Associations of Angiopoietin-like Protein 7 with Coronary Collateral Circulation and Prognosis of Patients with Severe Coronary Artery Stenosis

Congyi Cheng¹Chunlin Wang²Weichun Zhu¹Cong Su¹Youran Dong¹Junlin Teng¹Kang Fu¹Chungang Zhai^1*Lei Qiao^1*Wen-qiang Chen^1*

• ¹Qilu Hospital, Shandong University, Jinan, China
• ²Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

Backgroud: Angiogenesis and coronary collateral circulation (CCC) formation promote cardiac repair following severe coronary stenosis (SCS) or myocardial infarction (MI). Angiopoietin-like protein 7 (ANGPTL7) is a secreted protein associated with angiogenesis, but its role in CCC formation remains unclear. Objective: The aim of this study was to investigate the role of ANGPTL7 in angiogenesis and evaluate the predictive value of serum ANGPTL7 in CCC formation and the prognosis of patients with SCS. Materials and methods: The RNA sequencing was performed on myocardial tissues of mice to analyze the alterations of angiogenesis-related genes after MI. 100 patients with angiographically proven SCS and 36 controls were enrolled and retrospectively followed up. Serum ANGPTL7 was measured by enzyme-linked immunosorbent assays (ELISA). Human umbilical vein endothelial cells (HUVECs) and exogenous human recombinant ANGPTL7 protein were applied in assays including CCK-8, scratch, tube formation, cell immunofluorescence and western blot to demonstrate the proangiogenic effect of ANGPTL7. Gene Set Enrichment Analysis (GSEA) was used to perform KEGG pathway enrichment analysis on downstream mechanisms by which ANGPTL7 promoted angiogenesis. Results: The transcriptional level of Angptl7 was upregulated in ischemic myocardial tissues of MI mice, and its serum levels increased in both mice post-MI and patients with SCS. Spearman correlation analysis indicated that serum ANGPTL7 levels were positively correlated to CCC grades (r=0.518, P<0.001). Kaplan-Meier curves showed a higher serum ANGPTL7 was associated with a lower incidence of major adverse cardiovascular events (MACE) in patients with SCS (Log-rank test, P=0.002). Cox proportional hazards regression analyses showed that serum ANGPTL7 level was remained a protective factor after adjusting for different covariates. Time-dependent receiver-operating characteristics (ROC) curves further explored the prognostic value of ANGPTL7, with the area under the curve (AUC) of 0.77 at 1 year, 0.70 at 2 years and 0.85 at 3 years. Additionally, ANGPTL7 enhanced endothelial cell proliferation, migration and capillary-like structure formation, indicating a proangiogenic effect in vitro. Conclusion: ANGPTL7 serves as a predictive biomarker for CCC levels and the prognosis of patients with SCS, which probably attributed to its proangiogenic properties.