Curcumin, a dietary natural supplement, prolongs the action potential duration of KCNE1-D85N-induced pluripotent stem cell-derived cardiomyocytes.

ABSTRACT

BACKGROUND: 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. OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.