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.

Figure 1

Quantification of myocardial infarction. Images (top) present representative transmural sections of a left ventricle. Unstained (white) tissue within the myocardium indicates infarcted tissue. Infarct was quantified (bottom) as the percentage of total left ventricular area of all slices. Liraglutide did not reduce infarct size (saline: 15.5 ± 1.9% of myocardium infarcted [n = 4] vs. liraglutide: 13.9 ± 5.4% [n = 6]; P = 0.81).

Figure 2

Cardiac effects of liraglutide. Representative PV relationships of saline-treated (A) and liraglutide-treated (B) animals before dobutamine administration (solid lines) and at 10 μg/kg/min after dobutamine (dashed lines). Dobutamine administration resulted in a profound leftward shift in saline-treated animals that was attenuated in liraglutide-treated animals. C: The volume axis intercept (V₀) was significantly lower across the range of dobutamine infusions. D: Ees did not increase across a range of dobutamine administration in saline-treated animals but was significantly increased at the highest dobutamine dose in liraglutide-treated animals relative to saline-treated animals. Values for panels C and D are mean ± SE for saline (n = 5) and liraglutide (n = 7). *P < 0.05 vs. baseline value (same treatment). †P < 0.05 vs. dobutamine infusion rate-matched, saline controls.

Figure 3

Effects of liraglutide treatment on cardiac volumes, oxygen consumption, and power. A: Dobutamine administration resulted in similar and significant decreases in EDV in both saline- and liraglutide-treated animals. B: CO exhibited a similar decrease with dobutamine administration in liraglutide- but not saline-treated animals. C: PVA similarly decreased in liraglutide-treated animals only. D: Cardiac power, however, was significantly greater on average in liraglutide-treated animals relative to saline controls. Values are mean ± SE for saline (n = 5) and liraglutide (n = 7). Displayed P values denote the overall treatment group comparison for differences in response to dobutamine. *P < 0.05 comparing individual doses against baseline within the treatment group (significant in panel C only for the liraglutide-treated animals). †P < 0.05 comparing the treatment groups under resting conditions.

Figure 4

Liraglutide increases CO via a load-independent mechanism. Liraglutide treatment resulted in an increase in the slope of the relationship between CO and EDV (P = 0.002 by ANCOVA). As defined by the Frank-Starling law of the heart, a load-dependent increase in CO would result in a shift of values that would still fit the control line. A change in slope is indicative of a load-independent increase in CO. This analysis includes data points from all animals at all measurement points. Saline (n = 5) and liraglutide (n = 7).

Figure 5

Liraglutide increases cardiac efficiency. A: The slope of the relationship between cardiac power and PVA was greater in liraglutide-treated swine hearts. The increased ratio of PVA (an index of cardiac oxygen consumption) to cardiac power evident in liraglutide-treated animals establishes that liraglutide increased the ratio of cardiac work to cardiac energetics. P value is by ANCOVA; P = 0.02 for homogeneity of regressions. B: To better establish efficiency at each dose of dobutamine, the ratio of cardiac power to the PVA was calculated for each animal at each dose. Liraglutide therapy increased the efficiency of this relationship overall (P = 0.005) and at the highest dose of dobutamine relative to both baseline and the dobutamine dose-matched saline control. *P < 0.05 comparing individual doses against baseline within the treatment group. †P < 0.05 comparing the treatment groups under resting conditions. Saline (n = 5) and liraglutide (n = 7).

Figure 6

Liraglutide decreases expression of βADR. Liraglutide-treated animals exhibited significantly decreased left ventricular βADR abundance relative to saline-treated animals. Images show representative left ventricular myocardial staining for βADR in saline-treated (top) and liraglutide-treated (bottom) animals. Values are mean ± SE for saline (n = 4) and liraglutide (n = 4). †P < 0.05 vs. treatment same condition.