Grant: Proof of Principle Program - Phase I

The heart has four chambers, with two ventricles and two atria. The two atria are located above the ventricles and are responsible for pumping blood to the ventricles. The ventricles are then responsible for pumping blood to either the lungs or the rest of the body. Electrical signals coordinate the pumping of blood through these chambers so that there is an organized flow of blood through the heart, to the lungs to get oxygen and then back to the heart to pump the oxygen-rich blood to the rest of the body. These electrical signals are vital to the optimal performance of the heart. However, certain conditions can lead to these electrical signals becoming disorganized, thus causing either the atria or the ventricles to pump at inappropriate times or to pump in a rapid, uncontrolled and irregular way. When this occurs in the atria, it is called atrial fibrillation. Atrial fibrillation is the most common type of electrical disturbance in the heart and, with an aging population, is expected to affect 30 million North Americans and Europeans by 2050. Risk factors include age, high blood pressure, obesity, diabetes and existing heart disease. Disturbingly, people with atrial fibrillation are five times more likely to have a stroke that may lead to death or permanent disability in over half. Despite the increasing number of people expected to get atrial fibrillation, current drugs to prevent this either don't work well or have undesirable side effects. As such, we have designed a new drug and have shown it to be effective in a large animal model of atrial fibrillation. However, when taken orally this new drug is poorly absorbed and rapidly cleared from the body. Therefore, the purpose of the studies outlined in this application is to improve on this drug by making slight chemical modifications to it so that the drug is better absorbed and lasts longer in the blood stream so that it can then be used as an oral medication to treat people with atrial fibrillation.