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Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats

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Abstract

The study aimed to investigate the effects of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on chronic heart failure (HF) in normoglycemic rats. The effects of empagliflozin were compared with the standard medications for HF, e.g., angiotensin-converting enzyme (ACE) inhibitor fosinopril, beta-blocker bisoprolol, and aldosterone antagonist spironolactone. Myocardial infarction (MI) was induced in male Wistar rats via permanent ligation of the left descending coronary artery. One-month post MI, 50 animals were randomized into 5 groups (n = 10): vehicle-treated, empagliflozin (1.0 mg/kg), fosinopril (10 mg/kg), bisoprolol (10 mg/kg), and spironolactone (20 mg/kg). All medications except empagliflozin were titrated within a month and administered per os daily for 3 months. Echocardiography, 24-hour urine volume test, and treadmill exercise tests were performed at the beginning and at the end of the study. Treatment with empagliflozin slowed the progression of left ventricular dysfunction: LV sizes and ejection fraction were not changed and the minute volume was significantly increased (from 52.0 ± 15.5 to 61.2 ± 21.2 ml/min) as compared with baseline. No deaths occurred in empagliflozin group. The 24-hour urine volume tends to be higher in empagliflozin and spironolactone groups than in vehicle and fosinopril group. Moreover, empagliflozin exhibited maximal physical exercise tolerance in comparison with all investigated groups (289 ± 27 s versus 183 ± 61 s in fosinopril group, 197 ± 95 s in bisoprolol group, and 47 ± 46 s in spironolactone group, p = 0.0035 for multiple comparisons). Sodium-glucose co-transporter 2 inhibitor empagliflozin reduced progression of left ventricular dysfunction and improved tolerance of physical exercise in normoglycemic rats with HF. Empagliflozin treatment was superior with respect to physical tolerance compared with fosinopril, bisoprolol, and spironolactone.

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Abbreviations

ACE:

Angiotensin-converting enzyme

CV:

Cardiovascular

EF:

Ejection fraction

FS:

Left ventricular fraction shortening

HF:

Heart failure

HR:

Heart rate

IVST:

Interventricular septum thickness

LA_ap:

Left atrial antero-posterior dimension

LA_l:

Left atrial long axis dimension

LA_s:

Left atrial short axis dimension

LV:

Left ventricular

LV EDV:

Left ventricular end-diastolic

LV EDD:

Left ventricle end-diastolic diameter

LV ESD:

Left ventricle end-systolic diameters

LV ESV:

Left ventricular end-systolic volumes

LVM:

Left ventricular myocardium mass

MAPSE:

Mitral annular plane systolic excursion

MI:

Myocardial infarction

MV:

Left ventricular minute volume

PWT:

Left ventricular posterior wall thickness in diastole

RA_l:

Long axis dimensions

RA_s:

Right atrium short axis

RAAS:

Angiotensin aldosterone system

RV:

Right ventricle antero-posterior dimension

RWT:

Left ventricular relative wall thickness

SGLT2:

Sodium-glucose co-transporter 2

SV:

Stroke volume

T2D:

Type 2 diabetes

TAPSE:

Tricuspid annular plane systolic excursion

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Acknowledgments

We thank Kaiukov I.G., Beresneva O.N., and Galkina O.V. for their excellent technical assistance.

Funding

This work was supported by the St. Petersburg Chemical and Pharmaceutical University, Saint Petersburg, Russia.

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology, Center of Experimental Pharmacology Saint Petersburg Chemical Pharmaceutical University, Saint Petersburg, Russia

    Marina Krasnova, Sergey Okovityi & Dmitry Ivkin

  2. Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia

    Alexander Kulikov & Alexey Smirnov

  3. Almazov National Medical Research Centre, Saint Petersburg, Russia

    Andrey Karpov

  4. Charite Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, German Centre for Cardiovascular Research, Berlin, Germany

    Elena Kaschina

Authors
  1. Marina Krasnova
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  2. Alexander Kulikov
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  4. Dmitry Ivkin
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  5. Andrey Karpov
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  6. Elena Kaschina
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  7. Alexey Smirnov
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Contributions

M. Krasnova: provision of study material, collection and assembly of data, data analysis and interpretation, and manuscript writing; A. Kulikov: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; S. Okovityi: conception and design, administrative support, data analysis, and interpretation; D. Ivkin: collection and assembly of data and data analysis; A. Smirnov: collection and assembly of data; A. Karpov: statistical data analysis and interpretation; E. Kaschina: data analysis and interpretation, manuscript writing advising, and final approval of manuscript. All authors read and approved the manuscript.

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Correspondence to Marina Krasnova.

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Krasnova, M., Kulikov, A., Okovityi, S. et al. Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1649–1658 (2020). https://doi.org/10.1007/s00210-020-01873-7

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