Sudden Infant Death and Modulation of Late Sodium Current by Hypoxia, Investigated in Induced Pluripotent Stem Cells

Abstract

Sudden infant death (SIDS) occurs in about 0.4 per 1000 life births in the United States and other western countries. Recognized risk factors for SIDS are prone sleeping position, maternal smoking, and bed sharing. These factors point to the potential involvement of respiratory stress in the syndrome.Furthermore, in about 20% of SIDS cases, mutations in cardiac ion channels have been found. Of those, about 50% affect the cardiac sodium channel, which is also affected in individuals suffering from long-QT syndrome type 3 (LQT3). In these mutated ion channels, the late component of the sodium current during the plateau phase of the cardiac action potential is markedly increased, due to incomplete inactivation of the channels.We hypothesise that a combination of hypoxia, induced by respiratory stress, and cardiac sodium channel mutations that increase the late sodium current, cause an synergistic increase in late sodium current, which predisposes vulnerable infants to sudden arrhythmic death.Preliminary data using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) supports this hypothesis. Using microelectrode arrays, we were able to show that in a pharmacological model of LQT3, hypoxic conditions dramatically increase the field potential upstroke velocity, which is an indirect marker of the sodium channel availability.Cells were treated with Anthopleurin-A, which destabilises the inactive state of cardiac sodium channels. Under hypoxic conditions, the field potential upstroke velocity was increased by about 4-fold, compared to normoxic conditions. This effect was not present in untreated control cells. The late sodium current blocker Ranolazine was able to reduce this effect in a dose dependent manner, suggesting that indeed the late sodium current was responsible for this effect.