Dr. Jeffrey Balser
Study findings may lead to better antiarrhythmics
Researchers from Vanderbilt University Medical Center and The Johns Hopkins University School of Medicine have discovered how the antiarrhythmic drug lidocaine changes the behavior of sodium channels, the donut-like pores that let sodium pass across the heart cell membrane.
The findings, reported in the Journal of Clinical Investigation, could lead to the development of more effective antiarrhythmic drugs.
"Although cardiac arrhythmias are the leading cause of sudden death in the United States, treating these arrhythmias with drugs is one of the failures of biomedical pharmacology. Antiarrhythmic drugs tend to be toxic, and they don't work very well," said the report's senior author, Dr. Jeffrey R. Balser, associate professor of Anesthesiology and Pharmacology and holder of the James Taloe Gwathmy Clinician-Scientist Chair at Vanderbilt University.
"We know that the drug lidocaine is somewhat effective at reducing arrhythmias, but how it works is a mystery. If we can figure out exactly what it does to the sodium channel, we can design much better drugs."
Lidocaine and other drugs like it reduce the activity of sodium channels and are used to treat all forms of cardiac arrhythmias in patients with heart disease, the leading cause of death in the United States. These "sodium channel blockers" have found particular use in managing patients who, because of inherited mutations in their cardiac sodium channel gene, suffer from a condition called long QT syndrome.
Patients with long QT syndrome have an abnormally long time interval between two points (Q and T) on their electrocardiogram, a graphical recording of the electrical activity of the heart. The electrical changes in the heart that lengthen the QT interval predispose these patients to life-threatening cardiac arrhythmias.
Genetic mutations that cause sodium channels to stay open too long cause a specific form of long QT syndrome called LQT3. Sodium channels normally open only very briefly to initiate the electrical impulse that drives contraction of the heart.
"In LQT3, the diseased sodium channels open briefly, but then they sort of flicker on and off, like a light bulb that's about to go out. Those little openings are enough to produce these dangerous arrhythmias," Balser said. "Drugs like lidocaine get rid of the flickering behavior and normalize the QT interval in these patients. The question is: how do they do it?"
Balser and his collaborators studied the effects of lidocaine on the behavior of a particular mutant sodium channel, using electrophysiological techniques to measure the current (charged sodium ions) passing through the mutant channels.
"The long QT syndrome is a model system for understanding how an antiarrhythmic drug interacts with an ion channel," Balser said. "We hope that studying how lidocaine interacts with a mutated sodium channel will help us understand how drugs interact with sodium channels that behave abnormally because of much more common forms of heart disease that lead to heart attacks."
The investigators learned that lidocaine changes sodium channel behavior in a different way than they expected.
It was thought that lidocaine and other sodium channel blockers work to shut down sodium channels by binding inside the channel pore, like a cork plugging a wine bottle, Balser said. Instead, lidocaine "encourages" the channel to take a form that is closed and inactive–unable to open and let sodium through.
"Lidocaine appears to induce this particular conformational change," Balser said. "Lidocaine binds to the channel–somewhere other than just in the pore–and kicks it to make it shut off. Perhaps if we had drugs that did that better or with different kinetics, we would have better antiarrhythmics."
Balser's collaborators and former colleagues at The Institute of Molecular Cardiobiology at Johns Hopkins are Nicholas G. Kambouris, H. Bradley Nuss, David C. Johns, Eduardo Marbán, and Gordon F. Tomaselli. The work was supported by the National Institutes of Health.