Effects of empagliflozin and target-organ damage in a novel rodent model of heart failure induced by combined hypertension and diabetes

Kristin Kräker,Friedrich C Luft,Florian Herse,Michaela Golic,Natalia Alenina,Dominik N Müller,Ralf Dechend,Jana Grune,Manal Ebrahim,Michael Bader,Olaf Strauß,Nadine Haase,Arnd Heuser,Ulrich Kintscher,Nadine Reichhart,Sergio Crespo-Garcia

doi:10.1038/s41598-020-70708-5

Abstract

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.

Highlights

Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage
Transgenic rats carrying the murine Ren[27] gene represent a monogenetic model of hypertension induced end organ damage characterized by low plasma renin and high extra renal expression of the transgene[12]. It remains an unanswered question from the clinical trials whether the positive effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on heart failure occur predominantly in heart failure with a preserved ejection fraction (HFpEF) or heart failure with a reduced ejection fraction (HFrEF)
Surviving rats that could be measured had a marked reduction of systolic function and the worst global longitudinal strain, radial strain, and circumferential strain, we have introduced a novel model of two step heart failure (HF)

Summary

Introduction

Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. 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. Transgenic rats carrying the murine Ren[27] gene represent a monogenetic model of hypertension induced end organ damage characterized by low plasma renin and high extra renal expression of the transgene[12] It remains an unanswered question from the clinical trials whether the positive effects of SGLT2 inhibitors on heart failure occur predominantly in heart failure with a preserved ejection fraction (HFpEF) or heart failure with a reduced ejection fraction (HFrEF)

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Discussion

Conclusion