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

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 (Decay_30-90) 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 Decay_30-90 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.