Pub Date : 2026-01-02DOI: 10.1016/j.atherosclerosis.2025.120633
Carlos Guijarro, Alberto Ortiz
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Pub Date : 2025-12-29DOI: 10.1016/j.atherosclerosis.2025.120632
Koshiro Sakai , Toshiro Shinke , Ziad Ali , Takuya Mizukami , Hitoshi Matsuo , Hirohiko Ando , Tetsuya Amano , Thomas Engstrøm , Jeroen Sonck , Adriaan Wilgenhof , Divaka Perera , Masafumi Nakayama , William F. Fearon , Brian Ko , Javier Escaned , Daniel Munhoz , Frederic Bouisset , Kazumasa Ikeda , Taito Arai , Ethan Korngold , Carlos Collet
Background
The interplay between coronary artery hemodynamics and atherosclerotic plaque is not fully understood. The Pullback Pressure Gradient (PPG), a novel physiological metric, categorizes coronary artery disease (CAD) into focal or diffuse patterns based on coronary physiology.
Objectives
This study investigates the association between the PPG and coronary atherosclerosis, as characterized by intravascular ultrasound (IVUS).
Methods
This is a pre-specified analysis of the PPG Global study (NCT04789317). We included stable patients with hemodynamically significant lesions (FFR ≤0.80) undergoing percutaneous coronary intervention (PCI) guided by IVUS. PPG was calculated from manual FFR pullbacks before PCI. Pathophysiological CAD patterns were classified as focal or diffuse based on the median PPG (0.62).
Results
A total of 261 patients (264 vessels) with PPG and IVUS were included. The mean age was 69±11 years, 77% were male, and 33% had diabetes mellitus. A significant correlation was observed between PPG and plaque burden (r=0.53, 95% CI 0.43–0.61, p<0.001). Vessels with focal CAD exhibited significantly higher plaque burden compared to those with diffuse CAD (83±6% vs. 76±8%, p<0.001). The prevalence of attenuated plaques was greater in vessels with high PPG (68% vs. 39%, p <0.001), while calcified plaques were more frequent in vessels with low PPG (60% vs. 78%, p=0.003).
Conclusions
In vessels with flow-limiting stenoses, high PPG is associated with increased plaque burden. Vessels with high PPG (focal disease) predominantly exhibited lipid-rich plaques, whereas those with low PPG (diffuse disease) had a greater calcium burden.
背景：冠状动脉血流动力学与动脉粥样硬化斑块之间的相互作用尚不完全清楚。回拉压力梯度（PPG）是一种新的生理指标，根据冠状动脉生理学将冠状动脉疾病（CAD）分为局灶性或弥漫性模式。目的：本研究探讨PPG与冠状动脉粥样硬化之间的关系，以血管内超声（IVUS）为特征。方法：这是对PPG Global研究（NCT04789317）的预先指定分析。我们纳入了在IVUS引导下接受经皮冠状动脉介入治疗（PCI）的血流动力学显著病变（FFR≤0.80）的稳定患者。PPG通过PCI前手动FFR回拉计算。根据中位PPG（0.62）将病理生理CAD模式分为局灶性或弥漫性。结果：共纳入PPG和IVUS患者261例（264支血管）。平均年龄69±11岁，男性占77%，糖尿病患者占33%。PPG与斑块负担之间存在显著相关性（r=0.53, 95% CI 0.43-0.61）。结论：在血流受限狭窄的血管中，高PPG与斑块负担增加相关。高PPG（局灶性疾病）的血管主要表现为富含脂质斑块，而低PPG（弥漫性疾病）的血管则有更大的钙负担。
{"title":"Functional and morphological characterization of coronary atherosclerosis","authors":"Koshiro Sakai , Toshiro Shinke , Ziad Ali , Takuya Mizukami , Hitoshi Matsuo , Hirohiko Ando , Tetsuya Amano , Thomas Engstrøm , Jeroen Sonck , Adriaan Wilgenhof , Divaka Perera , Masafumi Nakayama , William F. Fearon , Brian Ko , Javier Escaned , Daniel Munhoz , Frederic Bouisset , Kazumasa Ikeda , Taito Arai , Ethan Korngold , Carlos Collet","doi":"10.1016/j.atherosclerosis.2025.120632","DOIUrl":"10.1016/j.atherosclerosis.2025.120632","url":null,"abstract":"<div><h3>Background</h3><div>The interplay between coronary artery hemodynamics and atherosclerotic plaque is not fully understood. The Pullback Pressure Gradient (PPG), a novel physiological metric, categorizes coronary artery disease (CAD) into focal or diffuse patterns based on coronary physiology.</div></div><div><h3>Objectives</h3><div>This study investigates the association between the PPG and coronary atherosclerosis, as characterized by intravascular ultrasound (IVUS).</div></div><div><h3>Methods</h3><div>This is a pre-specified analysis of the PPG Global study (NCT04789317). We included stable patients with hemodynamically significant lesions (FFR ≤0.80) undergoing percutaneous coronary intervention (PCI) guided by IVUS. PPG was calculated from manual FFR pullbacks before PCI. Pathophysiological CAD patterns were classified as focal or diffuse based on the median PPG (0.62).</div></div><div><h3>Results</h3><div>A total of 261 patients (264 vessels) with PPG and IVUS were included. The mean age was 69±11 years, 77% were male, and 33% had diabetes mellitus. A significant correlation was observed between PPG and plaque burden (r=0.53, 95% CI 0.43–0.61, p<0.001). Vessels with focal CAD exhibited significantly higher plaque burden compared to those with diffuse CAD (83±6% vs. 76±8%, p<0.001). The prevalence of attenuated plaques was greater in vessels with high PPG (68% vs. 39%, p <0.001), while calcified plaques were more frequent in vessels with low PPG (60% vs. 78%, p=0.003).</div></div><div><h3>Conclusions</h3><div>In vessels with flow-limiting stenoses, high PPG is associated with increased plaque burden. Vessels with high PPG (focal disease) predominantly exhibited lipid-rich plaques, whereas those with low PPG (diffuse disease) had a greater calcium burden.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120632"},"PeriodicalIF":5.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.atherosclerosis.2025.120634
Shinje Moon , Sangmo Hong , Kyungdo Han , Cheol-Young Park
Background
Cilostazol increases pain-free walking distance in patients with lower extremity peripheral arterial disease (PAD). However, the effect of cilostazol on the prognosis of PAD in patients with diabetes remains unclear. We analyzed its effects on the long-term prognosis of Korean patients with diabetes and lower extremity PAD.
