Grant: Project Grant

Inherited mutations and side-effects of many therapies results in deadly abnormal heart rhythms. It is among the most common and dangerous risks for drugs in development and significant challenge for managing arrhythmias, which impact millions of people world-wide. Even newly released anti-arrhythmic drugs, like ivabradine, block the IKr prolong action potential duration (APD) and induce potentially lethal arrhythmia known as Torsades de Pointes (TdP), especially when ivabradine is combined with polypharmacy and electrolyte disturbances. This is a clinically important and ongoing deficit in drug design and exposes apparent limitations in our understanding of how critical proteins - ion channels in cardiac membranes are regulated. New experimental data provide direct evidence for critical role played by cardiac membrane components such as fatty acids (endogenous and from dietary intake) in modulation of drug access to cardiac ion channels and as a potential for better and safer anti-arrhythmic therapies. Our team proposes a combined experimental and computer-based model framework to predict mechanisms of fatty acids efficacy in treatment and management of arrhythmias from the level of the receptor interaction to the cardiac rhythm. We will work hand in hand with a nation-wide screening of roles played by lipids in heart rhythm disorders. This information will form a basis for design of novel anti-arrhythmic therapeutics.