Adiponectin predicts MACE in older patients with an acute coronary event and augments endothelial tissue factor activity in senescent cells
L Liberale, Y Wang, F Bruno, A Tirandi, F Carbone, D Ramoni, M Moriero, D Di Vece, G G Camici, F Montecucco, T F Luscher, S KralerAbstract
Background
Adiponectin exerts anti-inflammatory and vasculoprotective effects in healthy individuals. Conversely, in patients with established cardiovascular disease, elevations in circulating adiponectin are paradoxically linked to adverse outcomes; however, the underlying mechanisms remain completely unclear.
Purpose
To investigate the association between circulating adiponectin and major adverse cardiovascular events (MACE) after an acute coronary syndrome (ACS) and to explore its effects on endothelial pro-thrombotic activity.
Methods
Plasma adiponectin was measured by ELISA in 4,787 ACS patients (SPUM-ACS) prior to coronary angiography. The primary endpoint was 1-year MACE. Associations were assessed using Spearman correlation and multivariable Cox regression, including age-stratified and restricted cubic spline analyses. Event-free survival across adiponectin tertiles was evaluated using Kaplan–Meier analysis and log-rank testing. Early-passage (p6) as well as senescent (p16) primary human aortic endothelial cells (HAECs) were exposed to adiponectin, and prothrombotic pathways were investigated by Western Blot and colorimetric activity assays.
Results
Circulating adiponectin correlated with age (Spearman ρ=0.32, p<0.001). In multivariable Cox analysis, each doubling was associated with higher 1-year MACE, with a significant age interaction (P-interaction=0.020) (Figure 1). In patients ≥55 years, adiponectin independently predicted MACE (adjusted HR per doubling 1.28, 95% CI 1.14–1.44; p<0.001), whereas no association was observed in those <55 years (HR 0.85, 95% CI 0.62–1.17; p=0.318). In older patients, risk increased across tertiles, with T3 vs T1 showing higher risk (adjusted HR 1.68, 95% CI 1.24–2.26; p<0.001), while T2 vs T1 was not significant (HR 1.25, 95% CI 0.91–1.73; p=0.172). No tertile association emerged in younger patients. Restricted cubic splines confirmed a progressive risk increase with higher adiponectin only in older patients. In vitro, 50 µg/mL adiponectin increased TF activity in senescent vs early-passage HAECs, without changes in TF, PAI-1, or TFPI expression (Figure).
Conclusions
Elevated adiponectin predicts adverse cardiovascular outcomes after ACS in an age-dependent manner. Its ability to increase TF activity in senescent HAECs suggests a novel link between adiponectin and pro-thrombotic risk during vascular aging.