5-Hydroxymethylcytosine signatures in cell-free DNA as biomarkers for distinguishing acute coronary syndrome following COVID-19 infection and its association with neutrophil activation and PDE4D expression

IF 2.5 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

IJC Heart and Vasculature Pub Date : 2025-07-28 DOI:10.1016/j.ijcha.2025.101727

Zhongheng Li , Maimaitiyasen Duolikun , Hangyu Chen , Lei Zhang , Yishuo Liu , Ruining Li , Dan Li , Lijie Sun , Long Chen

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引用次数: 0

Abstract

Background

While 5hmC features in cell-free DNA (cfDNA) show promise as early biomarkers for COVID-19 severity, myocardial injury, and long-term outcomes, their specific role in acute coronary syndrome (ACS) triggered shortly after COVID-19 infection remains unclear.

Methods

We generated genome-wide 5hmC profiles from plasma cfDNA using the 5hmC-Seal technique across three cohorts: ACS patients without prior COVID-19 infection (ACS, n = 16), patients experiencing ACS within 2 months post-COVID-19 (ACS2N, n = 24), and patients experiencing ACS beyond 2 months post-COVID-19 (ACS2W, n = 28). Differential 5hmC analysis, functional enrichment (GO, KEGG), immune cell deconvolution, and protein–protein interaction (PPI) network analysis were performed.

Results

Significant differences in 5hmC profiles were identified between ACS2N and ACS patients, but not between ACS2W and ACS. Functional analysis implicated immune and inflammatory pathways. Immune infiltration analysis revealed abnormal neutrophil activation specifically in the ACS2N group. PPI network analysis pinpointed phosphodiesterase 4D (PDE4D) as a key hub gene; it was highly expressed in the ACS2N group, a finding corroborated using external datasets.

Conclusions

Our findings indicate that plasma cfDNA 5hmC markers can distinguish ACS occurring shortly after COVID-19 infection (ACS2N) from ACS without prior infection. We observed distinct immune dysregulation, notably abnormal neutrophil activation, in ACS2N patients. Critically, we identified PDE4D as a potential key mediator, suggesting that recent COVID-19 infection may contribute to ACS onset by abnormally upregulating PDE4D expression. This study highlights 5hmC signatures and PDE4D as potential biomarkers and therapeutic targets for post-COVID ACS.

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无细胞DNA中5-羟甲基胞嘧啶特征作为区分COVID-19感染后急性冠状动脉综合征的生物标志物及其与中性粒细胞激活和PDE4D表达的关系

虽然无细胞DNA （cfDNA）中的5hmC特征有望作为COVID-19严重程度、心肌损伤和长期结局的早期生物标志物，但它们在COVID-19感染后不久引发的急性冠状动脉综合征（ACS）中的具体作用尚不清楚。方法：我们使用5hmC- seal技术从血浆cfDNA中生成全基因组5hmC图谱，涉及三个队列：既往无COVID-19感染的ACS患者（ACS, n = 16）， COVID-19后2个月内出现ACS的患者（ACS2N, n = 24），以及COVID-19后2个月以上出现ACS的患者（ACS2W, n = 28）。进行差异5hmC分析、功能富集（GO， KEGG）、免疫细胞反褶积和蛋白-蛋白相互作用（PPI）网络分析。结果ACS2N和ACS患者的5hmC谱存在显著差异，而ACS2W和ACS患者的5hmC谱无显著差异。功能分析涉及免疫和炎症途径。免疫浸润分析显示ACS2N组中性粒细胞活化异常。PPI网络分析确定磷酸二酯酶4D （PDE4D）为关键枢纽基因；它在ACS2N组中高度表达，这一发现得到了外部数据集的证实。结论血浆cfDNA 5hmC标志物可区分COVID-19感染后不久发生的ACS （ACS2N）与未感染的ACS。我们在ACS2N患者中观察到明显的免疫失调，特别是中性粒细胞活化异常。重要的是，我们发现PDE4D是一个潜在的关键介质，这表明最近的COVID-19感染可能通过异常上调PDE4D表达来促进ACS的发生。该研究强调5hmC特征和PDE4D是covid后ACS的潜在生物标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

IJC Heart and Vasculature Medicine-Cardiology and Cardiovascular Medicine

CiteScore

4.90

自引率

10.30%

发文量

216

审稿时长

56 days

期刊介绍： IJC Heart & Vasculature is an online-only, open-access journal dedicated to publishing original articles and reviews (also Editorials and Letters to the Editor) which report on structural and functional cardiovascular pathology, with an emphasis on imaging and disease pathophysiology. Articles must be authentic, educational, clinically relevant, and original in their content and scientific approach. IJC Heart & Vasculature requires the highest standards of scientific integrity in order to promote reliable, reproducible and verifiable research findings. All authors are advised to consult the Principles of Ethical Publishing in the International Journal of Cardiology before submitting a manuscript. Submission of a manuscript to this journal gives the publisher the right to publish that paper if it is accepted. Manuscripts may be edited to improve clarity and expression.