Methods
Data of patients with diabetes and lower extremity PAD between 2009 and 2018 were collected from the Korean National Health Information Database. The primary outcome was all-cause mortality from baseline to death or until December 31, 2022. The secondary outcomes were major adverse cardiac and cerebrovascular events (MACCE) and recurrent major adverse limb events (MALEs). Multiple Cox proportional hazard regression analyses were performed.
Results
We enrolled 14,768 patients with diabetes before PAD diagnosis with complete health screening data within 2 years of PAD diagnosis (5382 patients receiving cilostazol and 9386 controls). All-cause mortality was significantly lower in patients treated with cilostazol than in the controls. Antiplatelet treatment significantly lowered the risk of all-cause mortality compared to untreated controls, although the risk reduction did not differ significantly between antiplatelet agents. However, cilostazol administration did not reduce the risk of MACCEs. Treatment with cilostazol alone or in combination with antiplatelet agents was associated with a significant reduction in recurrent MALEs, without increasing the risk of major bleeding.
Conclusions
In patients with diabetes and lower extremity PAD, cilostazol may improve the prognosis without increasing the risk of bleeding. These findings provide epidemiological evidence for better PAD outcomes in patients with diabetes, although further research is required to elucidate the underlying mechanisms.
{"title":"Effects of cilostazol on the prognosis of lower extremity peripheral arterial disease in patients with diabetes mellitus in Korea: A nationwide population-based study","authors":"Shinje Moon , Sangmo Hong , Kyungdo Han , Cheol-Young Park","doi":"10.1016/j.atherosclerosis.2025.120634","DOIUrl":"10.1016/j.atherosclerosis.2025.120634","url":null,"abstract":"<div><h3>Background</h3><div>Cilostazol increases pain-free walking distance in patients with lower extremity peripheral arterial disease (PAD). However, the effect of cilostazol on the prognosis of PAD in patients with diabetes remains unclear. We analyzed its effects on the long-term prognosis of Korean patients with diabetes and lower extremity PAD.</div></div><div><h3>Methods</h3><div>Data of patients with diabetes and lower extremity PAD between 2009 and 2018 were collected from the Korean National Health Information Database. The primary outcome was all-cause mortality from baseline to death or until December 31, 2022. The secondary outcomes were major adverse cardiac and cerebrovascular events (MACCE) and recurrent major adverse limb events (MALEs). Multiple Cox proportional hazard regression analyses were performed.</div></div><div><h3>Results</h3><div>We enrolled 14,768 patients with diabetes before PAD diagnosis with complete health screening data within 2 years of PAD diagnosis (5382 patients receiving cilostazol and 9386 controls). All-cause mortality was significantly lower in patients treated with cilostazol than in the controls. Antiplatelet treatment significantly lowered the risk of all-cause mortality compared to untreated controls, although the risk reduction did not differ significantly between antiplatelet agents. However, cilostazol administration did not reduce the risk of MACCEs. Treatment with cilostazol alone or in combination with antiplatelet agents was associated with a significant reduction in recurrent MALEs, without increasing the risk of major bleeding.</div></div><div><h3>Conclusions</h3><div>In patients with diabetes and lower extremity PAD, cilostazol may improve the prognosis without increasing the risk of bleeding. These findings provide epidemiological evidence for better PAD outcomes in patients with diabetes, although further research is required to elucidate the underlying mechanisms<strong>.</strong></div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120634"},"PeriodicalIF":5.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.atherosclerosis.2025.120631
Zijie Wang , Xiao Hu , Jianshang Wen , Yanfang Xie , Mengqiu Zhang , Chuanqin Fang , Yanghua Tian , Qi Li
Background and aims
Systemic inflammation plays a significant role in cardiovascular disease (CVD). Monocyte to high-density lipoprotein (HDL) ratio (MHR) has emerged as a surrogate index of residual inflammation risk. We investigated the associations of MHR with incident CVD and mortality, and to explore the additional predictive value of combining MHR with C-reactive protein (CRP).
Methods
We included 366,705 UK Biobank participants without previous coronary heart disease, stroke, or transient ischemic attack. MHR was defined as the monocyte count divided by the HDL value. Quartiles of MHR were assessed as predictors of future CVD (myocardial infarction [MI] and stroke), cardiovascular death, and all-cause mortality after adjusting for sociodemographic, lifestyle, and clinical confounders.
Results
During a median follow-up of 12.7 years (IQR 11.9–13.4), 10,215 (2.8 %) developed MI, 6889 (1.9 %) cases of stroke, and 27,686 (7.5 %) died. Compared with the lowest MHR quartile, the highest MHR quartile (quartile 4) was associated with an increased risk of composite CVD (HR 1.45, 95 % CI 1.37–1.53), MI (1.59, 1.49–1.71), any stroke (1.23, 1.13–1.33); ischemic stroke (1.33, 1.21–1.46); cardiovascular mortality (1.42, 1.22–1.65), and all-cause mortality (1.11, 1.07–1.15) in the fully adjusted model. Risks of future MI, stroke, and mortality were significantly higher in participants with both elevated MHR (≥0.41) and CRP (≥2 mg/L).
Conclusions
MHR is associated with future CVD and mortality irrespective of CRP levels. MHR is an easily accessible marker to detect individuals with high inflammatory risk of CVD and mortality in clinical practice.
