第一部分 炎症对冠状动脉介入患者HDL-C和ApoA-I相关缺血风险的影响

摘要

背景：高密度脂蛋白胆固醇（High-Density Lipoprotein Cholesterol，HDL-C）和载脂蛋白A-I（Apolipoprotein A-I，ApoA-I）均为高密度脂蛋白颗粒的重要组成部分。然而，目前研究对于HDL-C和ApoA-I与冠心病患者心血管风险之间的关系结论尚不一致。此外，近期研究表明，高密度脂蛋白颗粒在炎症状态下可能存在功能失调。

目的：本研究旨在探讨炎症状态是否会改变HDL-C和ApoA-I对经皮冠状动脉介入治疗（Percutaneous Coronary Intervention，PCI）患者心血管风险的影响。

方法：本研究连续纳入2013年在阜外医院接受PCI治疗的10724例患者。炎症状态定义为患者基线高敏C反应蛋白（High-Sensitivity C-Reactive Proteins，hsCRP）水平≥2 mg/L。本研究的临床终点为心原性死亡。

结果：最终纳入9569例冠心病PCI患者。在5年随访期间，225例（2.4%）患者发生心原性死亡。在hsCRP水平≥2 mg/L组中，HDL-C水平与心原性死亡风险呈U形关系。多因素Cox回归分析显示，HDL-C水平处于最低五分位数（校正后风险比：2.50，95%置信区间：1.32-4.71）和最高五分位数（校正后风险比：2.28，95%置信区间：1.23-4.25）均与心原性死亡风险升高相关。然而，ApoA-I与心原性死亡风险呈L形关系，即仅最低五分位数的ApoA-I水平与心原性死亡风险升高相关（校正后风险比：2.19，95%置信区间：1.28-3.75）。在hsCRP水平<2 mg/L组中，HDL-C和ApoA-I水平与心原性死亡风险均无显著相关性（P > 0.05）。

结论：在hsCRP水平≥2 mg/L的冠心病PCI患者中，HDL-C水平过低或过高均与心原性死亡风险升高相关（U形关联），而ApoA-I仅低水平与风险升高相关（L形关联）。然而，在hsCRP水平<2 mg/L的患者中，HDL-C和ApoA-I水平均与心原性死亡风险无相关性。本研究结果强调了在管理冠心病PCI患者的HDL-C和ApoA-I水平时，应特别考虑炎症状态（尤其是hsCRP水平），并提示对于hsCRP水平≥2 mg/L的冠心病PCI患者，提高ApoA-I水平可能是一种潜在的治疗策略。

第二部分 糖尿病对冠状动脉介入患者HDL-C和ApoA-I相关缺血风险的影响

摘要

背景：高密度脂蛋白胆固醇（High-Density Lipoprotein Cholesterol，HDL-C）及其主要功能蛋白载脂蛋白A-I（Apolipoprotein A-I，ApoA-I）长期以来被认为具有心血管保护作用。近年来，有研究显示在未合并冠心病的患者中，HDL-C和ApoA-I与预后的关系受到糖尿病的影响。然而，对于接受经皮冠状动脉介入治疗（Percutaneous Coronary Intervention，PCI）的冠心病患者，HDL-C和ApoA-I在不同糖代谢状态下对缺血风险的影响仍存在研究空白。

目的：本研究旨在评估糖代谢状态是否对PCI患者中HDL-C和ApoA-I与缺血风险的关系产生调节作用。

方法：连续纳入2013年入院的10724名PCI患者，并将患者分为糖尿病和非糖尿病组。研究的主要终点为主要不良心脑血管事件（Major Adverse Cardiovascular and Cerebrovascular Events，MACCE），包括心原性死亡、心肌梗死和卒中。

结果：本研究最终纳入9397名PCI患者，5年随访期间共发生1052例（11.2%）MACCE。在总人群和糖尿病组中，HDL-C和ApoA-I水平与MACCE风险均呈L形关系。多因素Cox回归分析显示，在糖尿病组中，HDL-C水平处于最低五分位数（校正后风险比：1.326，95%置信区间：1.003-1.753）和ApoA-I水平处于最低五分位数（校正后风险比：1.503，95%置信区间：1.151-1.962）均与MACCE风险升高相关。然而，在非糖尿病组中，均未观察到HDL-C和ApoA-I与MACCE风险的相关性（P>0.05）。

