Association between angiopoietin-like protein 3 and frailty in cardiovascular disease patients

Abstract Background Frailty is increasingly prevalent in cardiovascular disease (CVD) patients and significantly impacts clinical outcomes, demanding better risk stratification. While Angiopoietin-like protein 3 (ANGPTL3), a regulator of lipid metabolism, is implicated in CVD development, its relationship with frailty in these patients remains unexplored. Aim To investigate the association between serum ANGPTL3 levels and frailty in CVD patients and to evaluate the prognostic significance and clinical determinants of ANGPTL3 in frail CVD patients. Methods This prospective observational study enrolled 357 CVD patients (143 frail, 214 non-frail) hospitalized between January 2022 and December 2023. Frailty was defined using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria. Fasting serum ANGPTL3 levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were followed for one year for major adverse cardiovascular events (MACE: all-cause death, non-fatal myocardial infarction, heart failure hospitalization, or ischemic stroke). Results Frail patients were older (76 71-82 vs. 72 64-78 years, p0.0001), more likely to be female (48.2% vs. 31.3%, p=0.001), and had a higher prevalence of diabetes (39.9% vs. 30.0%, p=0.033) compared to non-frail patients. Frail patients also exhibited lower albumin (3.89±0.43 vs. 4.08±0.36 g/dL, p0.0001), lower hemoglobin (12.5±2.2 vs. 13.3±1.7 g/dL, p0.0001), lower estimated glomerular filtration rate (57±23 vs. 62± 20 mL/min/1.73m², p=0.022), higher log-transformed C-reactive protein (-0.95±0.61 vs. -1.08±0.54, p=0.043), and lower triglycerides (92 63-132 vs. 105 68-153 mg/dL, p= 0.014). Notably, ANGPTL3 levels, which were not correlated with lipid parameters, were significantly higher in frail patients than in non-frail patients (83.1 67.8-109.2 vs. 79.7 59.4-99.9 ng/mL, p=0.014), with significant correlation with gait speed (r = -0.1755, p = 0.001), handgrip strength (r= -0.3018, p 0.0001), and muscle mass (r = -0.2117, p = 0.0001). While frail patients experienced more MACE than non-frail patients (log-rank test, p0.0001), ANGPTL3 demonstrated a discriminatory ability to identify further patients at higher risk of MACE within the frail group (cut-off value, 113 ng/mL; AUC=0.73, p=0.0001) but not in the non-frail group (p=0.65). Multivariate analysis identified aspartate aminotransferase and albumin as independent determinants of ANGPTL3 levels in frail patients. Conclusion Elevated ANGPTL3 levels are associated with frailty in CVD patients and predict MACE in frail individuals. ANGPTL3 may be a helpful risk stratification biomarker, specifically in the frail subset of CVD patients.