16.25 %) participants in CHARLS and 1026 (39.49 %) participants in ELSA developed CVD. In the fully adjusted Cox proportional hazards model, individuals in the highest tertile of the SPISE index had a significantly lower risk of CVD incidence compared with those in the lowest tertile (CHARLS: adjusted HR: 0.61, 95 % CI: 0.51–0.72; ELSA: adjusted HR: 0.83, 95 % CI: 0.71–0.98). RCS regression analysis showed a negative linear relationship between the SPISE index and the CVD incidence. A higher SPISE index had a lower cumulative incidence of CVD.
Subgroup analyses, stratified by gender, marital status, education level, smoking status, and alcohol drinking status, revealed no significant modification of the SPISE index–CVD incidence association. Mediation analysis examined how the SPISE index is linked to CVD events, with CHO, LDL-C, CRP, and HbA1c as potential mediators. In the CHARLS cohort, CHO (3.36 %) and LDL-C (3.81 %) partially mediated the association; in the ELSA cohort, CRP showed a significant mediating effect (11.98 %).
Conclusion
A higher SPISE index is associated with reduced CVD risk in middle-aged and older adults, indicating its value as a tool for CVD risk assessment.
{"title":"Association between the single-point insulin sensitivity estimator and cardiovascular disease incidence: A prospective nationwide cohort study involving two cohorts","authors":"Xiaotong Yao , Lina Liu , Lifen Zhao , Nianzhu Zhang","doi":"10.1016/j.atherosclerosis.2025.120591","DOIUrl":"10.1016/j.atherosclerosis.2025.120591","url":null,"abstract":"<div><h3>Background</h3><div>The single-point insulin sensitivity estimator (SPISE) index is a surrogate marker for insulin resistance. However, its association with cardiovascular disease (CVD) risk remains unclear.</div></div><div><h3>Methods</h3><div>The study included 5755 participants from the Chinese Longitudinal Healthy Longevity Survey (CHARLS) and 2598 from the English Longitudinal Study of Ageing (ELSA). Cox proportional hazards models were used to examine the association between the SPISE index and CVD incidence, reporting hazard ratios (HR) and 95 % confidence intervals (CI). Within the Cox proportional hazards model framework, restricted cubic splines were applied to evaluate non-linear associations, and cumulative hazard curves were generated to illustrate the dynamics of risk over time. Subgroup analyses were conducted to assess effect heterogeneity, and a mediation analysis was performed to explore potential underlying mechanisms.</div></div><div><h3>Results</h3><div>During the follow-up period (2004–2018 for ELSA and 2011–2018 for CHARLS), 935 (16.25 %) participants in CHARLS and 1026 (39.49 %) participants in ELSA developed CVD. In the fully adjusted Cox proportional hazards model, individuals in the highest tertile of the SPISE index had a significantly lower risk of CVD incidence compared with those in the lowest tertile (CHARLS: adjusted HR: 0.61, 95 % CI: 0.51–0.72; ELSA: adjusted HR: 0.83, 95 % CI: 0.71–0.98). RCS regression analysis showed a negative linear relationship between the SPISE index and the CVD incidence. A higher SPISE index had a lower cumulative incidence of CVD.</div><div>Subgroup analyses, stratified by gender, marital status, education level, smoking status, and alcohol drinking status, revealed no significant modification of the SPISE index–CVD incidence association. Mediation analysis examined how the SPISE index is linked to CVD events, with CHO, LDL-C, CRP, and HbA1c as potential mediators. In the CHARLS cohort, CHO (3.36 %) and LDL-C (3.81 %) partially mediated the association; in the ELSA cohort, CRP showed a significant mediating effect (11.98 %).</div></div><div><h3>Conclusion</h3><div>A higher SPISE index is associated with reduced CVD risk in middle-aged and older adults, indicating its value as a tool for CVD risk assessment.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120591"},"PeriodicalIF":5.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578371","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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