Empagliflozin rescues pro-arrhythmic and Ca2+ homeostatic effects of transverse aortic constriction in intact murine hearts

  • Sci Rep. 2024 Jul 8;14(1):15683. doi: 10.1038/s41598-024-66098-7.
Qiang Wen  #  1 ,  Rui Zhang  #  2 ,  Kejun Ye  2 ,  Jun Yang  2 ,  Hangchuan Shi  3  4 ,  Zhu Liu  2 ,  Yangpeng Li  2 ,  Ting Liu  2 ,  Shiyu Zhang  2 ,  Wanpei Chen  2 ,  Jingjing Wu  1 ,  Weichao Liu  2 ,  Xiaoqiu Tan  2 ,  Ming Lei  2  5 ,  Christopher L-H Huang  6  7  8 ,  Xianhong Ou  9  10
Affiliations
  • 1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Rd, Wuhan, 430022, Hubei Province, China.
  • 2. Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Department of Cardiology of the Affiliated Hospital, Southwest Medical University, 1 Xianglin Rd, Luzhou, 646000, Sichuan Province, China.
  • 3. Department of Clinical & Translational Research, University of Rochester Medical Center, 265 Crittenden Blvd, Rochester, NY, 14642, USA.
  • 4. Department of Public Health Sciences, University of Rochester Medical Center, 265 Crittenden Blvd, Rochester, NY, 14642, USA.
  • 5. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
  • 6. Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Department of Cardiology of the Affiliated Hospital, Southwest Medical University, 1 Xianglin Rd, Luzhou, 646000, Sichuan Province, China. [email protected].
  • 7. Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. [email protected].
  • 8. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK. [email protected].
  • 9. Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Department of Cardiology of the Affiliated Hospital, Southwest Medical University, 1 Xianglin Rd, Luzhou, 646000, Sichuan Province, China. [email protected].
  • 10. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, 15 Yucai Rd, Guilin, 541004, Guangxi Province, China. [email protected].
  • # Contributed equally.
PMID: 38977794 DOI: 10.1038/s41598-024-66098-7
Abstract

We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2-6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/CA2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and CA2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), CA2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak CA2+ (TTP100) and CA2+ decay constants (Decay30-90) during regular 10-Hz stimulation, and CA2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30-90 but sparing TTP100 and CA2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, CA2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.

Keywords
Action potential duration; Ca2+ homeostasis; Empagliflozin; Heart failure; Transverse aortic constriction (TAC); Ventricular arrhythmia.
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