PDF(Pubmed)
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.
摘要：
我们探索了钠-葡萄糖共转运蛋白2抑制剂empagliflozin在横行主动脉缩窄（TAC）后对完整的实验性肥大小鼠心脏的生理作用。术后药物（2-6周）激发导致晚期Na+电流减少，和增加磷酸化（p-）CaMK-II和Nav1.5，但不是总（t）-CaMK-II，和Na+/Ca2+交换表达，确认以前的心肌细胞水平报告。它挽救了TAC引起的超声心动图射血分数和缩短分数的减少，和舒张前后壁增厚。Langendorff灌注心脏的双电压和Ca2光学作图表明，依帕格列净在80％恢复时（APD80）挽救了TAC诱导的动作电位持续时间增加，恢复80%时的Ca2+瞬态峰值信号和持续时间(CaTD80),在常规10Hz刺激期间达到峰值Ca2+(TTP100)和Ca2+衰变常数(Decay30-90)的倍数，和Ca2+瞬时交替循环长度缩短。异丙肾上腺素在假手术和仅TAC心脏中缩短了APD80，在所有组中缩短CaTD80和Decay30-90，但保留TTP100和Ca2瞬时交替。所有组显示相似的APD80，而仅TAC的心脏显示更大的CaTD80，异丙肾上腺素攻击后的异质性。Empagliflozin消除或减少了室性心动过速和室性早搏以及相关的折返传导模式，在异丙肾上腺素激发的TAC手术心脏中，连续爆发起搏发作。Empagliflozin从而挽救TAC诱导的心室肥厚和收缩功能，Ca2+稳态，和完整心脏的致心律失常变化。
