Scientists have staved off heart failure in animals by using gene therapy to shut down the adrenal gland's excessive output of fight or flight hormones such as epinephrine and norepinephrine. By blocking GRK2, an important regulatory enzyme, they cut the hormone production that forces the heart to pump too hard, leading to heart failure. Such a novel approach - targeting the adrenal gland in addition to the heart - provides a potential new strategy against heart failure, and could lead to a new class of drugs.
The researchers, led by Walter Koch, Ph.D., W.W. Smith Professor of Medicine and director of the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College, report their findings in the journal Nature Medicine.
"The emphasis has always been in treating right at the heart," says Stephen B. Liggett, M.D., director of the cardiopulmonary genomics program at the University of Maryland School of Medicine, who has written an accompanying editorial.
"Despite our best efforts, about half of all heart failure patients die within five years of diagnosis, so clearly something new is needed. These results add a completely new dimension to the way physicians might be able to intervene to improve heart failure therapy."
When an individual's heart begins to fail, the sympathetic nervous system, attempting to compensate for the weakened heart, goes into overdrive, pumping out increasing levels of stimulants - catecholamines such as epinephrine and norepinephrine, making a bad situation worse. The typical treatment - beta blockers - inhibit the beta adrenergic receptors on the heart, blocking the hormones that force the heart to work overtime.
Dr. Koch's group focused instead on the source of catecholamines - the adrenal gland. It discovered that in heart failure, the extra hormones "desensitize" the adrenal's alpha 2 adrenergic receptors because of a rise in GRK2, or G protein-coupled receptor kinase 2, essentially turning them off. Using gene therapy to block adrenal gland GRK2 in animals in heart failure, the scientists were able to get the alpha 2 receptors working again and also found that the beta adrenergic receptors on the heart worked better as well.
"We've shown that in the adrenal gland, resetting the alpha adrenergic receptors by inhibiting GRK2 causes more normal regulation and the proper feedback control, and catecholamines are lowered," explains Dr. Koch, who also heads the George Zallie and Family Laboratory of Cardiovascular Gene Therapy in the Department of Medicine. "If less catecholamine is presented to the heart, then the beta receptors restabilize and that improves heart function. The heart is allowed to relax and get better."
"This is the first time anyone has identified a molecular mechanism involved in such sympathetic overdrive in heart failure," adds study first author Anastasios Lymperopoulos, Ph.D., a postdoctoral fellow in the Center for Translational Medicine, and means that adrenal gland GRK2 becomes a new target for heart failure medications.
"GRK2 inhibitors would be a totally new class of drugs if they come on the market," Dr. Koch says, adding that eventually, human gene therapy for heart failure could be feasible.