New and Emerging Therapies and Targets: Beta-3 Agonists

Abstract

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).

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

“…As for now, results of the ongoing KNO3CKOUT-HFpEF trial, investigating effects of orally active potassium nitrate capsules, should be awaited, as they could differ from these previous findings (NCT02840799). β 3 AR-selective agonists Conventional beta-blockers mainly target β 1 -and β 2 -adrenoreceptors (β 1 -AR/β 2 -AR), which can mediate maladaptive effects of prolonged catecholamine exposure including cardiac remodeling [93]. Moreover, a third subtype of β-adrenoreceptors, β 3 -AR, has been identified in human hearts [94].…”

“…β 3 AR-selective agonists Conventional beta-blockers mainly target β 1 - and β 2 -adrenoreceptors (β 1 -AR/β 2 -AR), which can mediate maladaptive effects of prolonged catecholamine exposure including cardiac remodeling [ 93 ]. Moreover, a third subtype of β-adrenoreceptors, β 3 -AR, has been identified in human hearts [ 94 ].…”

Mirabegron: potential off target effects and uses beyond the bladder

“…While the β 3 ‐adrenoceptors have been postulated as a target for the treatment of heart failure (see Michel and Balligand, ), a recent clinical trial (the BEAT‐HF trial) of mirabegron in 70 patients with chronic heart failure, failed to reach its primary end point of increases in left ventricular ejection fraction (LVEF) (Bundgaard et al, ). These patients were treated with 150 mg mirabegron twice daily for 6 months, with all patients also administered with a β‐blocker to minimize effects of mirabegron on cardiac β 1 ‐adrenoceptors.…”

Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension

“…β3-AR mRNA expression has been found in the human myocardium [42] and vessels [43], and it has been described to be upregulated in left heart disease [42]. The coupling of β3-AR to the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway results in a cardiovascular effect opposed to classical β1and β2-AR effects, that it is thought to protect against deleterious adrenergic overactivation [44]. In recent years, several publications have demonstrated the cardioprotective effects of β3-AR stimulation in different experimental models of ischemia-reperfusion injury [45][46][47] and HF [48,49], including HF with preserved LVEF [50], through a NO-mediated mechanism.…”