The cardiac ventricular action potential depends on several voltage-gated ion channels,
including Na-V, Ca-V, and K-V channels. Mutations in these channels can cause Long
QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden
cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics
for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate
that PUFA analogues vary in their selectivity for human voltage-gated ion channels
involved in the ventricular action potential. The effects of specific PUFA analogues
range from selective for a specific ion channel to broadly modulating cardiac ion
channels from all three families (Na-V, Ca-V, and K-V). In addition, a PUFA analogue
selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the
cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes.
Our data suggest that PUFA analogues could potentially be developed as therapeutics
for LQTS and cardiac arrhythmia.