背景与目的全身性炎症在心血管疾病（CVD）中起重要作用。单核细胞与高密度脂蛋白（HDL）比率（MHR）已成为残留炎症风险的替代指标。我们研究了MHR与心血管疾病发病率和死亡率的关系，并探讨MHR与c反应蛋白（CRP）联合的额外预测价值。方法：我们纳入了366,705名英国生物银行参与者，他们之前没有冠心病、中风或短暂性脑缺血发作。MHR定义为单核细胞计数除以HDL值。在调整社会人口统计学、生活方式和临床混杂因素后，评估MHR四分位数作为未来CVD（心肌梗死[MI]和卒中）、心血管死亡和全因死亡率的预测因子。结果在中位随访12.7年（IQR 11.9-13.4）期间，10,215例（2.8%）发生心肌梗死，6889例（1.9%）发生脑卒中，27,686例（7.5%）死亡。与最低MHR四分位数相比，最高MHR四分位数（四分位数4）与复合心血管疾病（HR 1.45, 95% CI 1.37-1.53）、心肌梗死（1.59,1.49-1.71）、任何中风（1.23,1.13-1.33）的风险增加相关；缺血性卒中（1.33,1.21-1.46）；在完全调整模型中，心血管死亡率（1.42,1.22-1.65）和全因死亡率（1.11,1.07-1.15）。MHR（≥0.41）和CRP（≥2mg /L）升高的参与者未来发生心肌梗死、卒中和死亡的风险显著增加。结论与CRP水平无关，smhr与未来CVD和死亡率相关。在临床实践中，MHR是检测心血管疾病高炎症风险和死亡率的一种容易获得的标志物。
{"title":"Monocyte to high-density lipoprotein ratio and risk of incident stroke, myocardial infarction, and mortality: A large prospective cohort study","authors":"Zijie Wang , Xiao Hu , Jianshang Wen , Yanfang Xie , Mengqiu Zhang , Chuanqin Fang , Yanghua Tian , Qi Li","doi":"10.1016/j.atherosclerosis.2025.120631","DOIUrl":"10.1016/j.atherosclerosis.2025.120631","url":null,"abstract":"<div><h3>Background and aims</h3><div>Systemic inflammation plays a significant role in cardiovascular disease (CVD). Monocyte to high-density lipoprotein (HDL) ratio (MHR) has emerged as a surrogate index of residual inflammation risk. We investigated the associations of MHR with incident CVD and mortality, and to explore the additional predictive value of combining MHR with C-reactive protein (CRP).</div></div><div><h3>Methods</h3><div>We included 366,705 UK Biobank participants without previous coronary heart disease, stroke, or transient ischemic attack. MHR was defined as the monocyte count divided by the HDL value. Quartiles of MHR were assessed as predictors of future CVD (myocardial infarction [MI] and stroke), cardiovascular death, and all-cause mortality after adjusting for sociodemographic, lifestyle, and clinical confounders.</div></div><div><h3>Results</h3><div>During a median follow-up of 12.7 years (IQR 11.9–13.4), 10,215 (2.8 %) developed MI, 6889 (1.9 %) cases of stroke, and 27,686 (7.5 %) died. Compared with the lowest MHR quartile, the highest MHR quartile (quartile 4) was associated with an increased risk of composite CVD (HR 1.45, 95 % CI 1.37–1.53), MI (1.59, 1.49–1.71), any stroke (1.23, 1.13–1.33); ischemic stroke (1.33, 1.21–1.46); cardiovascular mortality (1.42, 1.22–1.65), and all-cause mortality (1.11, 1.07–1.15) in the fully adjusted model. Risks of future MI, stroke, and mortality were significantly higher in participants with both elevated MHR (≥0.41) and CRP (≥2 mg/L).</div></div><div><h3>Conclusions</h3><div>MHR is associated with future CVD and mortality irrespective of CRP levels. MHR is an easily accessible marker to detect individuals with high inflammatory risk of CVD and mortality in clinical practice.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120631"},"PeriodicalIF":5.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1016/j.atherosclerosis.2025.120625
Diandra Daley , Aya Ayoub , Ralph K. Akyea , Veline L'Esperance , Luisa Silva , Anthony S. Wierzbicki , Helen Williams , Nadeem Qureshi , Mariam Molokhia
Background and aims
Familial hypercholesterolaemia (FH) is an inherited lipid disorder characterised by raised LDL-C and increased risk of premature atherosclerotic cardiovascular disease. Despite effective treatments, FH remains substantially underdiagnosed. Electronic health records (EHRs) enable systematic case-finding, but evidence on their effectiveness remains limited. This review aimed to evaluate EHR-based strategies for FH identification.
Methods
Seven databases and grey literature were systematically searched for relevant studies. Eligible studies reported on systematic EHR-based case-finding in adults (≥18 years). Meta-analysis of FH prevalence was conducted using random-effects modelling. Risk of bias was assessed using ROBINS-I; evidence certainty with GRADE.
Results
Of 831 citations screened, 12 eligible studies were included, including three from a prior review. Case-finding approaches included traditional diagnostic criteria (Simon–Broome, DLCN, MEDPED), hybrid models, and machine-learning algorithms (FAMCAT, FIND FH, TARB-Ex). FH prevalence estimates varied: 1.2% (95% CI 0.0%–3.0%; p=0.06) in general population studies, 41% (95% CI 2%–90%; p=0.02) in high-risk CVD populations, and 15% (95% CI 2%–34%; p=0.00) in genetically confirmed cohorts. Novel algorithmic approaches such as FAMCAT 2 and incorporating EHR-genomic data models demonstrated superior performance to traditional criteria. Secondary outcomes were inconsistently reported, though cholesterol levels at diagnosis were consistently higher in probable/confirmed FH, and markedly elevated in genetically confirmed cohorts. Certainty of evidence was moderate due to heterogeneity, non-randomised design, and potential publication bias.
Conclusions
Algorithmic/genomics augmented EHR-based methods can enhance FH identification, but evidence remains limited. Standardised, scalable approaches validated in diverse populations are required to inform equitable FH screening and policy development.
