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Aim An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methods Experiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findings LG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. Significance LG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.

Intense endurance exercise is linked to atrial fibrillation (AF). We established previously that interventions that simultaneously interfere with TNFα signaling, mediated via both the enzymatically liberated soluble and membrane-bound forms of TNFα, prevent atrial remodeling and AF vulnerability in exercised mice. To investigate which signaling modality underlies this protection, we treated exercised mice with XPRO®1595, a selective dominant-negative inhibitor of solTNFα. In male CD1 mice, 6 weeks of intense swim exercise induced reductions in heart rate, increased cardiac vagal tone, left ventricular (LV) dilation and enhanced LV function. By contrast, exercise induced hypertrophy, fibrosis, and increased inflammatory cell infiltrates in atria, and these changes were associated with increased AF susceptibility in isolated atria as well as mice, with and without parasympathetic nerve blockade. Although XPRO treatment had no effect on the beneficial physiological changes induced by exercise, it protected against adverse atrial changes as well as AF susceptibility. Our results establish that soluble TNFα is required for exercise-induced increases in AF vulnerability, which is linked to fibrosis, inflammation, and enlargement of the atria, but largely independent of changes in vagal tone.

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.