Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear.
Methods And Results: We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened the action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate.
Conclusion: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signalling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pacemaking. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in people treated with GLP-1 RAs.
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http://dx.doi.org/10.1093/cvr/cvae120 | DOI Listing |
G Ital Cardiol (Rome)
January 2025
Cardiochirurgia, Azienda Ospedaliero Universitaria delle Marche, Università Politecnica delle Marche, Ancona.
Background: The introduction of transcatheter procedures has focused on patient expectations for treatments with a less invasive approach and faster recovery. The aim of this study was to assess the short- and medium-term results in patients who underwent trans-axillary mitral valve repair with application of the ultra-fast-track protocol.
Methods: Data from 431 patients undergoing isolated trans-axillary mitral valve repair or associated with tricuspid valve treatment between January 2018 and December 2023 were prospectively collected.
G Ital Cardiol (Rome)
January 2025
U.O.C. Cardiologia 1, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo.
Mineralocorticoid receptor antagonists (MRAs) represent one of the cornerstones of treatment for heart failure with reduced ejection fraction. Post-hoc data from the TOPCAT trial, conducted in patients with heart failure mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), suggest the possible clinical benefit of MRAs, particularly for slightly reduced ejection fraction values. The advent of non-steroidal MRAs, including finerenone, seems to represent a turning point in the treatment for HFmrEF/HFpEF.
View Article and Find Full Text PDFJ Vis Exp
December 2024
State Key Laboratory of Trauma, Burns and Combined Injuries, Medical Center of Trauma and War Injury, Daping Hospital, Army Medical University;
In this study, we developed and validated a hybrid quantitative model for simulating upper extremity junctional hemorrhage in swine, aiming to advance the development of pre-hospital hemostatic products. Utilizing 12 healthy 8-month-old male Yorkshire swine, we demonstrated the feasibility of a swine axillary artery injury model for evaluating hemostatic efficacy. Animals were divided into three groups to undergo volume-controlled hemorrhage (VCH), mimicking Class I-III hemorrhagic shock by withdrawing blood at different rates.
View Article and Find Full Text PDFInt J Cardiol Congenit Heart Dis
March 2024
Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Background: Children with univentricular heart (UVH) have a limited life expectancy without early treatment. Long-term survival in UVH, in an unselected nationwide cohort, is unclear.
Objectives: To determine long-term survival in patients with UVH including non-operated patients compared with a control population in Sweden.
Int J Cardiol Congenit Heart Dis
March 2024
Sydney Medical School, The University of Sydney, Camperdown, Australia.
Background: Brady- and tachyarrhythmias commonly complicate adult congenital heart disease (ACHD). Permanent pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) are often utilised to prevent morbidity or mortality related to arrhythmia, but can also be associated with significant morbidity themselves.
Methods: We analysed outcomes from patients in our comprehensive ACHD database who were seen at least twice since 2000 and once since 2018.
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