Reversal of NA+-K+ pump inhibition in the failing heart

Abstract

Abnormally raised cytosolic Na+ concentration in cardiac myocytes is a nodal point of multiple interacting abnormalities that perpetuate the heart failure syndrome. Understanding regulation of the Na+-K+ pump in the context of heart failure (HF) is therefore necessary for the development of successful therapies for a syndrome that currently has no curative treatment. This thesis investigated a novel mechanism of oxidative regulation of the Na+-K+ pump in a rabbit model of HF, whether this mechanism is associated with the efficacy of current treatments of HF, and its potential as a therapeutic target. Clinical efficacy of βAR blockade remains a paradox in HF treatment, however data presented in this thesis strongly suggests that reversal of oxidative inhibition of the Na+-K+ pump is a mechanism of β1AR blockade. A β3AR agonist shown to increase function of the Na+-K+ pump in vitro, also demonstrated reversal of oxidative inhibition of the Na+-K+ pump and significantly improved clinical indices such as pulmonary congestion. An additive clinical benefit of combined β1AR blockade and β3AR agonism was not observed. Data from this thesis has lead in part to the commencement of a Phase II clinical trial; Beta 3 Agonist Treatment in Heart Failure (Beat-HF) ClinicalTrials.gov Identifier: NCT01876433.