Aims Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by a HCM sarcomere mutation. Methods and Results Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring a HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current. Conclusions SGLT2i (canagliflozin>dapagliflozin> empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM. Translational Perspective HCM is the most common inherited cardiomyopathy and treatment to prevent mutation-induced cardiac dysfunction is lacking. Early HCM characteristics are diastolic dysfunction and hypercontractility. We show in hiPSC-CM models that SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by HCM sarcomere mutations. SGLT2i acutely enhanced relaxation and altered Ca2+ handling in HCM hiPSC-CMs, targeting important early HCM disease hallmarks.

中文翻译：

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肥厚型心肌病功能障碍在人类工程心脏组织中模拟并通过 SGLT2 抑制剂得到改善

目的 肥厚型心肌病 (HCM) 是最常见的遗传性心肌病，通常由致病性肌节突变引起。HCM 的早期特征是舒张功能障碍和收缩过度。目前缺乏预防突变引起的心脏功能障碍的治疗方法。钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 是一组抗糖尿病药物，最近显示出对获得性心力衰竭患者有益的心血管结局。我们在这里研究 SGLT2i 是否代表一种潜在的疗法来纠正 HCM 肌节突变引起的心肌细胞功能障碍。方法和结果测量了在 2D 和 3D 工程心脏组织 (EHT) 中培养的含有 HCM 突变的人诱导多能干细胞来源的心肌细胞 (hiPSC-CM) 的收缩性。研究了编码 β-肌球蛋白重链 (MYH7-R403Q) 或心肌肌钙蛋白 T (TNNT2-R92Q) 的基因突变。在 2D 中，测定细胞内 [Ca2+]、动作电位和离子电流。hiPSC-CM 中的 HCM 突变会损害松弛或增加力量，模仿人类 HCM 中观察到的早期特征。与对照 hiPSC-CM 相比，SGLT2i 在 HCM 中更大程度地增强 hiPSC-CM 的松弛。此外，SGLT2i 对 R403Q EHT 中松弛的影响随着培养时间（即 hiPSC-CM 的成熟）而增加。卡格列净的放松效果比恩格列净和达格列净更明显。SGLT2i 急剧改变 HCM hiPSC-CM 中的 Ca2+ 处理。对可能是突变体 hiPSC-CM 增强松弛基础的 SGLT2i 介导机制的分析排除了 SGLT2、Na+/H+ 交换器、峰值和晚期 Nav1.5 电流以及 L 型 Ca2+ 电流，但表明 Na+/Ca2+ 交换器的重要作用。事实上，突变体 hiPSC-CM 中的电生理测量表明 SGLT2i 改变了 Na+/Ca2+ 交换电流。结论 SGLT2i（卡格列净>达格列净>恩格列净）可显着增强人 EHT 的松弛，特别是在 HCM 中和长时间培养后。SGLT2i 可能是纠正 HCM 早期心功能障碍的潜在疗法。转化视角 HCM 是最常见的遗传性心肌病，目前缺乏预防突变引起的心功能障碍的治疗方法。早期 HCM 特征是舒张功能障碍和收缩过度。我们在 hiPSC-CM 模型中表明，SGLT2i 是纠正 HCM 肌节突变引起的心肌细胞功能障碍的潜在疗法。SGLT2i 显着增强 HCM hiPSC-CM 的松弛并改变 Ca2+ 处理，针对重要的早期 HCM 疾病标志。