Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

Abstract

AbstractBackgroundReported one- and two-year mortality for patients with advanced heart failure (HF) treated medically are ~75% and nearly 100%. In such patients, reversible cellular abnormalities are potential treatment targets and a raised cytosolic Na+ concentration that impairs their myocardial contractility is one potential target. β3 adrenoceptor (β3 AR) agonists stimulate the myocyte Na+-K+ pump.MethodsWe induced severe HF in rabbits by coronary ligation and measured indices of organ congestion after treatment with β3 AR agonists. Na+-K+ pump current was measured in voltage-clamped myocytes isolated from non-infarct myocardium. To assess if β3 ARs might add benefit to optimised guideline-directed medical treatment we report outcomes of giving the β3 AR agonist mirabegron to patients hospitalized with advanced, treatment-refractory stage D HF.ResultsTreatment of rabbits after coronary ligation with β3 AR agonist reversed a decreased myocyte Na+-K+ pump current and significantly reduced organ congestion and prevalence of ascites. Oral treatment with mirabegron rapidly improved signs and symptoms of 9 patients with advanced HF and improvement of ≥1 NYHA Class was maintained early post-discharge with continued treatment. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 38 ± 4 months with NYHA Class II symptoms.ConclusionsParallel β3 AR agonist-induced reversal of Na+-K+ pump inhibition and severe HF in rabbits identify pump inhibition as a treatment target, and changed in-hospital clinical trajectory and post-discharge course more favorable than expected suggest efficacy of mirabegron in advanced human HF.