结论：本研究基于大样本长期随访数据，首次证实较低的HDL-C和ApoA-I水平与合并糖尿病的PCI患者的缺血风险显著相关，而在非糖尿病患者中未发现类似关联。本研究结果提示，未来在PCI患者的风险评估和管理中，应充分考虑糖代谢状态对HDL-C和ApoA-I与预后关联的调节作用，以优化个体化治疗策略。

第三部分 糖尿病对冠状动脉介入患者残余胆固醇相关缺血风险的调节作用

摘要

背景：残余胆固醇（Remnant Cholesterol，RC）是冠心病患者缺血事件的公认风险因素。近年来研究表明，RC与心血管代谢紊乱，特别是糖尿病之间存在密切关系。然而，不同的糖代谢状态是否会改变RC与经皮冠状动脉介入术（Percutaneous Coronary Intervention, PCI）后缺血风险之间的关联尚不清楚。

目的： 本研究旨在探讨糖尿病是否影响PCI患者RC水平与缺血风险之间的关系。

方法：本研究前瞻性连续纳入了2013年接受PCI治疗的10724名患者。根据糖代谢状态将患者分为糖尿病组和非糖尿病组。空腹RC的计算方式为总胆固醇减去低密度脂蛋白胆固醇和高密度脂蛋白胆固醇，并根据三分位数水平（低、中、高）进行分组分析。主要研究终点为主要不良心脑血管事件，包括心原性死亡、非计划性血运重建和卒中。

结果：本研究最终纳入9406例患者，平均年龄为58.44 ± 10.26岁，其中女性2142例（22.8%）。在5年随访期间，共1876例患者（19.9%）发生主要不良心脑血管事件。在总人群中，RC最高三分位组患者的主要不良心脑血管事件风险显著高于最低三分位组（风险比：1.129，95%置信区间：1.006-1.267，P=0.039）。在糖尿病组中，多因素Cox回归分析显示RC最高三分位组患者的主要不良心脑血管事件风险显著增加（风险比：1.172，95%置信区间：1.004-1.369，P=0.045），而在非糖尿病组中未观察到类似关联（P>0.05）。

结论：在这项大样本5年长期随访研究中，首次证实在PCI患者中，糖尿病状态显著影响了RC与缺血事件结局之间的关联性。糖尿病患者中，RC越高预示心血管风险越高。本研究强调了在合并糖尿病的PCI患者中强化RC降低治疗的潜在益处。

Part ⅠEffect of inflammation on the HDL-C and ApoA-I related mortality risk among patients undergoing percutaneous coronary intervention

Abstract

Background: The association between high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) and cardiovascular risk in patients with coronary artery disease remains inconsistent. Recent investigations indicated potential dysfunctionality of HDL under inflammation.

Objective: This study endeavors to explore whether the inflammatory status modifies the effects of HDL-C and ApoA-I on cardiovascular risk in individuals with percutaneous coronary intervention (PCI).

Methods: Consecutive 10724 PCI patients at Fuwai hospital in 2013 were enrolled. Inflammation status was defined by high-sensitivity C-reactive proteins (hsCRP) ≥ 2 mg/L. The study endpoint was cardiac mortality.

Results: Among 9569 PCI patients eventually included, 225 (2.4%) cardiac mortality happened during 5 years. In hsCRP ≥ 2 mg/L group, an U-shaped curve was observed for HDL-C and multivariate Cox regression showed that elevated risks of cardiac mortality correlated to both the lowest quintile (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.32-4.71) and the highest quintile of HDL-C (HR, 2.28; 95% CI, 1.23-4.25). However, an L-shaped curve existed in ApoA-I, indicating only the lowest quintile level of ApoA-I was associated with an increased cardiac mortality risk (HR, 2.19; 95% CI, 1.28-3.75). Nevertheless, in hsCRP < 2 mg/L group, no significant correlations between HDL-C and ApoA-I and cardiac mortality risk were identified (both P > 0.05).

