Engineered Heart Tissue Offers Insights into Irregular Heartbeats, Defibrillator Failure
Note: Video of electrical activity in engineered heart tissue is available as a Quicktime file or as a Realmedia file. In the movie, voltage sensitive dyes cause the cells to fluoresce in proportion to their electrical activity level. The colors, ranging from red to blue, denote the level of cell activity, with red indicating active cells and blue cells at rest.
Engineers who have induced heart cells in culture to mimic the properties of the heart have used the tissue to gain new insight into the mechanisms that spawn irregular heart rhythms. Studies of the engineered cardiac tissue revealed that while electric shocks such as those delivered by defibrillators usually stopped aberrant waves, in some cases they cause them to accelerate and multiply.
The Duke University and Johns Hopkins University team, led by Nenad Bursac of Duke’s Pratt School of Engineering, reported its findings in the Feb. 1, 2006, Cardiovascular Research. Bursac and study co-author Leslie Tung conducted the experiments at Johns Hopkins before Bursac joined the Duke faculty. The work was supported by the National Institutes of Health and the American Heart Association.
In their experiments, the researchers sought to understand the characteristics of ventricular tachycardia -- a condition characterized by abnormally fast beating of the heart’s pumping chambers. In particular, they sought to understand how such arrhythmia may lead to ventricular fibrillation, in which the heart's electrical activity becomes disordered, causing the ventricles to flutter rather than synchronously beat. As a result, pumping of the blood is inefficient, and death can result within minutes.
“Ventricular tachycardia and fibrillation are the leading causes of sudden death in the developed world,” Bursac said. “Yet, in humans and animals the anatomy is so complex that mechanisms of such arrhythmias are difficult to dissect systematically.”
In their study, Bursac and his colleagues created a simpler version of cardiac tissue using cells from the heart ventricles of neonatal rats. They transferred the cells into culture dishes on which they had stamped precise patterns of proteins known to support heart tissue growth. The proteins caused the cells to orient themselves, interconnect and grow in a manner that mimics normal heart tissue, Bursac explained.
The team then induced electrical activity in these engineered tissues as would occur in ventricular tachycardia and attempted to halt it with pace-setting pulses.
“In the beginning, there is a single rotating wave -- the 'culture dish' analog of ventricular tachycardia,” Bursac said. “After a short period, we applied trains of pulses in an attempt to terminate this wave.”
The pulses successfully halted the wave 80 percent of the time, they reported. In the remaining cases, however, the pulses converted the single wave into multiple waves that continued to activate the cardiac cells at an accelerated rate.
“In other words, instead of terminating it, the pacing actually perpetuated and worsened the initial condition in about 20 percent of the cases,” Bursac said. “That percentage approximates the frequency with which this is thought to occur in patients with implanted defibrillators.”
The researchers' analysis revealed a possible explanation for the two responses. They found significant differences in propagation of electrical activity through the engineered tissues between those that responded to pace-setting shocks by halting their aberrant rhythm, and those that responded by accelerating their rhythm.
Should such characteristic patterns hold in patients, physicians could potentially use them to identify those people for whom defibrillators are more likely to worsen abnormal heart rate, Bursac said.
So-called implantable cardioverter defibrillators (ICD) monitor the timing of heartbeats and can deliver small or large shocks to correct arrhythmias. Such devices have become increasingly common for patients who have experienced arrhythmias and are therefore at increased risk for future rhythm abnormalities, Bursac said.
In patients with implanted defibrillators, the devices often attempt to terminate ventricular tachycardia by delivering electrical pulses to a single site at a rate slightly higher than the rate of tachycardia. Such pacing usually overrides the abnormal heart waves to restore a normal rhythm, Bursac said.
In 5 to 20 percent of cases, however, the anti-tachycardia pacing can result in an accelerated heart rate or induction of ventricular fibrillation.
When pacing pulses accelerate tachycardia, current ICD devices usually deliver a strong and painful shock, he said. Further study of the engineered tissues might lead to more reliable and less painful strategies for halting arrhythmias, Bursac said. For example, preliminary observations suggested that pacing the engineered tissue at rates slightly below the rate of tachycardia may still slow down the accelerated rhythm.
The results in general demonstrated the promising utility of engineered tissue in the laboratory for studying the complex electrophysiological properties of the heart in both health and disease, they said.
“Implanted defibrillators can protect many patients, but sometimes the devices instead accelerate rapid heart beats,” Bursac said. “The mechanism responsible for this had remained unclear. We’ve now been able to show in these cardiac cell cultures that electric pulses sometimes break rotating waves rather than block them.”
Engineered cardiac tissues also might prove a useful testing ground for potential drug and gene therapies that could restore normal heart rhythms, he added.
“Bursac and Tung have presented a convincing mechanistic explanation for a clinically important phenomenon that they reproduced in a Petri dish,” Igor Efimov and Crystal Ripplinger, both of Washington University in St. Louis, wrote in an editorial. “Their study showed that, as in clinical therapy, anti-tachycardia pacing is highly successful; yet in some cases, it may result in acceleration of reentrant arrhythmia instead of its termination.”