Polyunsaturated fatty acids as anti-arrhythmic agents.

Project Summary
The cardiac action potential is primarily generated by sodium and calcium channels, which depolarize the
membrane potential, and by potassium channels that repolarize the membrane potential and terminate the
action potential. One of the major cardiac potassium currents is the slowly activating potassium current IKs that
contribute to the action potential termination. Over 300 different inherited mutations have been found in IKs
channels that cause cardiac arrhythmias in patients. IKs channels regulate the length of the cardiac contraction
and mutations that decreases the activity of IKs channels result in a prolongation of the cardiac contraction,
leading to Long QT Syndrome. In turn, Long QT syndrome is a risk factor for ventricular fibrillation and sudden
cardiac death. We have identified a family of compounds that activate IKs channels and are antiarrhythmic
when applied to cardiomyocytes. We will here test whether these compounds restores the length of the action
potential in human cardiomyocytes from Long QT Syndrome patients. We will also test the effect of these
compounds on in ex vivo animal hearts and in vivo in transgenic animals with Long QT Syndrome mutations, in
order to develop drug that restores the QT interval and that can be tested in future clinical trial. We will also
test variants of these compounds on heterologously expressed IKs channels using two-electrode voltage clamp,
to determine the important structure of these compounds for their effects on IKs channels. We will also make
mutations of IKs channels to determine the binding site of these compounds. Finally, we will test the efficacy of
these compounds to reverse different defects in IKs channels caused by different types of Long QT syndrome
mutations. This will be tested both in heterologous systems and in human cardiomyocytes. The anticipated
results of these experiments will provide proof-of-concept that this family of compounds can shorten the
cardiac action potential and prevent cardiac arrhythmia, and will provide preliminary animal model data to start
clinical trials of these compounds. We anticipate that this development of new anti-arrhythmic drugs will lead to
better treatments of cardiac arrhythmias and the prevention of sudden cardiac deaths in LQTS patients.

Grant Number: 5R01HL131461-08
NIH Institute/Center: NIH
Principal Investigator: Rene Barro-Soria