Targeting Flight-or-Fight Hormone Response to Combat Heart Failure
Can the body’s natural response to emotions such as fear and rage be used to combat heart failure? Results of a study published recently in the journal Circulation Research present a strong case.
Scientists found that two experimental compounds have the potential to restore pumping strength to failing hearts in part by harnessing the fight-or-flight response that makes hearts beat stronger.
The newly identified compounds ensure that the ability of the hormone adrenalin to drive heartbeat strength is maintained, and not thwarted, as it typically is in heart failure patients. The two therapies, when tested in mouse models of heart failure, were found to slow, and in some cases halt, the progression of the disease.
“Considering the limited efficacy of current drug therapies for heart failure, this discovery is both exciting and promising,” said Burns C. Blaxall, Ph.D., associate professor within the Aab Cardiovascular Research Institute at the Medical Center, and senior author of the study. “We are now taking a closer look at how these compounds compare to standard heart failure therapies, such as beta blockers, to further determine their efficacy in treating the disease.”
Blaxall’s lab is part of a nationwide effort that has linked adrenalin’s ability to propel heartbeat strength to a key protein, the beta adrenergic receptor. When adrenalin combines with this receptor it orders heart muscle cells to contract with greater speed and force. The problem in heart failure patients is that these receptors are chronically desensitized – they no longer respond to adrenalin, so the heart grows weak and does not pump as forcefully as it should.
“While adrenalin desensitization has been studied extensively, this is the first report of compounds that effectively target this specific process to reduce heart failure,” said Blaxall.
The desensitization is caused in large part by elevated levels of a particular enzyme (G-protein-coupled receptor kinase 2 or GRK2) when it interacts with G-proteins. So Blaxall collaborated with Alan Smrcka, Ph.D., who discovered two compounds, M119 and Gallein, that could block GRK2 regulation by G proteins.
The team found that Gallein not only slowed but halted heart failure progression when delivered to mice with pre-existing heart failure. Similarly, M119 reduced two characteristics of the disease – hypertrophy and fibrosis. Both compounds partially normalized the force of heart muscle contraction by making sure the beta adrenergic receptors became and remained responsive to adrenalin. This was done by both decreasing overall levels of GRK2 in the heart and by limiting its effectiveness.