背景和目的家族性高胆固醇血症（FH）是一种遗传性脂质疾病，以LDL-C升高和过早动脉粥样硬化性心血管疾病的风险增加为特征。尽管有有效的治疗，但FH仍未得到充分诊断。电子健康记录（EHRs）能够系统地发现病例，但关于其有效性的证据仍然有限。本综述旨在评估基于ehr的FH识别策略。方法系统检索7个数据库和灰色文献进行相关研究。符合条件的研究报告了系统的基于ehr的成人病例发现（≥18岁）。采用随机效应模型对FH患病率进行meta分析。使用ROBINS-I评估偏倚风险；具有GRADE的证据确定性。结果在筛选的831篇引用中，纳入了12项符合条件的研究，其中3项来自先前的综述。病例查找方法包括传统诊断标准（Simon-Broome、DLCN、MEDPED）、混合模型和机器学习算法（FAMCAT、FIND FH、TARB-Ex）。FH患病率估计值各不相同：在普通人群研究中为1.2% (95% CI 0.0%-3.0%; p=0.06)，在高危心血管疾病人群中为41% (95% CI 2%-90%; p=0.02)，在基因证实的队列中为15% （95% CI 2%-34%; p=0.00）。新的算法方法，如FAMCAT 2和结合ehr -基因组数据模型显示优于传统标准的性能。次要结局的报道不一致，尽管诊断时胆固醇水平在可能/确诊的FH中始终较高，并且在遗传确诊的队列中显着升高。由于异质性、非随机设计和潜在的发表偏倚，证据的确定性为中等。结论基于算法/基因组学的增强ehr方法可以提高FH的识别能力，但证据有限。需要在不同人群中得到验证的标准化、可扩展的方法，为公平的FH筛查和政策制定提供信息。
{"title":"Systematic identification of familial hypercholesterolaemia: An updated systematic review and meta-analysis","authors":"Diandra Daley , Aya Ayoub , Ralph K. Akyea , Veline L'Esperance , Luisa Silva , Anthony S. Wierzbicki , Helen Williams , Nadeem Qureshi , Mariam Molokhia","doi":"10.1016/j.atherosclerosis.2025.120625","DOIUrl":"10.1016/j.atherosclerosis.2025.120625","url":null,"abstract":"<div><h3>Background and aims</h3><div>Familial hypercholesterolaemia (FH) is an inherited lipid disorder characterised by raised LDL-C and increased risk of premature atherosclerotic cardiovascular disease. Despite effective treatments, FH remains substantially underdiagnosed. Electronic health records (EHRs) enable systematic case-finding, but evidence on their effectiveness remains limited. This review aimed to evaluate EHR-based strategies for FH identification.</div></div><div><h3>Methods</h3><div>Seven databases and grey literature were systematically searched for relevant studies. Eligible studies reported on systematic EHR-based case-finding in adults (≥18 years). Meta-analysis of FH prevalence was conducted using random-effects modelling. Risk of bias was assessed using ROBINS-I; evidence certainty with GRADE.</div></div><div><h3>Results</h3><div>Of 831 citations screened, 12 eligible studies were included, including three from a prior review. Case-finding approaches included traditional diagnostic criteria (Simon–Broome, DLCN, MEDPED), hybrid models, and machine-learning algorithms (FAMCAT, FIND FH, TARB-Ex). FH prevalence estimates varied: 1.2% (95% CI 0.0%–3.0%; <em>p=</em>0.06) in general population studies, 41% (95% CI 2%–90%; <em>p</em>=0.02) in high-risk CVD populations, and 15% (95% CI 2%–34%; <em>p=</em>0.00) in genetically confirmed cohorts. Novel algorithmic approaches such as FAMCAT 2 and incorporating EHR-genomic data models demonstrated superior performance to traditional criteria. Secondary outcomes were inconsistently reported, though cholesterol levels at diagnosis were consistently higher in probable/confirmed FH, and markedly elevated in genetically confirmed cohorts. Certainty of evidence was moderate due to heterogeneity, non-randomised design, and potential publication bias.</div></div><div><h3>Conclusions</h3><div>Algorithmic/genomics augmented EHR-based methods can enhance FH identification, but evidence remains limited. Standardised, scalable approaches validated in diverse populations are required to inform equitable FH screening and policy development.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120625"},"PeriodicalIF":5.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880916","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}
Despite the frequent co-occurrence of frailty and abdominal aortic aneurysm (AAA), it remains unclear whether frailty is a risk factor for the development of AAA. This study aims to determine the association.
Methods
The study recruited a large-scale cohort from the UK Biobank. The baseline frailty level was assessed through frailty phenotype and frailty index, categorizing participants as non-frail, pre-frail, or frail. The primary outcome was incidence of AAA during follow-up. Cox proportional hazards model was used to explore the association of frailty with AAA risk. The genetic susceptibility was assessed by polygenic risk score.
Results
A total of 410,606 participants were enrolled in this study. Over a median follow-up of 12.56 years, AAA developed in 692(0.3 %), 931(0.5 %), and 180(1.0 %) participants categorized as non-frail, pre-frail, and frail respectively under the frailty phenotype, while the frailty index revealed 626(0.3 %), 873(0.6 %), and 304(1.1 %) cases across corresponding frailty strata. Compared with the non-frail participants, the risk of AAA was significantly elevated in pre-frail participants (frailty phenotype: HR = 1.28, 95 %CI = 1.16–1.42; frailty index: HR = 1.43, 95 %CI = 1.28–1.59) and frail participants (frailty phenotype: HR = 1.82, 95 % CI = 1.52–2.18; frailty index: HR = 2.03, 95 %CI = 1.74–2.37). The association remained robust in further adjustment of genetic susceptibility and subgroup analysis. Using non-frail participants with low genetic susceptibility as the reference group, those frail participants with high genetic susceptibility demonstrated the greatest hazard for incident AAA, underscoring their synergistic effect on AAA.
Conclusions
Frailty was longitudinally associated with a high long-term risk of AAA, suggesting frailty as a new independent risk factor for AAA.
