The unload-then-agonise hypothesis: Haemodynamic unloading as a biophysical prerequisite for apelin receptor agonism in heart failure

Heart failure remains a major cause of morbidity and mortality, and the apelin receptor (APJ) represents a biologically attractive therapeutic target. Direct APJ agonists have shown favourable haemodynamic and structural effects in preclinical models yet have not demonstrated convincing clinical benefit in heart failure trials. This experience contrasts with sodium glucose co-transporter 2 inhibitors (SGLT2i), which reduce heart failure events and appear to enhance apelin related signalling and ventricular remodelling. We propose the unload-then-agonise hypothesis to reconcile these divergent findings. APJ is a mechanosensitive receptor; in chronically pressure- and volume-overloaded ventricles, increased mechanical stretch biases the receptor toward β-arrestin-dominated, desensitised signalling and away from Gαi-mediated cardioprotective pathways. Consequently, direct APJ agonists are delivered into a receptor population that is biophysically refractory to ligand-driven activation. We suggest that sustained haemodynamic unloading is therefore a critical biophysical prerequisite for effective apelinergic therapy. Within this framework, SGLT2 inhibitors act as receptor permissibility factors that reduce ventricular wall stress and reset the APJ ensemble into a more Gαi-accessible state, allowing endogenous or exogenous agonists to exert meaningful benefit. The unload-then-agonise hypothesis provides a mechanistic explanation for the neutral results of prior APJ agonist trials and generates testable predictions regarding the timing and context in which future APJ targeted strategies should be evaluated.