Effects of liraglutide on heart function and myocardial perfusion entropy in a type-2 diabetic rat model

Abstract

Coronary microvascular dysfunction (CMD) is associated with a higher rate of major adverse cardiovascular events (MACEs) in diabetic patients. Liraglutide, a glucagon-like peptide-1 analog, decreases MACEs and all-cause mortality in this population. The present paper aims to study the effects of liraglutide on heart function and myocardial perfusion entropy (MPE) as a surrogate marker of coronary microvascular dysfunction (CMVD) in a rat model of type-2 diabetes. Thirty-nine rats were divided into three groups, control (CTL), diabetic (T2D) and liraglutide (DT2-LIR). T2D and T2D-LIR rats were fed a high-fat diet and injected with 35 mg/kg streptozotocin intra-peritoneally (IP) to induce diabetes. T2D-LIR rats were injected with a subcutaneous liraglutide solution for four weeks. Heart structure and function were assessed with trans-thoracic-doppler echocardiography and CMVD was assessed with a novel 201 Thallium SPECT-technique, measuring MPE, under stress conditions. Histological analysis was later performed. T2D rats had a significantly lower left ventricular (LV) ejection fraction (LVEF) versus CTL (64.5 ± 4.3% vs. 74.4 ± 9.2% P < 0.01), higher indexed LV mass (5.5 ± 1 g/m 2 vs. 3.8 ± 0.7 g/m 2 P < 0.001) and increased LV end diastolic diameter (LVEDD) (8.7 ± 0.4 mm vs. 7.5 ± 0.6 mm P < 0.001). Liraglutide increased LVEF (72.2 ± 6.9% vs. 64.5 ± 4.3% P < 0.05), LVSF (43.4 ± 6.6% vs. 36.9 ± 3.3% P < 0.05) versus T2D rats. MPE was significantly increased in T2D rats (7.59 ± 0.5 vs. 7.09 ± 0.5 P < 0.05), and there was no difference between T2D rats and T2D-LIR rats. In accordance with MPE analysis, CD31 immunohistochemistry analysus indicated a significant decrease in LV capillary density in TD2 animals, which was not improved by liraglutide. Liraglutide is associated with an improvement in heart systolic function and reduced LV hypertrophy in type 2 diabetic rats but only has a small specific effect on CMVD.