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While crucial for the acute physiologic response to stress, the adrenergic system may become maladaptive upon prolonged stimulation in the course of development of heart failure. This has been the basis for the development of beta-blocking therapies, targeting mainly beta1-2 adrenoreceptors (B1-2AR). The third isotype, B3AR, was more recently identified in cardiac myocytes and endothelial cells from human (and many other animal species), where its distinctive coupling to nitric oxide and antioxidant pathways suggested potential protective properties that were unexploited so far. The observation of beneficial effects of B3AR expression/activation on myocardial remodeling and the availability of specific agonists for clinical use now open the way for directly testing the hypothesis in heart failure patients. We will briefly review the specificities of B3AR signaling in the context of the cardiovascular adrenergic system, the evidence supporting its beneficial effects and outline an ongoing clinical trial using the B3AR agonist, mirabegron in patients with/at risk of developing heart failure with preserved ejection fraction (HFpEF).