Dr. Mark Anderson is leading the arrhythmia research at VUMC. (photo by Dana Johnson)
VUMC research could predict arrhythmias
Representative ECG tracings showing evolution of U-wave amplitude before intiation of TdP in drug-induced arrhythmia in rabbit. (A) Baseline before infusion of drug. (B) ECG tracing 12 minutes after drug infusion shows emergence of a U wave (marked by arrowhead in this and subsequent panels). C and D show progressive increase in U wave amplitude 2 min (C) and 10s (D) before TdP initiation. (E) U-wave amplification increases further and is associated with premature beats and TdP. Scale bar is 10 mV (vertical) and 200 ms (horizontal) throughout.
Torsade de pointes. It sounds like something you might hear in ballet class. Instead of describing a dancer’s graceful turn on pointed toe, however, this French phrase takes on a darker tone in referring to the twisting pattern of peaks seen in the electrocardiogram, or ECG, of a particular type of irregular heart rhythm, one that can cause sudden death.
Results from the laboratory of Dr. Mark E. Anderson, associate professor of Medicine and Pharmacology, published in the latest issue of the journal Circulation, suggest not only a new way to predict the onset of this arrhythmia from the pattern seen in an ECG, but also link that specific ECG parameter to a calcium-dependent signaling pathway within the cells of the heart. Understanding this cellular signaling could lead to the development of targeted drugs designed to prevent this life-threatening condition.
The problem leading to torsade de pointes—or TdP—is an electrical one. The action potential is the basic unit of the heart’s electrical system, and it is this electrical spark that causes mechanical contraction of the heart, the two elements collaborating to create the 60 to 100 beats per minute that keep our bodies running properly. TdP happens when typical electrical firing in each heartbeat within a series is disrupted and the action potential isn’t able to return to the normal starting point during a complex process known as repolarization.
“Although how the action potential is started is complicated,” Anderson said, “it’s quite simple compared to the second part, which is how the action potential recovers to get back down to a negative resting potential.”
The trigger for the action potential is the inward flow of sodium ions through a pore in the cell membrane called the sodium channel. What follows, according to Anderson, is a “whole dance of ion channels” that account for repolarization of the electrical system. Potassium channels make up the lion’s share of those responsible, with different combinations of subunits making up a range of potassium channel variations. But calcium, Anderson believes, is the ion most integral to recovery of rhythm.
“The cardiac action potential has a long repolarization process because that is the electrical platform for calcium to enter the cell,” he said. “And the calcium is the thing that triggers the contraction itself. But when the repolarization process is excessively prolonged, it can be a setup for arrhythmia.”
Patients with a congenital condition called long-QT syndrome are born with an ion channel defect, usually in a potassium channel, that can cause TdP. Acquired long-QT syndrome has been shown to result from the use of a number of different drugs, including some agents typically given to treat arrhythmias, as well as other more commonly used drugs such as some antibiotics. The syndrome, named for the elongation of the so-called QT interval of the heartbeat identifiable in the ECG, can be mimicked by much more common diseases where arrhythmias cause a significant percentage of mortality. The best example is congestive heart failure, which can happen following a serious heart attack. The same electrical effect can also be seen in primary disease of the heart muscle called cardiomyopathy, but may also follow pathogenic viral infection of the heart muscle.
“When you have a heart that doesn’t contract as much, it’s more prone to heart failure,” Anderson said. “It’s also prone to electrical instability, and it seems that this instability may be due to a process of electrical remodeling where repolarization becomes excessively prolonged.”
Anderson’s lab and others have implicated disorders of the calcium current flowing into cardiac cells during repolarization as being most directly responsible for arrhythmia. Calcium is a signaling molecule that initiates a cascade of other signaling events in the cell by binding to a calcium sensor protein called calmodulin. To study the effects of calcium on electrical stability, the researchers use a rabbit model developed by a Swedish scientist about 10 years ago. These rabbits can be made to reproducibly experience arrhythmias when repolarization is prolonged—as seen in the extended QT interval on the ECG—using potassium channel blocking drugs.
Anderson reasoned that to really home in on the causative factor of TdP arrhythmia, he needed to create a situation in which a long repolarization occurred without a resulting loss of rhythm. He found a calmodulin-blocking drug—named W-7—which prevented arrhythmia in the rabbits in spite of the presence of a long QT interval on their ECG. From this he concluded that calmodulin—and hence, calcium—dependent signaling molecules must be critical to arrhythmia-induction.
“This finding opens up the possibility that, instead of targeting ion channels, which is what most anti-arrhythmic drugs do—with little documented mortality benefit—you could target signaling molecules, and there are a lot of them to target,” Anderson said. “This would be a totally new way to treat arrhythmias.”
But to do that, according to Anderson, you would have to first identify any ECG parameters that indicate, or predict, the presence of an arrythmia. By having advance warning that an ECG-monitored patient in the cardiac care unit was in danger, for example, the nursing staff could give more immediate attention to that patient.
The lab investigated the value of using a measure of the change in length, from shortest to longest, of the QT intervals recorded simultaneously from 12 different electrode placements —called the QT dispersion—which has been considered by some a good predictor of arrhythmias in humans. They found that this measure did not predict TdP arrhythmia in their rabbits.
A cardiology research fellow in Anderson’s lab, Dr. David Gbadebo, did see something else in the ECG of arrhythmic rabbits that caught his eye, however. He noticed that just before an arrhythmia occurred, a particular hump appeared on the ECG that had not been there before. And it reappeared, each time a little bigger, just about 30 seconds to a minute before the TdP started. The existence of this peak—called the U wave—has been known for almost a century, but no one before had noted how the amplitude of the wave grew during the development of arrhythmia.
When arrhythmic rabbits were given the calmodulin-blocking drug, W-7, the U wave hump did not appear in the ECG. This experimental result suggests that the electrical activity represented by the U wave is associated with the effects of calmodulin, and lends support to the argument that calcium ion signaling is a tightly associated trigger of arrhythmia.
According to Anderson, these research findings tell us three main things.
“One, that traditional measures of the ECG don’t seem to be fundamental for predicting arrhythmias,” he said. “Two, that this new measure—the presence and increase in amplitude of the U wave on the ECG—seems to accurately and specifically predict the onset of arrhythmia in the best studied model available. And, finally, that this it the first time that a specific parameter of the ECG—which is probably the most ordered test in the hospital—can be linked to a signaling molecule in the heart cell itself.”
The next step for Anderson and his lab is to figure out, using more specific agents, which molecules activated by calmodulin are critical to TdP arrhythmia induction.
“Not only would that be useful for enhancing the value of the ECG as a diagnostic and predictive tool,” he said, “but also for making drugs that would more proximately target the cause of disease.”
In an editorial comment that appears in the same issue of Circulation, Dr. Douglas P. Zipes, a noted electrophysiologist and current president of the American College of Cardiology, observed that though further studies on W-7 and other similar calmodulin inhibitors are needed to define their physiological effects and to evaluate their potential for treating patients with long-QT syndrome, the findings in the paper are promising.
“To be able to predict the onset of TdP by using the U wave could have significant clinical potential in identifying patients at increased risk of TdP and can lead to prevention therapies,” Zipes said.
Other Vanderbilt researchers listed as co-authors on the publication of this work include Dr. David Gbadebo; Robert W. Trimble; Michelle S. C. Khoo; Dr. Joel Temple; and Dr. Dan Roden.
The research was funded by grants from the National Institutes of Health, the American Heart Association, and the Stahlman Scholars Program.