Across the world, emergency medical teams often administer a powerful clot-busting drug called tissue plasminogen activator (t-PA) to help patients stricken by heart attack.
But a new study led by researchers at Weill Cornell Medical College in New York City suggests the drug may have a darker side — raising patients’ risk for dangerous arrhythmias and triggering an unhealthy constriction of coronary vessels.
“In some cases, using this drug might make matters worse. In our study, we found that t-PA boosts cardiac nerve cell production of a powerful neurotransmitter called norepinephrine,” explains study senior author Dr. Roberto Levi, professor of pharmacology at Weill Cornell Medical College.
“Besides being a powerful vasoconstrictor, norepinephrine has also been linked to a heightened risk of arrhythmia,” he adds. “Our finding could help explain the excess risk for dangerous and even fatal arrhythmias in heart attack patients who have received t-PA.”
Dr. Levi’s team published their findings recently in the Journal of Experimental Medicine.
The drug t-PA is actually a recombinant form of a protease enzyme that’s released naturally by the human body.
“The body uses it just as doctors do — to make sure that clotting doesn’t get out of hand,” Dr. Levi explains.
For a long time, scientists believed that the enzyme was only secreted by the endothelial cells that line blood vessels. But research carried out at the University of Connecticut by J. O’Rourke revealed that nerve cells in and around the heart also emit t-PA.
“Our question was, ‘What is it doing there?'” Dr. Levi says.
Working with postdoctoral fellow Dr. Ulrich Schaefer (now at the University of Lubeck, Germany) and Dr. Sidney Strickland, and colleagues at The Rockefeller University in New York City, Dr. Levi used a line of genetically engineered “knockout” mice to help solve the puzzle.
These mice, whose cardiac nerve cells did not generate t-PA, had greatly subdued sympathetic nervous systems when stimulated by an electrical field, the researchers found. Moreover, the hearts of t-PA-deficient mice also failed to produce the spike in norepinephrine seen in normal mice when they were placed under electrical field stimulation.
“In addition, t-PA deficient mice subjected to cardiac ischemia — a sudden reduction in blood flow that simulates heart attack — showed a much smaller release of the neurotransmitter than normal mice, suggesting that t-PA is a necessary ‘switch’ for this jump in norepinephrine,” Dr. Levi says.
Significantly, mice without functioning t-PA also had much lower rates of arrhythmia when subjected to ischemia and reperfusion (a return of blood to the heart) compared to normal mice.
These findings support the notion that t-PA release by cardiac nerve cells is a prime culprit in cardiac arrhythmias associated with heart attack, the researchers say.
The exact biochemical chain of events linking the enzyme to norepinephrine release is not yet known. However, scientists do know that norepinephrine raises arrhythmia risk by activating beta receptors on the surface of cardiac cells.
“Remember, beta receptors are the therapeutic target for beta-blocker medications, one of the most widely used anti-arrhythmia agents that we have,” notes Dr. Levi.
So, does it make sense to give heart attack patients a drug that might actually raise their risk for arrhythmia?
According to Dr. Levi, these data are preliminary, and it’s still too early to offer any recommendations in terms of clinical practice — especially since t-PA remains one of the few effective, widely available weapons emergency room teams have when battling stroke and heart attack.
“Still, our finding does raise intriguing new questions about this therapy. It also opens a new window into the mechanisms behind arrhythmia, suggesting possible new therapeutic targets,” Dr. Levi says. “We hope to learn much more in future research.”