Effects of empagliflozin and target-organ damage in a novel rodent model of heart failure induced by combined hypertension and diabetes
Creators: name: Kräker, Kristin
name: Herse, Florian
name: Golic, Michaela
name: Reichhart, Nadine
name: Crespo-Garcia, Sergio
name: Strauß, Olaf
name: Grune, Jana
name: Kintscher, Ulrich
name: Ebrahim, Manal
name: Bader, Michael
name: Alenina, Natalia
name: Heuser, Arnd
name: Luft, Friedrich C.
name: Müller, Dominik N.
name: Dechend, Ralf
name: Haase, Nadine
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2020
Subjects: subject: Animals
subject: Benzhydryl Compounds
subject: C-Peptide
subject: Cardiotonic Agents
subject: Diabetes Mellitus, Type 2
subject: Disease Models, Animal
subject: Glucosides
subject: Heart Failure
subject: Hyperinsulinism
subject: Rats
subject: Rats, Sprague-Dawley
subject: Rats, Transgenic
subject: Sodium-Glucose Transporter 2 Inhibitors
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

description: Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. Lowering blood sugar by the sodium-glucose co-transporter 2 inhibitor empagliflozin provides cardiac protection. We established a new rat model that develops both inducible diabetes and genetic hypertension and investigated the effect of empagliflozin treatment to test the hypothesis if empagliflozin will be protective in a heart failure model which is not based on a primary vascular event. The transgenic Tet29 rat model for inducible diabetes was crossed with the mRen27 hypertensive rat to create a novel model for heart failure with two stressors. The diabetic, hypertensive heart failure rat (mRen27/tetO-shIR) were treated with empagliflozin (10 mg/kg/d) or vehicle for 4 weeks. Cardiovascular alterations were monitored by advanced speckle tracking echocardiography, gene expression analysis and immunohistological staining. The novel model with increased blood pressure und higher blood sugar levels had a reduced survival compared to controls. The rats develop heart failure with reduced ejection fraction. Empagliflozin lowered blood sugar levels compared to vehicle treated animals (182.3 ± 10.4 mg/dl vs. 359.4 ± 35.8 mg/dl) but not blood pressure (135.7 ± 10.3 mmHg vs. 128.2 ± 3.8 mmHg). The cardiac function was improved in all three global strains (global longitudinal strain − 8.5 ± 0.5% vs. − 5.5 ± 0.6%, global radial strain 20.4 ± 2.7% vs. 8.8 ± 1.1%, global circumferential strain − 11.0 ± 0.7% vs. − 7.6 ± 0.8%) and by increased ejection fraction (42.8 ± 4.0% vs. 28.2 ± 3.0%). In addition, infiltration of macrophages was decreased by treatment (22.4 ± 1.7 vs. 32.3 ± 2.3 per field of view), despite mortality was not improved. Empagliflozin showed beneficial effects on cardiovascular dysfunction. In this novel rat model of combined hypertension and diabetes, the improvement in systolic and diastolic function was not secondary to a reduction in left ventricular mass or through modulation of the afterload, since blood pressure was not changed. The mRen27/tetO-shIR strain should provide utility in separating blood sugar from blood pressure-related treatment effects.