In the study, stimulation of the beta1-adrenergic receptor, in vitro in human and mouse cells and in vivo in mice, was shown to activate a beta-arrestin signaling pathway that required the G protein–coupled receptor kinases 5 and 6 and resulted in transactivation of EGFR. Signaling downstream of EGFR activation protected the heart muscle cells from the toxic effects of chronic signals from the beta1-adrenergic receptor transmitted through Gs-dependent adenylyl cyclase activation. The latter signals are associated with heart failure and so the authors suggest that drugs that block Gs-dependent adenylyl cyclase activation but activate beta-arrestin signaling might provide a new type of therapeutic for the prevention of heart failure.-Journal of Clinical Investigation