Conclusions: In PCI patients with hsCRP ≥ 2 mg/L. both low and high HDL-C levels correlated with higher cardiac mortality risk (U-shaped), while only low ApoA-I levels were linked to elevated risk (L-shaped). However, in patients with hsCRP < 2 mg/L, neither HDL-C nor ApoA-I levels were associated with higher cardiac mortality risk. These findings shed light on the importance of considering inflammation status, particularly hsCRP levels, in managing HDL-C and ApoA-I levels, and suggest targeting elevated ApoA-I levels as a potential therapeutic approach for PCI patients with hsCRP ≥ 2 mg/L.

Part II Modulation effect of glucose metabolism status on the ApoA-I related ischemic risk among patients with percutaneous coronary intervention

Abstract

Background: High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) have long been recognized for their cardioprotective effects. Recent studies suggest that the relationship between HDL-C, ApoA-I, and cardiovascular outcomes may be influenced by diabetes in patients without coronary artery disease (CAD). However, gaps persist in the association between HDL-C and ApoA-I on ischemic risk in patients with different glucose metabolism statuses in CAD patients undergoing percutaneous coronary intervention (PCI).

Objective: This study aim to investigate whether glucose metabolism status modifies the HDL-C and ApoA-I related ischemic risk in PCI patients.

Methods: This cohort study prospectively enrolled 10724 patients who underwent PCI in 2013. Patients were stratified into diabetes mellitus (DM) and non-DM groups. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, myocardial infarction, and stroke.

Results: Among 9397 PCI patients finally included, 1052 (11.2%) MACCEs occurred at 5-year follow-up. In the overall and DM cohort, both HDL-C and ApoA-I exhibited an L-shaped association with MACCE risk. Multivariable Cox regression analysis showed that in the DM group, patients in the lowest quintile of HDL-C (adjusted hazard ratio [HR]=1.326, 95% confidence interval [CI]: 1.003-1.753) and the lowest quintile of ApoA-I (adjusted HR=1.503, 95% CI: 1.151-1.962) had a significantly higher risk of MACCE. However, no significant association between HDL-C, ApoA-I, and MACCE risk was observed in the non-DM group (P>0.05).

Conclusions: In a large-scale 5-year follow-up study, we firstly demonstrated that lower HDL-C and ApoA-I levels are significantly associated with an increased ischemic risk in PCI patients with DM, whereas no such relationship was observed in non-DM patients. These findings suggest that future risk assessment and management strategies for PCI patients should consider the modulation effect of glucose metabolism status on HDL-C and ApoA-I to optimize personalized treatment approaches.

Part III Effect of glucose metabolism status on the relationship between remnant cholesterol and ischemic risk after percutaneous coronary intervention

Abstract

Background: Elevated remnant cholesterol (RC) is considered a risk factor for ischemic events in patients with coronary artery disease. Recently evidence demonstrates a close connection between RC and cardiometabolic disorders, particularly diabetes mellitus (DM). However, it remains unclear whether different glucose metabolism statuses modify the association between RC and ischemic risk after percutaneous coronary intervention (PCI).
Objective: This study aims to explore whether diabetes alter the relationship between RC and ischemic risk in PCI patients undergoing PCI.
Methods: This prospective study enrolled consecutive 10724 PCI patients undergoing PCI throughout 2013. Patients were categorized into DM and non-DM group. Fasting RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and was analyzed based on tertile levels (low, middle, and high). The clinical endpoint was major adverse cardiovascular and cerebrovascular events (MACCE, including cardiac mortality, revascularization and stroke).
Results: A total of 9406 PCI patients were ultimately included, among whom the average age was 58.44 ± 10.26 years and 2142 (22.8%) were female. During 5-year follow-up, 1876 (19.9%) patients experienced MACCE. In the overall cohort, the highest RC tertile was associated with a higher risk of MACCE (hazard ratio [HR]: 1.129, 95% confidence interval [CI]: 1.006-1.267, P=0.039) compared to those in the lowest tertile. Importantly, in the DM group, multivariate Cox regression analysis revealed that the highest tertile of RC significantly increased a 1.172-fold risk of MACCE (HR:1.172, 95% CI:1.004-1.369,  P=0.045). However, the non-DM group did not show any significant association between RC and MACCE (both P > 0.05).

Conclusions: In a large-scale 5-year follow-up study, we are the first to demonstrate that RC-related ischemic risk may be exacerbated by diabetes in PCI patients undergoing PCI, highlighting the potential benefits of intensifying RC-lowering treatments for PCI patients combined with DM.