Dissertation Defense: Sodium Channel Loss of Function Sensitizes Conduction to Changes in Extracellular Sodium Concentration

About this Dissertation

In all large animals, life is sustained by the regular coordinated beating of the heart to pump blood throughout the body. Throughout this continuous activity, and even with minute to minute changes in heart rate, this electrically driven activity continues without major disruption. Until it doesn’t. Major arrhythmias can occur suddenly, and without warning. Over the last century, we have begun to understand some of the reasons why heart, even an injured one, will work normally for hundreds of thousands of beats, and on the next fall into a life-threatening new pattern, and one of the most important of these reasons is the speed of conduction: the spread of electrical activation throughout the heart tissue. Understanding the mechanisms of conduction provide a way to assess and mitigate the risk of arrhythmias and may open up new avenues for treatment and prevention. This dissertation presents evidence for a previously theoretical mechanism of conduction called ephaptic coupling. Adams, mentored by Steven Poelzing, show sthat this electric field mediated form of conduction can be modulated with clinically used osmotic agents, and that it has a physiologically relevant impact on conduction. His research also shows that hyponatremia (i.e. low sodium), a condition that is traditionally thought to have minimal impact on cardiac conduction, because a significant modulator of conduction when sodium channel functions are impaired. As a great many drugs block sodium channels, this sensitization to hyponatremia and the factors that mediate it are underappreciated concerns that are relevant to a wide array of patients. The new findings presented in this dissertation advance our collective understanding of the mechanisms of cardiac conduction and provide evidence for new avenues of exploration in the prevention and management of arrhythmias and conduction disorders.

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