Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. / Lubberding, Anniek Frederike; Veedfald, Simon; Achter, Jonathan Samuel; Nissen, Sarah Dalgas; Soattin, Luca; Sorrentino, Andrea; Torres Vega, Estefania; Linz, Benedikt; Eggertsen, Caroline Harriet Eggert; Mulvey, John; Toräng, Signe; Larsen, Sara Agnete; Nissen, Anne; Petersen, Lonnie Grove; Erbil Bilir, Secil; Bentzen, Bo Hjorth; Rosenkilde, Mette Marie; Hartmann, Bolette; Lilleør, Thomas Nikolaj Bang; Qazi, Saddiq; Møller, Christian Holdflod; Tfelt-Hansen, Jacob; Sattler, Stefan Michael; Jespersen, Thomas; Holst, Jens Juul; Lundby, Alicia.

In: Cardiovascular Research, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lubberding, AF, Veedfald, S, Achter, JS, Nissen, SD, Soattin, L, Sorrentino, A, Torres Vega, E, Linz, B, Eggertsen, CHE, Mulvey, J, Toräng, S, Larsen, SA, Nissen, A, Petersen, LG, Erbil Bilir, S, Bentzen, BH, Rosenkilde, MM, Hartmann, B, Lilleør, TNB, Qazi, S, Møller, CH, Tfelt-Hansen, J, Sattler, SM, Jespersen, T, Holst, JJ & Lundby, A 2024, 'Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node', Cardiovascular Research. https://doi.org/10.1093/cvr/cvae120

APA

Lubberding, A. F., Veedfald, S., Achter, J. S., Nissen, S. D., Soattin, L., Sorrentino, A., Torres Vega, E., Linz, B., Eggertsen, C. H. E., Mulvey, J., Toräng, S., Larsen, S. A., Nissen, A., Petersen, L. G., Erbil Bilir, S., Bentzen, B. H., Rosenkilde, M. M., Hartmann, B., Lilleør, T. N. B., ... Lundby, A. (2024). Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. Cardiovascular Research. https://doi.org/10.1093/cvr/cvae120

Vancouver

Lubberding AF, Veedfald S, Achter JS, Nissen SD, Soattin L, Sorrentino A et al. Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. Cardiovascular Research. 2024. https://doi.org/10.1093/cvr/cvae120

Author

Lubberding, Anniek Frederike ; Veedfald, Simon ; Achter, Jonathan Samuel ; Nissen, Sarah Dalgas ; Soattin, Luca ; Sorrentino, Andrea ; Torres Vega, Estefania ; Linz, Benedikt ; Eggertsen, Caroline Harriet Eggert ; Mulvey, John ; Toräng, Signe ; Larsen, Sara Agnete ; Nissen, Anne ; Petersen, Lonnie Grove ; Erbil Bilir, Secil ; Bentzen, Bo Hjorth ; Rosenkilde, Mette Marie ; Hartmann, Bolette ; Lilleør, Thomas Nikolaj Bang ; Qazi, Saddiq ; Møller, Christian Holdflod ; Tfelt-Hansen, Jacob ; Sattler, Stefan Michael ; Jespersen, Thomas ; Holst, Jens Juul ; Lundby, Alicia. / Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. In: Cardiovascular Research. 2024.

Bibtex

@article{996930abed2946409900563b618ccc35,
title = "Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node",
abstract = "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 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 (snRNAseq) 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 signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.",
author = "Lubberding, {Anniek Frederike} and Simon Veedfald and Achter, {Jonathan Samuel} and Nissen, {Sarah Dalgas} and Luca Soattin and Andrea Sorrentino and {Torres Vega}, Estefania and Benedikt Linz and Eggertsen, {Caroline Harriet Eggert} and John Mulvey and Signe Tor{\"a}ng and Larsen, {Sara Agnete} and Anne Nissen and Petersen, {Lonnie Grove} and {Erbil Bilir}, Secil and Bentzen, {Bo Hjorth} and Rosenkilde, {Mette Marie} and Bolette Hartmann and Lille{\o}r, {Thomas Nikolaj Bang} and Saddiq Qazi and M{\o}ller, {Christian Holdflod} and Jacob Tfelt-Hansen and Sattler, {Stefan Michael} and Thomas Jespersen and Holst, {Jens Juul} and Alicia Lundby",
note = "{\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2024",
doi = "10.1093/cvr/cvae120",
language = "English",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",

}

RIS

TY - JOUR

T1 - Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node

AU - Lubberding, Anniek Frederike

AU - Veedfald, Simon

AU - Achter, Jonathan Samuel

AU - Nissen, Sarah Dalgas

AU - Soattin, Luca

AU - Sorrentino, Andrea

AU - Torres Vega, Estefania

AU - Linz, Benedikt

AU - Eggertsen, Caroline Harriet Eggert

AU - Mulvey, John

AU - Toräng, Signe

AU - Larsen, Sara Agnete

AU - Nissen, Anne

AU - Petersen, Lonnie Grove

AU - Erbil Bilir, Secil

AU - Bentzen, Bo Hjorth

AU - Rosenkilde, Mette Marie

AU - Hartmann, Bolette

AU - Lilleør, Thomas Nikolaj Bang

AU - Qazi, Saddiq

AU - Møller, Christian Holdflod

AU - Tfelt-Hansen, Jacob

AU - Sattler, Stefan Michael

AU - Jespersen, Thomas

AU - Holst, Jens Juul

AU - Lundby, Alicia

N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2024

Y1 - 2024

N2 - 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 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 (snRNAseq) 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 signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

AB - 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 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 (snRNAseq) 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 signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

U2 - 10.1093/cvr/cvae120

DO - 10.1093/cvr/cvae120

M3 - Journal article

C2 - 38832935

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

ER -

ID: 393859663