β3-Adrenergic Receptor Agonism Reduces Right Ventricular Systolic Pressure in a Preclinical Model of Heart Failure With Preserved Ejection Fraction-Associated Pulmonary Hypertension

Purpose Pulmonary hypertension (PH) commonly complicates heart failure with preserved ejection fraction (HFpEF), driving morbidity and mortality, yet no therapies exist for HFpEF-PH. β3-adrenergic receptor (ADRB3) agonists may provide cardiometabolic and anti-inflammatory benefits. We evaluated pharmacological ADRB3 modulation in a preclinical HFpEF-PH model. Methods HFpEF-PH was induced in male and female AKR/J mice via high-fat diet feeding for 16-20 weeks. At 12-16 weeks of feeding, mice were randomized to low-dose mirabegron (LDM, 3.6 mg/kg/day), high-dose mirabegron (HDM, 14.4 mg/kg/day), nebivolol (1.0 mg/kg/day), or vehicle for 4 weeks. A separate cohort received the ADRB3 antagonist SR59230A (0.5 mg/kg/day) or vehicle. Right ventricular systolic pressure (RVSP), left ventricular end-diastolic pressure (LVEDP), body weight change, and gene expression of nitric oxide synthases ( Nos1 , Nos2 , Nos3 ), thermogenic markers ( Ucp1 , Ppargc1a ), and inflammatory cytokines ( Il1b , Il6 , Tnf ) were assessed. Results HDM and nebivolol significantly reduced RVSP compared to controls ( P =0.010 and P =1.0×10 -4 ), whereas SR59230A increased RVSP ( P =0.006). LDM did not significantly affect RVSP, and LVEDP was unchanged across all treatment groups. HDM also reduced weight gain vs. control ( P =0.023). HDM increased Ucp1 and Ppargc1a expression in adipose tissue, and nebivolol increased Ppargc1a expression in adipose tissue. These molecular findings remained significant in sensitivity analyses. Conclusion HDM and nebivolol reduced RVSP in a preclinical model of HFpEF-PH, whereas ADRB3 antagonism increased RVSP. These findings provide pharmacological evidence consistent with involvement of ADRB3 signaling and support further investigation of ADRB3-targeted approaches; the molecular pathways underlying these hemodynamic effects remain to be established.