Glucagon-like peptide-1 directly increases heart rate and shortens atrial refractoriness: an in vivo and ex vivo study in pigs

Abstract

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Synergy program Novo Nordisk Foundation Center for Basic Metabolic Research Background Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes not only reduces hyperglycaemia, but also improves cardiovascular outcomes. However, GLP-1 RA treatment also increases heart rate: an apparent paradox. Purpose Whether the heart rate increase is a direct effect, and whether GLP-1 affects other aspects of cardiac electrophysiology, remain unclear. To answer these questions we investigated the effect of GLP-1 infusion on cardiac electrophysiology in vivo and ex vivo in pigs and pig hearts, respectively, during sinus rhythm and pacing. Methods Anaesthetised pigs (n = 8) received infusions of GLP-1 (10 pmol/kg/min). Electrocardiogram, atrial monophasic action potentials and atrial conduction velocity data were collected and atrial and ventricular effective refractory periods (ERP) were measured. For the ex vivo studies, pig hearts (n = 7) were excised, retrogradely perfused and exposed to consecutive bolus perfusions of 2 and 4 nmol GLP-1, 100 nmol of the GLP-1 receptor antagonist exendin-9-39 and a final 4 nmol bolus of GLP-1. The same electrophysiological parameters were measured. Results In anaesthetised pigs, GLP-1 increased heart rate, cardiac output and diastolic pressure, while systemic vascular resistance was decreased. Infusion of GLP-1 decreased PQ interval in sinus rhythm (P = 0.019, n = 8) and during atrial pacing (P = 0.027, n = 6) with 8 ± 3 % and 12 ± 3 %, respectively. Additionally, GLP-1 decreased atrial ERP at all pacing cycle lengths (P = 0.04, n = 7), while ventricular ERP was unaffected (P = 0.29, n = 7). In the isolated perfused heart, GLP-1 increased heart rate with 13 ± 2 bpm (P = 0.001, n = 7). This increase in heart rate was completely abolished by pre-administration of exendin-9-39. Atrial ERP shortened after GLP-1 perfusion (P = 0.01, n = 7) comparable to the in vivo studies, with an average decrease of 11 ± 2 %. This effect was also abolished by exendin-9-39. Conclusion GLP-1 increases heart rate through activation of the GLP-1 receptor in the isolated perfused heart, suggesting a direct effect of GLP-1 rather than activation through the central nervous system. Additionally, GLP-1 affects atrial electrophysiology, but not ventricular electrophysiology, in vivo and ex vivo independent of the increase in heart rate.