Association of Hepatocyte Growth Factor and Angiopoietin-2 with Systemic Cardiovascular Risk in Patients with Peripheral Artery Disease

Abstract

Background/Objectives: Major adverse cardiovascular events (MACE) are the primary cause of mortality among individuals with peripheral artery disease (PAD). Despite this, there is limited research on biomarkers that can predict MACE risk in this population. Proteins involved in angiogenesis are integral to both systemic circulation and the development of atherosclerosis, indicating their potential as prognostic markers. This study aimed to identify angiogenesis-related proteins associated with MACE risk in PAD patients. Methods: We conducted a prospective cohort study involving 250 patients diagnosed with PAD. At baseline, plasma levels of 17 angiogenesis-related proteins were measured. Participants were followed for two years, with the primary outcome being the incidence of MACE-a composite of stroke, myocardial infarction, or death. Protein concentrations were compared between those who experienced 2-year MACE and those who did not using the Mann-Whitney U test. Proteins showing significant differences were further analyzed using Cox proportional hazards modeling to assess their independent associations with MACE, adjusting for baseline demographic and clinical variables, including prior coronary and cerebrovascular disease. Kaplan-Meier survival analysis was also employed to compare MACE-free survival based on protein concentration levels. Results: The average age of participants was 69 years (SD 9), with 32% (n = 80) being female. Over the two-year follow-up, 48 patients (19.8%) experienced MACE. Among the proteins assessed, only hepatocyte growth factor (HGF) and angiopoietin-2 were significantly elevated in patients who developed MACE (HGF: 390.83 [SD 319.16] vs. 300.55 [SD 177.53] pg/mL, p < 0.001; angiopoietin-2: 23.67 [SD 17.60] vs. 19.36 [SD 12.06] pg/mL, p = 0.020). Multivariable Cox analysis confirmed that elevated levels of both HGF (adjusted HR 1.37; 95% CI 1.14-1.64; p = 0.001) and angiopoietin-2 (adjusted HR 1.27; 95% CI 1.04-1.55; p = 0.016) were independently associated with increased 2-year MACE risk. Kaplan-Meier curves demonstrated significantly reduced MACE-free survival in patients with higher levels of HGF and angiopoietin-2. Conclusions: HGF and angiopoietin-2 emerged as significant, independent predictors of 2-year MACE in patients with PAD. Measuring plasma levels of these proteins may enhance risk stratification, guiding referrals to appropriate cardiovascular specialists and informing the intensity of medical management. This biomarker-based precision medicine approach holds potential for improving cardiovascular outcomes in the PAD population.

Keywords: angiogenesis-related proteins; angiopoietin-2; hepatocyte growth factor; major adverse cardiovascular events; peripheral artery disease; prognosis.

Figure 1

Kaplan–Meier survival analysis showing freedom from major adverse cardiovascular events in individuals with peripheral artery disease, stratified by high versus low HGF levels, determined by the median plasma concentration in the cohort of 317.9 pg/mL. The Cox proportional hazards model was applied, adjusting for variables including age, sex, hypertension, dyslipidemia, diabetes, current/past smoking, congestive heart failure, coronary artery disease, and previous stroke. Abbreviations: HR (hazard ratio), MACE (major adverse cardiovascular event), and CI (confidence interval).

Figure 2

Kaplan–Meier survival analysis showing freedom from major adverse cardiovascular events in individuals with peripheral artery disease, stratified by high versus low angiopoietin-2 levels, determined by the median plasma concentration in the cohort of 20.2 pg/mL. The Cox proportional hazards model was applied, adjusting for variables including age, sex, hypertension, dyslipidemia, diabetes, current/past smoking, congestive heart failure, coronary artery disease, and previous stroke. Abbreviations: HR (hazard ratio), MACE (major adverse cardiovascular event), and CI (confidence interval).