背景与目的：尽管虚弱和腹主动脉瘤（AAA）经常共存，但尚不清楚虚弱是否是发生腹主动脉瘤的危险因素，本研究旨在确定两者之间的关系。方法：该研究从英国生物银行招募了一个大规模队列。基线虚弱水平通过虚弱表型和虚弱指数进行评估，将参与者分为非虚弱、虚弱前期和虚弱。主要观察指标为随访期间AAA发生率。采用Cox比例风险模型探讨脆弱性与AAA风险的关系。采用多基因风险评分法评估遗传易感性。结果：本研究共纳入410,606名受试者。在中位12.56年的随访中，在脆弱表型下，AAA分别在692（0.3%）、931（0.5%）和180（1.0%）名参与者中被分类为非虚弱、预虚弱和虚弱，而虚弱指数显示在相应的虚弱层中有626（0.3%）、873（0.6%）和304（1.1%）例。与非体弱组相比，体弱前组（脆弱表型：HR = 1.28, 95% CI = 1.16-1.42；脆弱指数：HR = 1.43, 95% CI = 1.28-1.59）和体弱组（脆弱表型：HR = 1.82, 95% CI = 1.52-2.18；脆弱指数：HR = 2.03, 95% CI = 1.74-2.37）发生AAA的风险显著升高。在进一步的遗传易感性调整和亚群分析中，这种相关性仍然很强。以低遗传易感性、非体弱的受试者为参照组，体弱高遗传易感性的受试者发生AAA的风险最大，强调了它们对AAA的协同作用。结论：体弱与AAA的高长期风险纵向相关，提示体弱是AAA的一个新的独立危险因素。
{"title":"Frailty, genetic susceptibility, and the risk of abdominal aortic aneurysm: Evidence from the UK Biobank cohort study","authors":"Yiyang Tang , Mukamengjiang Juaiti , Xinyi Zhou , Baohua Peng , Zhenzhen Da , Ziwei Ou , Wenchao Lin , Mengqiu Zhang , Zaixin Yu , Lihuang Zha , Benhui Liang","doi":"10.1016/j.atherosclerosis.2025.120623","DOIUrl":"10.1016/j.atherosclerosis.2025.120623","url":null,"abstract":"<div><h3>Background and aims</h3><div>Despite the frequent co-occurrence of frailty and abdominal aortic aneurysm (AAA), it remains unclear whether frailty is a risk factor for the development of AAA. This study aims to determine the association.</div></div><div><h3>Methods</h3><div>The study recruited a large-scale cohort from the UK Biobank. The baseline frailty level was assessed through frailty phenotype and frailty index, categorizing participants as non-frail, pre-frail, or frail. The primary outcome was incidence of AAA during follow-up. Cox proportional hazards model was used to explore the association of frailty with AAA risk. The genetic susceptibility was assessed by polygenic risk score.</div></div><div><h3>Results</h3><div>A total of 410,606 participants were enrolled in this study. Over a median follow-up of 12.56 years, AAA developed in 692(0.3 %), 931(0.5 %), and 180(1.0 %) participants categorized as non-frail, pre-frail, and frail respectively under the frailty phenotype, while the frailty index revealed 626(0.3 %), 873(0.6 %), and 304(1.1 %) cases across corresponding frailty strata. Compared with the non-frail participants, the risk of AAA was significantly elevated in pre-frail participants (frailty phenotype: HR = 1.28, 95 %CI = 1.16–1.42; frailty index: HR = 1.43, 95 %CI = 1.28–1.59) and frail participants (frailty phenotype: HR = 1.82, 95 % CI = 1.52–2.18; frailty index: HR = 2.03, 95 %CI = 1.74–2.37). The association remained robust in further adjustment of genetic susceptibility and subgroup analysis. Using non-frail participants with low genetic susceptibility as the reference group, those frail participants with high genetic susceptibility demonstrated the greatest hazard for incident AAA, underscoring their synergistic effect on AAA.</div></div><div><h3>Conclusions</h3><div>Frailty was longitudinally associated with a high long-term risk of AAA, suggesting frailty as a new independent risk factor for AAA.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120623"},"PeriodicalIF":5.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.atherosclerosis.2025.120624
Yanjun Zhang, Yu Huang, Xiaoqin Gan, Ziliang Ye, Yuanyuan Zhang, Sisi Yang, Hao Xiang, Yiwei Zhang, Yiting Wu, Xianhui Qin
Background and aims
Abdominal aortic aneurysm (AAA) lacks reliable circulating biomarkers and effective pharmacological therapies. This study aimed to investigate the observational and causal associations between plasma proteins and AAA to enhance understanding of its biological mechanisms, improve disease prediction, and identify potential therapeutic targets.
Methods
We included 51,381 participants from the UK Biobank(43,317 in the training set and 8064 in the test set) without aortic aneurysm or dissection. Observational associations between 2911 plasma proteins and incident AAA were assessed, and causal associations were evaluated using two-sample cis-Mendelian randomization (MR) analyses.
Results
Over a median follow-up of 13.1 years, 329 incident AAA cases were identified. 113 plasma proteins were significantly associated with AAA, enriched in collagen-containing extracellular matrix and pathways related to immune response, death receptor activity, cytokine-cytokine receptor interaction, and apoptosis. A simple predictive model incorporating MMP12(macrophage metalloelastase-12), CXCL17(CXC motif chemokine-17), IL6(interleukin-6), and WFDC2(WAP four-disulfide core domain protein-2)—alone or in combination—along with age and sex, demonstrated comparable predictive performance(C-index: 0.826–0.864) to the clinical risk factors model(C-index: 0.852). In cis-MR analyses, MMP12 (OR: 1.14; 95 %CI: 1.09–1.20), WFDC2 (OR:1.32; 95 %CI: 1.13–1.55), and NCR3LG1 (natural cytotoxicity triggering receptor 3 ligand 1; OR: 1.15; 95 %CI: 1.09–1.22) were causally associated with AAA. Notably, MMP12 is already a drug target for aortic aneurysm and other diseases.
Conclusions
MMP12, CXCL17, IL6, and WFDC2 are effective circulating biomarkers for AAA prediction, while MMP12, WFDC2, and NCR3LG1 represent promising therapeutic targets for AAA. These findings provide valuable insights into AAA pathogenesis and highlight potential avenues for drug development.
