Yang Hsiang-Yu, Firth Jahn M, Francis Alice J, Alvarez-Laviada Anita, MacLeod Kenneth T
National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defence Medical Center, Taipei, Taiwan.
Am J Physiol Heart Circ Physiol. 2017 Nov 1;313(5):H1031-H1043. doi: 10.1152/ajpheart.00249.2017. Epub 2017 Aug 4.
This study addressed the hypothesis that long-term deficiency of ovarian hormones after ovariectomy (OVx) alters cellular Ca-handling mechanisms in the heart, resulting in the formation of a proarrhythmic substrate. It also tested whether estrogen supplementation to OVx animals reverses any alterations to cardiac Ca handling and rescues proarrhythmic behavior. OVx or sham operations were performed on female guinea pigs using appropriate anesthetic and analgesic regimes. Pellets containing 17β-estradiol (1 mg, 60-day release) were placed subcutaneously in selected OVx animals (OVx + E). Cardiac myocytes were enzymatically isolated, and electrophysiological measurements were conducted with a switch-clamp system. In fluo-4-loaded cells, Ca transients were 20% larger, and fractional sarcoplasmic reticulum (SR) Ca release was 7% greater in the OVx group compared with the sham group. Peak L-type Ca current was 16% larger in OVx myocytes with channel inactivation shifting to more positive membrane potentials, creating a larger "window" current. SR Ca stores were 22% greater in the OVx group, and these cells showed a higher frequency of Ca sparks and waves and shorter wave-free intervals. OVx myocytes showed higher frequencies of early afterdepolarizations, and a greater percentage of these cells showed delayed afterdepolarizations after exposure to isoprenaline compared with sham myocytes. The altered Ca regulation occurring in the OVx group was not observed in the OVx + E group. These findings suggest that long-term deprivation of ovarian hormones in guinea pigs lead to changes in myocyte Ca-handling mechanisms that are considered proarrhythmogenic. 17β-Estradiol replacement prevented these adverse effects. Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17β-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca regulation, potentially creating proarrhythmic substrates.
卵巢切除术后（OVx）长期缺乏卵巢激素会改变心脏细胞的钙处理机制，从而导致致心律失常基质的形成。该研究还测试了给OVx动物补充雌激素是否能逆转心脏钙处理的任何改变并挽救致心律失常行为。使用适当的麻醉和镇痛方案对雌性豚鼠进行OVx或假手术。将含有17β-雌二醇（1mg，60天释放）的药丸皮下植入选定的OVx动物（OVx + E）。通过酶解法分离心肌细胞，并用膜片钳系统进行电生理测量。在加载Fluo-4的细胞中，与假手术组相比，OVx组的钙瞬变幅度大20%，肌浆网（SR）钙释放分数高7%。OVx心肌细胞的L型钙电流峰值大16%，通道失活向更正的膜电位偏移，产生更大的“窗口”电流。OVx组的SR钙储备高22%，这些细胞显示出更高频率的钙火花和钙波以及更短的无波间隔。与假手术心肌细胞相比，OVx心肌细胞的早期后去极化频率更高，并且在暴露于异丙肾上腺素后，这些细胞中出现延迟后去极化的比例更大。在OVx + E组中未观察到OVx组中发生的钙调节改变。这些发现表明，豚鼠长期缺乏卵巢激素会导致心肌细胞钙处理机制发生变化，这些变化被认为具有致心律失常性。17β-雌二醇替代可预防这些不良反应。与假手术心肌细胞相比，去卵巢豚鼠心肌细胞的钙波频率更高，并且经异丙肾上腺素刺激的细胞表现出更多的早期后去极化、延迟后去极化和额外搏动。在补充17β-雌二醇的去卵巢豚鼠的心肌细胞中未观察到这些钙调节改变，这表明卵巢激素缺乏会改变心脏钙调节，可能产生致心律失常基质。
