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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 + /Ca 2+ 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 Ca 2+ -optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD 80 ), Ca 2+ transient peak signals and durations at 80% recovery (CaTD 80 ), times to peak Ca 2+ (TTP 100 ) and Ca 2+ decay constants (Decay 30–90 ) during regular 10-Hz stimulation, and Ca 2+ transient alternans with shortening cycle length. Isoproterenol shortened APD 80 in sham-operated and TAC-only hearts, shortening CaTD 80 and Decay 30–90 but sparing TTP 100 and Ca 2+ transient alternans in all groups. All groups showed similar APD 80 , and TAC-only hearts showed greater CaTD 80 , 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, Ca 2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.
Wen et al. (Mon,) studied this question.