{"title":"Identifying plasma proteomic biomarkers for risk prediction and therapeutic targets of abdominal aortic aneurysm: Prospective cohort and Mendelian randomization analyses","authors":"Yanjun Zhang, Yu Huang, Xiaoqin Gan, Ziliang Ye, Yuanyuan Zhang, Sisi Yang, Hao Xiang, Yiwei Zhang, Yiting Wu, Xianhui Qin","doi":"10.1016/j.atherosclerosis.2025.120624","DOIUrl":"10.1016/j.atherosclerosis.2025.120624","url":null,"abstract":"<div><h3>Background and aims</h3><div>Abdominal aortic aneurysm (AAA) lacks reliable circulating biomarkers and effective pharmacological therapies. This study aimed to investigate the observational and causal associations between plasma proteins and AAA to enhance understanding of its biological mechanisms, improve disease prediction, and identify potential therapeutic targets.</div></div><div><h3>Methods</h3><div>We included 51,381 participants from the UK Biobank(43,317 in the training set and 8064 in the test set) without aortic aneurysm or dissection. Observational associations between 2911 plasma proteins and incident AAA were assessed, and causal associations were evaluated using two-sample cis-Mendelian randomization (MR) analyses.</div></div><div><h3>Results</h3><div>Over a median follow-up of 13.1 years, 329 incident AAA cases were identified. 113 plasma proteins were significantly associated with AAA, enriched in collagen-containing extracellular matrix and pathways related to immune response, death receptor activity, cytokine-cytokine receptor interaction, and apoptosis. A simple predictive model incorporating MMP12(macrophage metalloelastase-12), CXCL17(CXC motif chemokine-17), IL6(interleukin-6), and WFDC2(WAP four-disulfide core domain protein-2)—alone or in combination—along with age and sex, demonstrated comparable predictive performance(C-index: 0.826–0.864) to the clinical risk factors model(C-index: 0.852). In <em>cis</em>-MR analyses, MMP12 (OR: 1.14; 95 %CI: 1.09–1.20), WFDC2 (OR:1.32; 95 %CI: 1.13–1.55), and NCR3LG1 (natural cytotoxicity triggering receptor 3 ligand 1; OR: 1.15; 95 %CI: 1.09–1.22) were causally associated with AAA. Notably, MMP12 is already a drug target for aortic aneurysm and other diseases.</div></div><div><h3>Conclusions</h3><div>MMP12, CXCL17, IL6, and WFDC2 are effective circulating biomarkers for AAA prediction, while MMP12, WFDC2, and NCR3LG1 represent promising therapeutic targets for AAA. These findings provide valuable insights into AAA pathogenesis and highlight potential avenues for drug development.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120624"},"PeriodicalIF":5.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.atherosclerosis.2025.120627
Robert S. Rosenson , Eliot A. Brinton , Daniel Gaudet , Frederick J. Raal , Carissa Baker-Smith , Patrick M. Moriarty , Susanne Greber-Platzer , Jean Bergeron , Brian W. McCrindle , Alpana Waldron , Shazia Ali , Richard T. George , Robert Pordy , Xue-Qiao Zhao , Albert Wiegman
Background and aims
Children and adolescents with homozygous familial hypercholesterolemia (HoFH) routinely require advanced lipid-lowering therapies (LLTs). We assess the long-term efficacy and safety of evinacumab, a novel LLT, in children and adolescents with HoFH.
Methods
Study 17100 (NCT04233918) was a phase 3, single-arm, open-label study enrolling 20 children aged 5–11 years with HoFH. ELIPSE-OLE (NCT03409744) was a phase 3, single-arm study enrolling 14 adolescents aged 12−17 years with HoFH. Participants received intravenous evinacumab 15 mg/kg every 4 weeks; all individuals received stable LLT and most received lipoprotein apheresis (60 % of children aged 5–11 years; 64 % of adolescents aged 12−17 years). Outcomes included change from baseline to weeks 48 and 72 in low-density lipoprotein cholesterol (LDL-C) and other lipid parameters. Safety was assessed as treatment-emergent adverse events (TEAEs).
Results
In children aged 5–11 years, mean (standard deviation [SD]) baseline LDL-C (301.9 [149.1] mg/dL) was lowered by 45 % (131.1 mg/dL) at week 48 and 41 % (115.8 mg/dL) at week 72. In adolescents aged 12–17 years, mean (SD) baseline LDL-C (300.4 [100.5] mg/dL) was lowered by 48 % (156.4 mg/dL) at week 48 and 51 % (165.6 mg/dL) at week 72. TEAEs occurred in 100 % and 86 % of participants aged 5–11 and 12–17 years, respectively. TEAEs were considered treatment related in four individuals aged 5–11 years (20 %); no one aged 12–17 years had treatment-related TEAEs (0 %).
Conclusions
Evinacumab markedly reduced LDL-C in children and adolescents with HoFH, beyond optimized standard LLT and lipoprotein apheresis. LDL-C remains above goal in most pediatric patients with HoFH, and evinacumab should be routinely considered whenever further LDL-C lowering is needed.
