Atrial Electrophysiology and Arrhythmogenesis: Impacts of Diabetes Mellitus and Bruton's Tyrosine Kinase Inhibitors

Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder and is highly prevalent in patients with diabetes mellitus (DM). Despite this, the mechanisms by which DM initiates and progresses AF are poorly understood. Accordingly, the initial aim of this thesis was to investigate atrial electrical remodeling in db/db mice, an obesogenic model of type 2 DM. Db/db mice were found to have increased susceptibility to AF in association with a unique pattern of atrial electrical remodeling. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut that aids in glycemic control and has cardioprotective properties. Thus, additional studies were conducted to assess whether treating insulin-resistant db/db mice with GLP-1 or a GLP-1 mimetic (i.e., liraglutide) would prevent pathological atrial remodeling. In vivo studies showed that GLP-1 and liraglutide both significantly improved various aspects of atrial electrophysiology in the setting of DM. GLP-1 specifically improved atrial electrical remodeling in both intact atrial preparations and in atrial myocytes.The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, used in the treatment of B-cell lymphomas, also leads to new-onset AF in patients; however, a thorough investigation of the effects of BTK inhibitors on atrial electrophysiology has not been conducted. BTK inhibition can modulate similar signaling pathways to insulin, suggesting the possibility of common mechanisms with DM. The second aim of this thesis was to measure the effects of the BTK inhibitors ibrutinib and acalabrutinib on atrial electrophysiology. Acute superfusion of ibrutinib on atrial preparations resulted in slowed conduction velocity and prolonged action potentials; moreover, ibrutinib had direct effects on ionic currents in atrial myocytes. However, the next-generation BTK inhibitor acalabrutinib had fewer effects on atrial electrophysiology both in isolated preparations and myocytes. These results suggest that ibrutinib causes AF via off-target effects. While BTK inhibitors were hypothesized to have similar effects on atrial electrophysiology to type 2 DM, these studies provide new insight into the distinct mechanisms that underlie AF mediated by type 2 DM and BTK inhibitors. Additionally, these data suggest GLP-1 can aid in the prevention of atrial electrical remodeling in type 2 DM.