Acquired long QT syndrome and phosphoinositide 3-kinase

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Congenital long QT syndrome arises from ion channel mutations.
• Drug-induced acquired long QT syndrome (aLQTS) is primarily attributed to IKr channel block.
• The phosphoinositide 3-kinase (PI3K) signaling pathway's role in aLQTS is under investigation.

Purpose of the Study:

• To review evidence linking PI3K inhibition to acquired long QT syndrome.
• To explore the mechanisms by which PI3K inhibition affects cardiac ion currents.
• To discuss the implications for drug safety and aLQTS risk assessment.

Main Methods:

• Review of existing scientific literature on PI3K signaling and cardiac electrophysiology.
• Analysis of studies investigating the effects of PI3K inhibitors on ion channel function.
• Examination of drug-induced aLQTS cases and their potential association with PI3K pathway modulation.

Main Results:

• PI3K inhibition affects multiple cardiac plateau currents, including reductions in IKr, IKs, and ICaL.
• PI3K inhibition leads to an increase in the persistent sodium current (INaP).
• The electrophysiological effects of PI3K inhibitors manifest gradually over hours to days.

Conclusions:

• Inhibition of PI3K signaling represents a significant, albeit slower-developing, mechanism for acquired long QT syndrome.
• Drugs like dofetilide and terfenadine, previously linked to IKr block, also inhibit PI3K.
• Assessing PI3K-dependent, time-dependent effects could enhance drug safety evaluations for aLQTS risk.