Background Arrhythmias in patients with Short QT syndrome (SQTS) occur at certain situations like rest or night, suggesting roles of co-factors besides gene mutation. This study was aimed to investigate effects of some environmental factors on hERG channel current and gating kinetics in presence of a mutation (N588K) in hERG-gene.
 
Methods The human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from three healthy donors (donor-hiPSC-CMs) and a patient with short QT syndrome type 1 carrying a mutation (N588K) in hERG (SQTS-hiPSC-CMs) and patch clamp techniques were used for the study.

Results The SQTS-hiPSC-CMs showed a shortened action potential period (APD) and enhanced hERG channel current (IKr), consistent with phenotype (QT shortening) of the SQTS. Isoprenaline (Iso) but not carbachol (CCh) shortened APD in SQTS- and donor-hiPSC-CMs, whereas both Iso and CCh showed no effect on IKr. Increasing stimulation frequency enhanced IKr in donor- but not in SQTS-hiPSC-CMs. Acidosis (pH 6.0) inhibited IKr similarly in donor-and SQTS-hiPSC-CMs. Hyperthermia (40 °C) and lipopolysaccharide (LPS) and reactive oxygen species (ROS) increased IKr more strongly in SQTS-hiPSC-CMs than in donor-hiPSC-CMs. Acidosis reduced the time constant of inactivation and shifted the inactivation curve to more negative potential and shifted the activation curve to more positive potential similarly in donor-and SQTS-hiPSC-CMs. However, hyperthermia, LPS and ROS shifted the activation curve to more negative potential and the inactivation curve to more positive potential more strongly in SQTS-hiPSC-CMs than in donor-hiPSC-CMs. LPS and ROS accelerated the deactivation of IKr only in SQTS-hiPSC-CMs.

Conclusions The N588K-hERG channels can be differentially affected by environmental factors. Fever, inflammation and oxygen stress may be potential trigger for the occurrence of arrhythmias in SQTS-patients with hERG mutations.