Accelerated atherosclerosis associated with immune checkpoint inhibitors: a systematic review and meta-analysis of pre-clinical studies

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis Pub Date : 2025-05-07 DOI:10.1016/j.atherosclerosis.2025.119219

Anniek Strijdhorst , Winnie G. Vos , Laura A. Bosmans , Kim E. Dzobo , Pascal J.H. Kusters , Nordin M.J. Hanssen , Jeffrey Kroon , Esther Lutgens , Hanneke W.M. van Laarhoven , Tom T.P. Seijkens , Nick van Es

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Abstract

Background

Patients with cancer treated with immune checkpoint inhibitors are at increased risk of myocardial infarction and ischemic stroke. The mechanism is incompletely understood but may involve accelerated atherosclerosis due to enhanced inflammation. Pre-clinical studies may provide insight in these mechanisms.

Aim

To assess the effects of modulating co-inhibitory immune checkpoint proteins on atherosclerosis progression in animal models.

Methods

A systematic review was performed in MEDLINE, Embase, Web of Science, and Scopus up to March 2025. Animal studies were included if the effect of modulation of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and/or lymphocyte-activation gene 3 (LAG-3) on atherosclerotic plaque size was evaluated. Secondary outcomes were plaque composition and systemic inflammation. The ratios of means (RoM) across the studies were pooled in a random effects meta-analysis. Risk of bias was assessed using the SYRCLE tool, focusing on randomization, blinding, and completeness of outcome reporting.

Results

Fourteen eligible studies were included. All studies used an atherosclerotic mouse model (ApoE^−/−, Ldlr^−/−, ApoE3∗Leiden, or AAV8-PCSK9) and either evaluated pharmacological or genetic modulation of co-inhibitory immune checkpoint proteins. Upon inhibition, atherosclerotic plaque size in the aorta was 53 % higher in exposed mice compared to control mice (RoM, 1.53; 95 % CI, 1.29–1.83; I² = 89 %). Plaque composition was predominantly characterized by a greater abundance of CD4⁺ T cells, CD8⁺ T cells, and macrophages. Studies stimulating co-inhibitory immune checkpoint proteins corroborated these findings and demonstrated that atherosclerotic plaque size was reduced by 28 % in treated mice compared to controls (RoM, 0.72; 95 % CI, 0.65–0.80; I2 = 85 %). This reduction was paralleled by a decrease in the number of macrophages and T cells in plaques.

Conclusion

Immune checkpoint inhibition leads to increased plaque inflammation and a significant increase in murine atherosclerotic plaque size. These changes may reflect the cause of the increased risk of myocardial infarction and ischemic stroke in patients treated with immune checkpoint inhibitors.

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加速动脉粥样硬化与免疫检查点抑制剂相关：临床前研究的系统回顾和荟萃分析

背景：接受免疫检查点抑制剂治疗的癌症患者发生心肌梗死和缺血性卒中的风险增加。其机制尚不完全清楚，但可能与炎症增强导致的动脉粥样硬化加速有关。临床前研究可能会对这些机制提供一些见解。目的探讨调节共抑制免疫检查点蛋白对动脉粥样硬化动物模型进展的影响。方法对截至2025年3月的MEDLINE、Embase、Web of Science和Scopus数据库进行系统评价。如果评估程序性细胞死亡蛋白1 （PD-1）、程序性死亡配体1 （PD-L1）、细胞毒性t淋巴细胞相关蛋白4 （CTLA-4）和/或淋巴细胞激活基因3 （LAG-3）对动脉粥样硬化斑块大小的调节作用，则纳入动物研究。次要结果是斑块组成和全身性炎症。所有研究的平均比率（RoM）在随机效应荟萃分析中汇总。使用sycle工具评估偏倚风险，重点是随机化、盲法和结果报告的完整性。结果纳入14项符合条件的研究。所有研究都使用了动脉粥样硬化小鼠模型（ApoE−/−,Ldlr−/−，ApoE3 * Leiden或AAV8-PCSK9），并评估了共抑制免疫检查点蛋白的药理学或遗传调节。经抑制后，暴露小鼠的主动脉粥样硬化斑块大小比对照小鼠高53% (RoM, 1.53；95% ci, 1.29-1.83；i2 = 89%)。斑块组成的主要特征是CD4+ T细胞、CD8+ T细胞和巨噬细胞的丰度更高。刺激共抑制免疫检查点蛋白的研究证实了这些发现，并表明与对照组相比，治疗小鼠的动脉粥样硬化斑块大小减少了28% (RoM, 0.72；95% ci, 0.65-0.80；i2 = 85%)。这种减少与斑块中巨噬细胞和T细胞数量的减少是平行的。结论免疫检查点抑制可导致斑块炎症增加，显著增加小鼠动脉粥样硬化斑块大小。这些变化可能反映了接受免疫检查点抑制剂治疗的患者心肌梗死和缺血性卒中风险增加的原因。

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来源期刊

Atherosclerosis 医学-外周血管病

CiteScore

9.80

自引率

3.80%

发文量

1269

审稿时长

36 days

期刊介绍： Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.