Acquired long QT syndrome and phosphoinositide 3-kinase

While it is well known that mutation of several different ion channels can cause congenital long QT syndrome, block of I_Kr is widely thought to be responsible for most cases of drug-induced acquired long QT syndrome (aLQTS). In this article, we review evidence supporting another cause of aLQTS due to inhibition of phosphoinositide 3-kinase (PI3K) signaling. Inhibition of PI3K affects multiple plateau currents, reducing I_Kr, I_Ks, and I_CaL while increasing the persistent sodium current (I_NaP). The effects of PI3K inhibitors develop slowly, requiring hours to days to reach steady state. Dofetilide and terfenadine, an antihistamine on which much of the original I_Kr hypothesis was based, are among the many drugs that inhibit the PI3K pathway. Reduced PI3K signaling may also play a role in aLQTS associated with diabetes. Drug safety testing to identify aLQTS risk may be improved by examining PI3K-dependent effects that develop over time.