{"title":"Evinacumab in patients aged 5–17 years with homozygous familial hypercholesterolemia","authors":"Robert S. Rosenson , Eliot A. Brinton , Daniel Gaudet , Frederick J. Raal , Carissa Baker-Smith , Patrick M. Moriarty , Susanne Greber-Platzer , Jean Bergeron , Brian W. McCrindle , Alpana Waldron , Shazia Ali , Richard T. George , Robert Pordy , Xue-Qiao Zhao , Albert Wiegman","doi":"10.1016/j.atherosclerosis.2025.120627","DOIUrl":"10.1016/j.atherosclerosis.2025.120627","url":null,"abstract":"<div><h3>Background and aims</h3><div>Children and adolescents with homozygous familial hypercholesterolemia (HoFH) routinely require advanced lipid-lowering therapies (LLTs). We assess the long-term efficacy and safety of evinacumab, a novel LLT, in children and adolescents with HoFH.</div></div><div><h3>Methods</h3><div>Study 17100 (NCT04233918) was a phase 3, single-arm, open-label study enrolling 20 children aged 5–11 years with HoFH. ELIPSE-OLE (NCT03409744) was a phase 3, single-arm study enrolling 14 adolescents aged 12−17 years with HoFH. Participants received intravenous evinacumab 15 mg/kg every 4 weeks; all individuals received stable LLT and most received lipoprotein apheresis (60 % of children aged 5–11 years; 64 % of adolescents aged 12−17 years). Outcomes included change from baseline to weeks 48 and 72 in low-density lipoprotein cholesterol (LDL-C) and other lipid parameters. Safety was assessed as treatment-emergent adverse events (TEAEs).</div></div><div><h3>Results</h3><div>In children aged 5–11 years, mean (standard deviation [SD]) baseline LDL-C (301.9 [149.1] mg/dL) was lowered by 45 % (131.1 mg/dL) at week 48 and 41 % (115.8 mg/dL) at week 72. In adolescents aged 12–17 years, mean (SD) baseline LDL-C (300.4 [100.5] mg/dL) was lowered by 48 % (156.4 mg/dL) at week 48 and 51 % (165.6 mg/dL) at week 72. TEAEs occurred in 100 % and 86 % of participants aged 5–11 and 12–17 years, respectively. TEAEs were considered treatment related in four individuals aged 5–11 years (20 %); no one aged 12–17 years had treatment-related TEAEs (0 %).</div></div><div><h3>Conclusions</h3><div>Evinacumab markedly reduced LDL-C in children and adolescents with HoFH, beyond optimized standard LLT and lipoprotein apheresis. LDL-C remains above goal in most pediatric patients with HoFH, and evinacumab should be routinely considered whenever further LDL-C lowering is needed.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120627"},"PeriodicalIF":5.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.atherosclerosis.2025.120622
Stefano Manzini , Alice Colombo , Elsa Franchi, Giada Poletti, Marco Busnelli , Giulia Chiesa
Background and aims
With the aim of increasing our knowledge on the mutual interplay between miRNAs and lipids, which is still limited, a novel approach integrating miRNomic and lipidomic data gathered from mice with specific lipid traits was explored.
Methods
miRNomic and lipidomic analyses were previously performed in wild-type, Pcsk9 and Ldlr knockout mice fed normal laboratory diet or Western diet. miRNAs were high-throughput sequenced in liver, aorta, white adipose tissue, duodenum, jejunum, ileum and brain, whereas lipids were quantified by high-throughput mass-spectrometry in liver, aorta and plasma. miRNA expression levels were tested for correlation with each lipid measurement in different samples, and correlations were selected based on strict stringency criteria. In vitro experiments with miRNA mimics or inhibitors in mouse hepatoma cells were performed to validate correlations.
Results
Correlation analyses between miRNA expression levels and lipid concentrations in the different experimental conditions led to the selection of miRNAs potentially playing a major role in the regulation of lipid levels. Correlations mainly clustered in liver. Among selected miRNAs, some were already known to be related to lipid metabolism (miR-33, miR-210 and miR-21a) whereas others, including miR-431–5p, miR-434–3p, miR-434–5p and miR-677–5p had never been associated to lipidome perturbations before. In vitro experiments allowed to highlight a possible role of miR-431–5p andmiR-677–5p in the modulation of cholesterol and triglyceride concentrations.
Conclusions
This study bridged miRNomic and lipidomic data in relevant mouse models, allowing to highlight novel miRNAs potentially playing a role in the modulation of lipid levels.
{"title":"Integrated high-throughput miRNomics and lipidomics in mice with altered lipoprotein metabolism","authors":"Stefano Manzini , Alice Colombo , Elsa Franchi, Giada Poletti, Marco Busnelli , Giulia Chiesa","doi":"10.1016/j.atherosclerosis.2025.120622","DOIUrl":"10.1016/j.atherosclerosis.2025.120622","url":null,"abstract":"<div><h3>Background and aims</h3><div>With the aim of increasing our knowledge on the mutual interplay between miRNAs and lipids, which is still limited, a novel approach integrating miRNomic and lipidomic data gathered from mice with specific lipid traits was explored.</div></div><div><h3>Methods</h3><div>miRNomic and lipidomic analyses were previously performed in wild-type, Pcsk9 and Ldlr knockout mice fed normal laboratory diet or Western diet. miRNAs were high-throughput sequenced in liver, aorta, white adipose tissue, duodenum, jejunum, ileum and brain, whereas lipids were quantified by high-throughput mass-spectrometry in liver, aorta and plasma. miRNA expression levels were tested for correlation with each lipid measurement in different samples, and correlations were selected based on strict stringency criteria. <em>In vitro</em> experiments with miRNA mimics or inhibitors in mouse hepatoma cells were performed to validate correlations.</div></div><div><h3>Results</h3><div>Correlation analyses between miRNA expression levels and lipid concentrations in the different experimental conditions led to the selection of miRNAs potentially playing a major role in the regulation of lipid levels. Correlations mainly clustered in liver. Among selected miRNAs, some were already known to be related to lipid metabolism (miR-33, miR-210 and miR-21a) whereas others, including miR-431–5p, miR-434–3p, miR-434–5p and miR-677–5p had never been associated to lipidome perturbations before. <em>In vitro</em> experiments allowed to highlight a possible role of miR-431–5p andmiR-677–5p in the modulation of cholesterol and triglyceride concentrations.</div></div><div><h3>Conclusions</h3><div>This study bridged miRNomic and lipidomic data in relevant mouse models, allowing to highlight novel miRNAs potentially playing a role in the modulation of lipid levels.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"413 ","pages":"Article 120622"},"PeriodicalIF":5.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.atherosclerosis.2025.120574
