Li Ben, Shaikh Farah, Younes Houssam, Abuhalimeh Batool, Chin Jason, Rasheed Khurram, Zamzam Abdelrahman, Abdin Rawand, Qadura Mohammad
Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada.
Division of Vascular Surgery, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada.
J Cardiovasc Dev Dis. 2024 Dec 13;11(12):402. doi: 10.3390/jcdd11120402.
The most common cause of death in patients with peripheral artery disease (PAD) are major adverse cardiovascular events (MACEs), including myocardial infarction (MI) and stroke. However, data on biomarkers that could be used to help predict MACEs in patients with PAD to guide clinical decision making is limited. Angiogenesis-related proteins have been demonstrated to play an important role in systemic atherosclerosis and may act as prognostic biomarkers for MACEs in patients with PAD. In this study, we evaluated a large panel of angiogenesis-related proteins and identified specific biomarkers associated with MACEs in patients with PAD.
We conducted a prognostic study using a prospectively recruited cohort of 406 patients (254 with PAD and 152 without PAD). Plasma concentrations of 22 circulating angiogenesis-related proteins were measured at baseline, and the cohort was followed for 2 years. The primary outcome was 2-year MACEs (composite of MI, stroke, or death). Plasma protein concentrations were compared between PAD patients with and without 2-year MACEs using Mann-Whitney U tests. Differentially expressed proteins were further investigated in terms of their prognostic potential. Specifically, Cox proportional hazards analysis was performed to determine the independent association between differentially expressed proteins and 2-year MACEs, controlling for all baseline demographic and clinical characteristics, including existing coronary artery disease and cerebrovascular disease. Kaplan-Meier analysis was conducted to assess 2-year freedom from MACEs in patients with low vs. high levels of the differentially expressed proteins based on median plasma concentrations.
The mean age of the cohort was 68.8 (SD 11.1), and 134 (33%) patients were female. Two-year MACEs occurred in 63 (16%) individuals. The following proteins were significantly elevated in PAD patients with 2-year MACEs compared to those without 2-year MACEs: endostatin (69.15 [SD 58.15] vs. 51.34 [SD 29.07] pg/mL, < 0.001), angiopoietin-like protein 4 (ANGPTL4) (0.20 [SD 0.09] vs. 0.12 [SD 0.04] pg/mL, < 0.001), and ANGPTL3 (51.57 [SD 21.92] vs. 45.16 [SD 21.90] pg/mL, = 0.001). Cox proportional hazards analysis demonstrated that these three proteins were independently associated with 2-year MACEs after adjusting for all baseline demographic and clinical characteristics: endostatin (HR 1.39 [95% CI 1.12-1.71] < 0.001), ANGPTL4 (HR 1.35 [95% CI 1.08-1.68], < 0.001), and ANGPTL3 (HR 1.35 [95% CI 1.12-1.63], < 0.001). Over a 2-year follow-up period, patients with higher levels of endostatin, ANGPTL4, and ANGPTL3 had a lower freedom from MACEs. Supplementary analysis demonstrated that these three proteins were not significantly associated with 2-year MACEs in patients without PAD.
Among a panel of 22 angiogenesis-related proteins, endostatin, ANGPTL4, and ANGPTL3 were identified to be independently and specifically associated with 2-year MACEs in patients with PAD. Measurement of plasma concentrations of these proteins can support MACE risk stratification in patients with PAD, thereby informing clinical decisions on multidisciplinary referrals to cardiologists, neurologists, and vascular medicine specialists and guiding aggressiveness of medical treatment, thereby improving cardiovascular outcomes in patients with PAD.
外周动脉疾病（PAD）患者最常见的死亡原因是主要不良心血管事件（MACE），包括心肌梗死（MI）和中风。然而，关于可用于帮助预测PAD患者MACE以指导临床决策的生物标志物的数据有限。血管生成相关蛋白已被证明在全身动脉粥样硬化中起重要作用，并且可能作为PAD患者MACE的预后生物标志物。在本研究中，我们评估了一大组血管生成相关蛋白，并确定了与PAD患者MACE相关的特定生物标志物。
我们使用前瞻性招募的406名患者队列（254名PAD患者和152名无PAD患者）进行了一项预后研究。在基线时测量22种循环血管生成相关蛋白的血浆浓度，并对该队列进行了2年的随访。主要结局是2年MACE（MI、中风或死亡的复合结局）。使用Mann-Whitney U检验比较有和没有2年MACE的PAD患者之间的血浆蛋白浓度。对差异表达的蛋白质的预后潜力进行了进一步研究。具体而言，进行Cox比例风险分析以确定差异表达的蛋白质与2年MACE之间的独立关联，同时控制所有基线人口统计学和临床特征，包括现有的冠状动脉疾病和脑血管疾病。基于血浆浓度中位数，进行Kaplan-Meier分析以评估低水平与高水平差异表达蛋白的患者2年无MACE情况。
该队列的平均年龄为68.8岁（标准差11.1），134名（33%）患者为女性。63名（16%）个体发生了2年MACE。与没有2年MACE的PAD患者相比，有2年MACE的PAD患者中以下蛋白质显著升高：内皮抑素（69.15 [标准差58.15] vs. 51.34 [标准差29.07] pg/mL，P < 0.001）、血管生成素样蛋白4（ANGPTL4）（0.20 [标准差0.09] vs. 0.12 [标准差0.04] pg/mL，P < 0.001）和ANGPTL3（51.57 [标准差21.92] vs. 45.16 [标准差21.90] pg/mL，P = 0.001）。Cox比例风险分析表明，在调整所有基线人口统计学和临床特征后，这三种蛋白质与2年MACE独立相关：内皮抑素（HR 1.39 [95% CI 1.12 - 1.71]，P < 0.001）、ANGPTL4（HR 1.35 [95% CI 1.08 - 1.68]，P < 0.001）和ANGPTL3（HR 1.35 [95% CI 1.12 - 1.63]，P < 0.001）。在2年的随访期内，内皮抑素、ANGPTL4和ANGPTL3水平较高的患者无MACE的情况较少。补充分析表明，在无PAD的患者中，这三种蛋白质与2年MACE无显著关联。
在22种血管生成相关蛋白中，内皮抑素、ANGPTL4和ANGPTL3被确定与PAD患者的2年MACE独立且特异性相关。测量这些蛋白质的血浆浓度可以支持PAD患者的MACE风险分层，从而为转诊至心脏病专家、神经科医生和血管医学专家的多学科临床决策提供信息，并指导积极的药物治疗，从而改善PAD患者的心血管结局。
