Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
Heart Rhythm. 2023 Apr;20(4):580-586. doi: 10.1016/j.hrthm.2022.12.034. Epub 2022 Dec 28.
Curcumin, a polyphenolic dietary natural compound and active ingredient in turmeric, exerts antioxidant, anti-inflammatory, antidiabetic, anticancer, and antiarrhythmic properties. KCNE1-D85N, present in ∼1% of white, is a common, potentially proarrhythmic variant that predisposes individuals to drug-induced QT prolongation under certain conditions.
The purpose of this article was to test the hypothesis that curcumin might cause action potential duration (APD) prolongation in KCNE1-D85N-derived human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Gene-edited/variant-corrected isogenic control and patient-specific KCNE1-D85N-containing iPSC-CMs were generated previously. Voltage-sensing dye, multielectrode array (MEA), and whole-cell patch clamp technique were used to measure APD without and with 4-hour incubation with 10 nM curcumin.
KCNE1-D85N-derived iPSC-CMs demonstrated significant APD prolongation with treatment of 10 nM curcumin. Using voltage-sensing dye, action potential duration at 90% repolarization (APD90) was 578 ± 7 ms (n = 39) at baseline and was prolonged to 658 ± 13 ms (n = 35) with curcumin incubation (P < .0001). Using MEA, APD90 at baseline was 237 ± 6 ms (n = 24) compared with 280 ± 6 ms (n = 12) with curcumin incubation (P = .0002). The whole-cell patch clamp technique confirmed these results, with APD90 being 544 ± 37 ms at baseline and 664 ± 40 ms with treatment of curcumin (P < .005). However, APD from isogenic control iPSC-CMs remained unchanged with curcumin treatment.
This study provides pharmacological and functional evidence to suggest that curcumin, a dietary natural supplement, might cause APD prolongation in patients with common, potentially proarrhythmic functional variants such as KCNE1-D85N. Whether this supplement is potentially dangerous for the Caucasian subpopulation that has this variant warrants further investigation.
姜黄素是一种多酚类膳食天然化合物，也是姜黄的活性成分，具有抗氧化、抗炎、抗糖尿病、抗癌和抗心律失常的特性。KCNE1-D85N 存在于约 1%的白人中，是一种常见的、潜在的致心律失常变体，使个体在某些条件下易发生药物诱导的 QT 延长。
本文旨在检验姜黄素可能导致 KCNE1-D85N 衍生的人诱导多能干细胞衍生心肌细胞（iPSC-CMs）动作电位持续时间（APD）延长的假设。
先前已经生成了基因编辑/变体校正的同基因对照和患者特异性 KCNE1-D85N 内含子 iPSC-CMs。使用电压敏感染料、多电极阵列（MEA）和全细胞膜片钳技术测量无和用 10 nM 姜黄素孵育 4 小时后的 APD。
KCNE1-D85N 衍生的 iPSC-CMs 在用 10 nM 姜黄素处理后表现出明显的 APD 延长。使用电压敏感染料，在基线时动作电位复极 90%（APD90）为 578 ± 7 ms（n = 39），用姜黄素孵育后延长至 658 ± 13 ms（n = 35）（P <.0001）。使用 MEA，在基线时 APD90 为 237 ± 6 ms（n = 24），而用姜黄素孵育时为 280 ± 6 ms（n = 12）（P =.0002）。全细胞膜片钳技术证实了这些结果，APD90 在基线时为 544 ± 37 ms，用姜黄素处理时为 664 ± 40 ms（P <.005）。然而，同基因对照 iPSC-CMs 的 APD 在用姜黄素处理后保持不变。
这项研究提供了药理学和功能证据，表明姜黄素，一种膳食天然补充剂，可能导致 KCNE1-D85N 等常见的、潜在的致心律失常功能性变体患者的 APD 延长。这种补充剂是否对具有这种变体的白种人群体有潜在的危险，需要进一步研究。
