ADRB2 and hydrops fetalis: Importantly, it has been clearly shown both in humans and animal models that β-AR dysfunction in HF is GRK2-mediated: SNS hyperactivity triggers GRK2 upregulation that is activated at the beginning to counteract the excessive catecholaminergic drive but later, elevated GRK2 levels leads to dysfunctional β-AR signaling and decreased contractility/inotropic reserve (Figure 2) (Post et al., 1999; Floras, 2002; Penela et al., 2006; Agüero et al., 2012; Rengo et al., 2012b; Sato et al., 2015).