Glucagon-Like Peptide 1 Receptor Activation Augments Cardiac Output and Improves Cardiac Efficiency in Obese Swine After Myocardial Infarction

Abstract

This study tested the hypothesis that glucagon-like peptide 1 (GLP-1) therapies improve cardiac contractile function at rest and in response to adrenergic stimulation in obese swine after myocardial infarction. Obese Ossabaw swine were subjected to gradually developing regional coronary occlusion using an ameroid occluder placed around the left anterior descending coronary artery. Animals received subcutaneous injections of saline or liraglutide (0.005–0.015 mg/kg/day) for 30 days after ameroid placement. Cardiac performance was assessed at rest and in response to sympathomimetic challenge (dobutamine 0.3–10 μg/kg/min) using a left ventricular pressure/volume catheter. Liraglutide increased diastolic relaxation (dP/dt; Tau 1/2; Tau 1/e) during dobutamine stimulation (P < 0.01) despite having no influence on the magnitude of myocardial infarction. The slope of the end-systolic pressure volume relationship (i.e., contractility) increased with dobutamine after liraglutide (P < 0.001) but not saline administration (P = 0.63). Liraglutide enhanced the slope of the relationship between cardiac power and pressure volume area (i.e., cardiac efficiency) with dobutamine (P = 0.017). Hearts from animals treated with liraglutide demonstrated decreased β1-adrenoreceptor expression. These data support that GLP-1 agonism augments cardiac efficiency via attenuation of maladaptive sympathetic signaling in the setting of obesity and myocardial infarction.

Potential off-target effects of beta-blockers on gut hormone receptors: In silico study including GUT-DOCK—A web service for small-molecule docking

“…Gut hormone receptors are evolutionarily related to beta-adrenergic receptors (the intended targets of beta-blockers), though they are class B and class A GPCRs, respectively. Recently, the gut hormone receptors GLP1R and GCGR have also been experimentally confirmed as being important for cardiovascular system functioning [11–13]. GLP1RIn addition to the gastrointestinal tract, where many drugs are absorbed, gut hormone receptors are also expressed in the membranes of cardiac and vascular cells [14, 15], an expression pattern similar to that of beta-adrenergic receptors.…”

“…Similar cell and tissue expression patterns of the intended and unintended targets of a drug might favor the occurrence of the off-target interactions [16]. Recently, a relationship has been discovered between GLP-1-based therapies and the abundance of myocardial beta-1 adrenergic receptors, confirming an association between these two signaling pathways [11]. Additionally, studies have evaluated the use of glucagon in treating beta-blocker overdose [13] and heart failure [12].…”

Large Animal Models of Heart Failure

“…Early studies placed 2.0- to 2.5-mm ameroid constrictors around the LCx coronary artery, with gradual occlusion of blood flow resulting in a highly variable infarct size (5% to 37% of the LV) ( 96 , 97 ). Recently, an ameroid constrictor was placed on the LAD coronary artery for 4 weeks in obese Ossabaw swine, which resulted in infarct sizes of approximately 15% ( 98 ). Other studies that examined obese Ossabaw swine placed an ameroid constrictor around the LCx for 7 weeks, which resulted in a model of chronic ischemia as opposed to MI-induced HF because no infarcts were observed ( 99 , 100 ).…”

A GLP-1 Analog Liraglutide Reduces Intimal Hyperplasia After Coronary Stent Implantation via Regulation of Glycemic Variability and NLRP3 Inflammasome/IL-10 Signaling in Diabetic Swine

“…Angiography and optical coherence tomography (OCT) were performed at the end of 22 weeks. The six pigs in the L group received subcutaneous injections of liraglutide (0.005 mg/kg/day) referring to the previous publication (Sassoon et al, 2017) after stent implantation at 3 weeks until the end of 22 weeks.…”