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

Area of Science:

• Cardiovascular Physiology
• Endocrinology
• Molecular Cardiology

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for type 2 diabetes and obesity.
• While GLP-1 RAs improve cardiovascular outcomes, they are associated with an unexplained increase in heart rate.

Purpose of the Study:

• To elucidate the mechanism by which GLP-1 RAs cause an increase in heart rate.
• To investigate the direct cardiac effects of GLP-1.

Main Methods:

• Utilized a large animal model (female landrace pig) with in vivo and ex vivo approaches.
• Conducted pharmacological challenges, electrophysiology studies, and high-resolution mass spectrometry.
• Performed single nucleus RNA sequencing and quantitative phosphoproteomics on sinus node samples.

Main Results:

• GLP-1 administration increased heart rate in anesthetized pigs, an effect not abolished by autonomic or HCN channel blockade.
• GLP-1 directly increased heart rate in isolated perfused pig hearts, an effect blocked by GLP-1 receptor antagonists.
• GLP-1 modulated electrical activity in the atria and conduction system, shortening action potential cycle length in isolated sinus node pacemaker cells.
• GLP-1 receptor expression was confirmed in porcine pacemaker cells.
• GLP-1 induced phosphorylation changes in calcium cycling proteins within the sinus node.

Conclusions:

• GLP-1 exerts direct chronotropic effects on the heart via GLP-1 receptors in sinus node pacemaker cells.
• The mechanism involves calcium signaling, specifically PKA-dependent phosphorylation of calcium cycling proteins, altering action potential morphology and pacemaker site.
• Targeting the pacemaker calcium clock presents a potential strategy to mitigate GLP-1 RA-induced tachycardia.