GLP-1 increases heart rate by a direct action on the sinus node

Anniek Frederike Lubberding; Simon Veedfald; Jonathan Samuel Achter; Sarah Dalgas Nissen; Luca Soattin; Andrea Sorrentino; Estefania Torres Vega; Benedikt Linz; Caroline Harriet Eggert Eggertsen; John Mulvey; Signe Toräng; Sara Agnete Larsen; Anne Nissen; Lonnie Grove Petersen; Secil Erbil Bilir; Bo Hjorth Bentzen; Mette Marie Rosenkilde; Bolette Hartmann; Thomas Nikolaj Bang Lilleør; Saddiq Qazi; Christian Holdflod Møller; Jacob Tfelt-Hansen; Stefan Michael Sattler; Thomas Jespersen; Jens Juul Holst; Alicia Lundby

doi:10.1093/cvr/cvae120

GLP-1 increases heart rate by a direct action on the sinus node

Anniek Frederike Lubberding, Simon Veedfald, Jonathan Samuel Achter, Sarah Dalgas Nissen, Luca Soattin, Andrea Sorrentino, Estefania Torres Vega, Benedikt Linz, Caroline Harriet Eggert Eggertsen, John Mulvey, Signe Toräng, Sara Agnete Larsen, Anne Nissen, Lonnie Grove Petersen, Secil Erbil Bilir, Bo Hjorth Bentzen, Mette Marie Rosenkilde, Bolette Hartmann, Thomas Nikolaj Bang Lilleør, Saddiq QaziChristian Holdflod Møller, Jacob Tfelt-Hansen, Stefan Michael Sattler, Thomas Jespersen, Jens Juul Holst^*, Alicia Lundby^*

^*Corresponding author for this work

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.

Original language	English
Journal	Cardiovascular Research
ISSN	0008-6363
DOIs	https://doi.org/10.1093/cvr/cvae120
Publication status	E-pub ahead of print - 4 Jun 2024

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

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

@article{6ed6657b836d4ef3a82698295248cdb7,

title = "GLP-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 Vega, {Estefania Torres} 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 Bilir, {Secil Erbil} 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",

month = jun,

day = "4",

doi = "10.1093/cvr/cvae120",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

TY - JOUR

T1 - GLP-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 - Vega, Estefania Torres

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 - Bilir, Secil Erbil

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

PY - 2024/6/4

Y1 - 2024/6/4

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

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

ER -

GLP-1 increases heart rate by a direct action on the sinus node

Abstract

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