Raffaele Piccolo , Angelo Laino , Antonio Pio Vitale , Anna Franzone , Daniele Giacoppo , Eduardo Bossone , Davide Capodanno , Giovanni Esposito
<div><h3>Background and aims</h3><div>C-reactive protein (CRP) has been associated with an increased risk of cardiovascular events in the setting of primary prevention; however, its risk association in secondary cardiovascular prevention remains unclear. We evaluated the prognostic role of CRP across the spectrum of patients with established atherosclerotic cardiovascular disease (ASCVD).</div></div><div><h3>Methods</h3><div>We performed a systematic review and meta-analysis by screening Embase and MEDLINE databases from inception through November 2024. We included studies reporting adjusted risk associations between CRP and cardiovascular events among patients with ASCVD. Two reviewers extracted data and assessed the risk of bias. Data were extracted using an adaption of the Checklist for Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies (CHARMS-PF). The primary analysis was conducted using a random-effects model within a Bayesian framework. Risk of bias was assessed using the Quality in Prognosis Studies tool. The GRADE (grading of recommendations assessment, development, and evaluation) approach was used to rate the certainty in the prognostic yield of CRP. The principal outcome was major adverse cardiovascular events. Additional outcomes included: all-cause death, myocardial infarction, cardiovascular death, and cerebrovascular events.</div></div><div><h3>Results</h3><div>We included 27 studies, published from 2002 to 2024, and involving 193,761 participants (65,204 or 34 % females). Higher CRP levels were defined accordingly to the included studies and ranged from 0.5 to 5.0 mg/L 26 studies adjusted for conventional cardiovascular risk factors (age, sex, smoking, diabetes, dyslipidemia, hypertension); one omitted smoking status but included the others. Higher CRP levels were associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR, 1.55, 95 % credible intervals, CrI, 1.39 to 1.73; tau = 0.24, 95 %CrI 0.14 to 0.34; high certainty), all-cause death (aHR 1.92, 95 %CrI 1.52 to 2.41; tau = 0.30, 95 %CrI 0.14 to 0.51; moderate certainty), myocardial infarction (aHR 1.40, 95 %CrI 1.22 to 1.63; tau = 0.066, 95 %CrI 0.001 to 0.28; moderate certainty), and cardiovascular death (aHR 1.35, 95 %CrI 0.98 to 1.84; tau = 0.20, 95 %CrI 0.001 to 0.54; low certainty) after adjustment for traditional risk factors. The association between CRP and the risk of cerebrovascular events was inconclusive (aHR 1.52, 95 %CrI 0.69 to 3.32; tau = 0.33 95 %CrI 0.001 to 0.85; very low certainty). Dose-response Bayesian meta-analysis showed a non-linear association between CRP and major cardiovascular events, with levels between 2 and 4 mg/L being associated with clinically relevant higher risk. A similar dose-response relationship was observed also for all-cause death.</div></div><div><h3>Conclusions</h3><div>Among patients with ASCVD, elevated levels of CRP are associated with an increase
{"title":"Association between C-reactive protein and adverse events in secondary cardiovascular prevention: A systematic review and meta-analysis of prognostic factor studies","authors":"Raffaele Piccolo , Angelo Laino , Antonio Pio Vitale , Anna Franzone , Daniele Giacoppo , Eduardo Bossone , Davide Capodanno , Giovanni Esposito","doi":"10.1016/j.atherosclerosis.2025.120574","DOIUrl":"10.1016/j.atherosclerosis.2025.120574","url":null,"abstract":"<div><h3>Background and aims</h3><div>C-reactive protein (CRP) has been associated with an increased risk of cardiovascular events in the setting of primary prevention; however, its risk association in secondary cardiovascular prevention remains unclear. We evaluated the prognostic role of CRP across the spectrum of patients with established atherosclerotic cardiovascular disease (ASCVD).</div></div><div><h3>Methods</h3><div>We performed a systematic review and meta-analysis by screening Embase and MEDLINE databases from inception through November 2024. We included studies reporting adjusted risk associations between CRP and cardiovascular events among patients with ASCVD. Two reviewers extracted data and assessed the risk of bias. Data were extracted using an adaption of the Checklist for Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies (CHARMS-PF). The primary analysis was conducted using a random-effects model within a Bayesian framework. Risk of bias was assessed using the Quality in Prognosis Studies tool. The GRADE (grading of recommendations assessment, development, and evaluation) approach was used to rate the certainty in the prognostic yield of CRP. The principal outcome was major adverse cardiovascular events. Additional outcomes included: all-cause death, myocardial infarction, cardiovascular death, and cerebrovascular events.</div></div><div><h3>Results</h3><div>We included 27 studies, published from 2002 to 2024, and involving 193,761 participants (65,204 or 34 % females). Higher CRP levels were defined accordingly to the included studies and ranged from 0.5 to 5.0 mg/L 26 studies adjusted for conventional cardiovascular risk factors (age, sex, smoking, diabetes, dyslipidemia, hypertension); one omitted smoking status but included the others. Higher CRP levels were associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR, 1.55, 95 % credible intervals, CrI, 1.39 to 1.73; tau = 0.24, 95 %CrI 0.14 to 0.34; high certainty), all-cause death (aHR 1.92, 95 %CrI 1.52 to 2.41; tau = 0.30, 95 %CrI 0.14 to 0.51; moderate certainty), myocardial infarction (aHR 1.40, 95 %CrI 1.22 to 1.63; tau = 0.066, 95 %CrI 0.001 to 0.28; moderate certainty), and cardiovascular death (aHR 1.35, 95 %CrI 0.98 to 1.84; tau = 0.20, 95 %CrI 0.001 to 0.54; low certainty) after adjustment for traditional risk factors. The association between CRP and the risk of cerebrovascular events was inconclusive (aHR 1.52, 95 %CrI 0.69 to 3.32; tau = 0.33 95 %CrI 0.001 to 0.85; very low certainty). Dose-response Bayesian meta-analysis showed a non-linear association between CRP and major cardiovascular events, with levels between 2 and 4 mg/L being associated with clinically relevant higher risk. A similar dose-response relationship was observed also for all-cause death.</div></div><div><h3>Conclusions</h3><div>Among patients with ASCVD, elevated levels of CRP are associated with an increase","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"412 ","pages":"Article 120574"},"PeriodicalIF":5.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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