TY - JOUR

T1 - Regulation of APD and Force by the Na+/Ca2+ Exchanger in Human-Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue

AU - Ismaili, Djemail

AU - Gurr, Katrin

AU - Horvath, Andras

AU - Yuan, Lei

AU - Lemoine, Marc D.

AU - Schulz, Carl

AU - Sani, Jascha

AU - Petersen, Johannes

AU - Reichenspurner, Hermann

AU - Kirchhof, Paulus

AU - Jespersen, Thomas

AU - Eschenhagen, Thomas

AU - Hansen, Arne

AU - Koivumaeki, Jussi T.

AU - Christ, Torsten

PY - 2022

Y1 - 2022

N2 - The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 +/- 0.2 pA/pF and 3.2 +/- 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 mu M) markedly shortened the APD(90) in EHT (by 26.6 +/- 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 +/- 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 +/- 5.4%, p < 0.05) and EHT (by 20.8 +/- 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.

AB - The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca2+ extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 +/- 0.2 pA/pF and 3.2 +/- 0.2 pA/pF for human ventricle and EHT, respectively, p < 0.05). SEA0400 (10 mu M) markedly shortened the APD(90) in EHT (by 26.6 +/- 5%, p < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 +/- 1.6%, p < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; p > 0.05). Force was increased by the NCX block in rat ventricle (by 31 +/- 5.4%, p < 0.05) and EHT (by 20.8 +/- 3.9%, p < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.

KW - hiPSC-CM

KW - human ventricular cardiomyocytes

KW - rat ventricular cardiomyocytes

KW - NCX

KW - APD

KW - force

KW - SEA0400

KW - SODIUM-CALCIUM EXCHANGER

KW - NA+-CA2+ EXCHANGER

KW - SEA0400 FAILS

KW - CA2+ CURRENT

KW - INHIBITION

KW - CANINE

KW - CARDIOMYOCYTES

KW - ARRHYTHMOGENESIS

KW - CONTRACTILITY

KW - ARRHYTHMIAS

U2 - 10.3390/cells11152424

DO - 10.3390/cells11152424

M3 - Journal article

C2 - 35954268

VL - 11

JO - Cells

JF - Cells

SN - 2073-4409

IS - 15

M1 - 2424

ER -