From Bench-Based PhD Project to First-in-Man Use of β3 Adrenergic Agonist in Patients with Treatment-Resistant Decompensated Congestive Heart Failure

Abstract

Na-K pump activity was reduced by 40% compared with controls, expected to raise cytosolic Na+ (Na+i), in myocytes from rabbits with a left ventricular ejection fraction (LVEF) < 25%, organ congestion and ascites after coronary artery ligation. Raised Na+i is harmful in congestive heart failure (CHF) and treatment with β3 adrenergic receptor (β3AR) agonists reversed pump inhibition, organ congestion and ascites. A trial of the β3AR agonist, mirabegron in patients with stable NYHA Class II CHF gave a signal for improved LVEF in patients with markedly reduced baseline LVEF. Based on our human and animal studies we have now prescribed mirabegron off-label on compassionate grounds in 7 patients aged 76 ± 6 years (±SD) with worsening CHF (WCHF) deemed treatment-resistant by 2 cardiologists. The patients were in NYHA Class III–IV, had a LVEF of 27 ± 6% and a systolic blood pressure of 112 ± 12 mm Hg. They received ACE-inhibitors and β1AR antagonists as tolerated and 2-3 different diuretics, furosemide given intravenously. Mirabegron was given orally as an alternative to, or with relapse of CHF after intravenous inotropes. Signs and symptoms improved markedly within 1-2 days of starting treatment. Mirabegron was well tolerated post-discharge, improvement was maintained and no patient re-admitted for CHF after 7.3 ± 3.5 months. In-hospital change in clinical trajectory, no readmission/death from CHF (∼50% for WCHF in general by 6 months and expected higher for patients here) and a mechanistic rationale for efficacy supports conducting a randomised trial of β3AR agonists in WCHF.