Using an experimental method that breaks from conventional wisdom about how to treat heart failure, scientists at Duke University Medical Center have shown in rabbits that blocking a key enzyme pathway can prevent the onset of heart failure.
The scientists found that blocking an enzyme called ß-adrenergic receptor kinase (ßARK) directly after a heart attack can preserve heart function. The results, reported in the April 25 issue of the Proceedings of the National Academy of Sciences, provide a promising new avenue for treating and perhaps preventing heart failure, they say. They explain why their new method works, despite conventional wisdom, in a second paper, published in the April 11 issue of the journal Circulation.
"Rather than harming the heart, as some theories predict, blocking ßARK actually helps protect the heart from overstimulation that can lead to heart failure," said Walter Koch, the study's lead author.
The experiments are a first step in developing a new type of treatment for congestive heart failure, a debilitating and deadly condition in which heart muscle loses its ability to stretch and contract, due to clogged arteries caused by coronary artery disease. The disease is often accelerated after a heart attack. If the results of the animal experiments can be confirmed in people, Koch says ßARK inhibitors might be used during a heart attack to prevent or delay heart failure, much as aspirin or other blood thinners are now given to reduce the risk of stroke or new heart blockage.
Koch, an associate professor of experimental surgery, and his colleagues have been working for several years to find ways to boost heart function.
In earlier experiments, conducted in the laboratory of Dr. Robert J. Lefkowitz, a Howard Hughes Medical Institute investigator at Duke, the scientists showed that two key proteins in heart cells work together to regulate heart function. In diseased hearts, the body releases the hormone norepinephrine, the "fight-or-flight" hormone, directly into the heart, causing it to work up to five times harder than normal. Norepinephrine stimulates beta adrenergic receptors (ßARs) present on heart cells. This stimulation initially allows the heart to increase the power of its contractions, but in heart failure it quickly becomes self-defeating: the receptors become desensitized, meaning they no longer are able to respond to hormone stimulation. Desensitization is caused by the actions of ßARK, which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation. Studies subsequently showed that ßARK is elevated in failing human heart tissue.
The researchers wanted to know whether halting the abnormal increase in ßARK could prevent heart failure in its initial stages. The idea seemed to make sense based on the researchers experiments, but it contradicted other observations that doctors have made about the changes that occur in the heart during heart failure. For example, when doctors tried to reverse heart failure by treating patients with medicine that increases the activity of ßARs (which is one of the therapeutic goals of blocking ßARK), patients usually became worse over time. That finding led many doctors to believe that decreasing ßARs is the body's way of protecting itself from overstimulation by norepinephrine and other stimulatory hormones. As a consequence, few scientists have tried to restore heart function using this pathway. But Koch and his colleagues, Lefkowitz, David White, Jonathan Hata, Ashish Shah and Dr. Donald Glower, were confident that if they could intervene early enough in the process, they could stop the downward spiral that leads to heart failure.
In the April 11 issue of Circulation, Koch, Lefkowitz and Howard Rockman, also of Duke, explain why they believe ßARK inhibitors may make a good therapy for heart failure. ßARK inhibitors, they explain, act to restore equilibrium to the hormone signaling pathways in the heart. They believe elevated ßARK and decreased ßAR function that occurs in heart failure is not protective, as is now thought, but rather escalates the decline in heart function that eventually leads to death. To support their claim, the researchers point to ß blockers, a class of drugs that have only recently been shown to be effective in treating symptoms of heart failure. ß blockers work by interrupting the cycle of increased hormone leading to decreased ßAR signaling. By blocking the ability of ßARs to "see" norepinephrine hormones, they are no longer overstimulated and thereby ßARK is no longer needed to desensitize them. So, indirectly, ß blockers also reduce ßARK, which may explain why they work, the researchers say.
Koch and his colleagues see ßARK inhibitors as a new approach to treating heart failure, one that may be complementary to ß blockers. They argue that while ß blockers help reduce the toxic effects of too much norepinephrine, ßARK inhibitors may help preserve the ability of ßARs to react to hormone signaling during exercise or when under stress.
To test their theory, they inserted a gene that codes for a protein molecule that blocks ßARK into a modified form of the adenovirus, the same virus that causes the common cold. The researchers then injected the virus into a living rabbit's heart just after it experienced a surgically induced heart attack. The researchers used a new surgical method to ensure that the adenovirus spread throughout the heart. In this method, they injected the virus into the left ventricle of live rabbits while the aorta was clamped for a few seconds. This technique allowed the virus enough time to spread through all the coronary vessels. Clamping the aorta is sometimes used in human heart surgery, Koch said, making this gene delivery method feasible in people. Then the scientists measured the pumping action of the heart. The heart function of the animals that were treated with the ßARK inhibitor was normal, while the untreated animals showed markedly decreased heart function, which is expected after a heart attack.
The effect of the introduced gene lasted for about three weeks. Koch said he believes the immune system eventually clears the adenovirus from the body, eliminating the therapeutic effect. He emphasizes that better delivery systems for gene therapy need to be developed before gene therapy for heart failure in people becomes a practical option. However, he said a small drug molecule that mimics the action of the protein-based ßARK blocker could also be a potent medicine to treat heart failure. Currently there are no such drugs available, but research is underway to identify promising drug candidates at several pharmaceutical companies, he said.
The research was supported by grants from the National Institutes of Health and the American Heart Association.
Journal
Proceedings of the National Academy of Sciences