Common antidepressant may hold the key to heart failure reversal

Common antidepressant may hold the key to heart failure reversal
A normal human heart. Heart failure occurs when the heart muscle’s ability to pump blood is impaired. Credit: C. Bickel/ Science Translational Medicine

A team led by researchers at Temple University School of Medicine (TUSM) found that a commonly prescribed antidepressant restored heart function in mice with heart failure, a finding that could lead to clinical trials for a disease long considered irreversible.

The team, which was led by Walter J. Koch, PhD, the William Wikoff Smith Endowed Chair in Cardiovascular Medicine and Director of the Center for Translational Medicine at TUSM, found that the antidepressant (also known as Paxil), reversed heart failure in mice. The findings were published in the March 4 issue of the journal Science Translational Medicine. The effect of paroxetine was not because of its antidepressant properties, but the inhibition of a specific enzyme that is a side-effect of the drug.

"This may open the way for a new class of therapies for a disease for which we lack effective interventions," Koch said. "At a minimum, the research suggests that physicians may want to consider prescribing paroxetine for heart failure patients who also suffer from clinical depression. If you have to give these patients an antidepressant, why not give them this one, which may improve ?" Koch asked.

The disease reversal occurred at concentrations of paroxetine similar to those found in the blood of people treated for depression, although Koch cautioned that what happens in mice is no guarantee of the same response in humans.

More than a half million Americans are diagnosed with heart failure every year, and 5.1 million live with the disease. That number is projected to increase 25 percent by 2030, according to the American Heart Association. The cost of treating the disease will more than double, from $30.7 billion in 2012 to nearly $70 billion in 2030. While treatment has improved significantly in recent years with the use of beta blockers and angiotensin-converting enzyme inhibitors, once the deterioration of the begins, there has been no way to reverse it without having a heart transplant. About half the people diagnosed with heart failure die within five years.

The current study grows out of Koch's two decades of investigation into an enzyme called GRK2, which stands for G protein-coupled receptor kinase-2. Levels of this enzyme rise when the heart is failing. Previous research by Koch and his colleagues has demonstrated the role of GRK2 in heart failure. That research relied on genetic manipulation to control GRK2 levels and, when GRK2 is lowered in various animal models, heart failure is reversed. Koch said he hopes next year to begin clinical trials of a gene therapy approach to lowering GRK2 levels.

But paroxetine is the first small molecule shown to successfully and selectively turn off GRK2's enzymatic activity, and it is a small molecule already known to be safe in humans, which has a real advantage.

John J.G. Tesmer, at the Life Sciences Institute at the University of Michigan, a co-author on the current work, stumbled onto paroxetine. He was testing a procedure for screening compounds that affect GRK2 using a series of FDA-approved compounds. But the test run discovered that the antidepressant both bound GRK2 and inhibited its activity. Tesmer sent Koch an unlabeled sample of the compound and Koch tried it on isolated cardiac myocytes - heart cells —and found they beat stronger.

"I was excited. I've been trying to find a GRK2 inhibitor for 20 years. I've talked to drug companies for years trying to get them interested in producing small molecules to inhibit GRK2. Now we have our small molecule." Tesmer is now working to create a derivative of paroxetine that can shut off GRK2 at lower doses without the antidepressant effect, Koch said.

In the current paper, Koch's team tested paroxetine against a placebo and a second antidepressant - fluoxetine (also known as Prozac). Mice were given myocardial infarctions—heart attacks—and developed heart failure over the next two weeks. When the heart failure was well developed, they were treated with placebo, paroxetine, or fluoxetine. Only paroxetine-treated mice showed the reversal of heart failure. Many antidepressants, including Prozac and Paxil, work by affecting levels of the brain signaling chemical, serotonin. Fluoxetine's failure to restore heart function demonstrates that the paroxetine's effect on the heart is unrelated to the serotonin system. The researchers also tested paroxetine against the beta-blocker metoprolol, a current standard of care for heart failure. "The beneficial effects of paroxetine were far greater than beta-blocker therapy," Koch said.

Sarah M. Schumacher, PhD, of the Temple Center for Translational Medicine and Department of Pharmacology, is lead author of the paper. She pointed to the durable effects of paroxetine in this study. Typically, drugs for heart failure must be taken for life. But in this trial, one group of mice was treated with paroxetine for four weeks and then left untreated for two. "The improvement was maintained," Schumacher said. "We think we reset the system. We stopped the vicious cycle of heart failure and restored basic function."

When the heart muscle is damaged by a , the body attempts to compensate for its lost pumping power by increasing adrenaline levels to boost heart rate. This leads to a series of maladaptive adjustments, and the heart grows larger and less efficient as its contractile force weakens. GRK2 is a major player in this unfortunate remodeling, which leaves patients with a heart less able to supply blood to the entire body.

One measure of cardiac efficiency is called ejection fraction, which calculates how much oxygenated blood the left ventricle pumps to the body with each beat. In the mice in the study, ejection fraction fell from a pre-heart attack level of 70 percent to 35 percent in two weeks following the heart attack. But after paroxetine treatment, rose by roughly 30 percent. Paroxetine also enhanced contractility after the heart attack, and restored efficiency shown through a measurement called left-ventricular end diastolic pressure (LVEDP), which essentially measures the pressure in the heart the moment before its next beat. Positive pressure means the chamber is not emptying sufficiently. In the mice with heart failure, LVEDP rose 2.5-fold, but in mice treated with paroxetine, the increase vanished. Paroxetine also reduced heart weight and length, both of which increase in heart failure. Lung weight doubled in animals treated with fluoxetine or placebo, but the increase was reversed in paroxetine treated mice.

During a heart attack, portions of the heart muscle deprived of oxygen by the blockage to cardiac circulation die. GRK2 actually induces even more cells to die, leading to patches of scar tissue that are unable to contract, contributing to the weakening and thinning of the heart tissue and dilation of the heart. When GRK2 activity was limited, the resulting dilation was far smaller.

"We believe this validates that GRK2 is a viable therapeutic target for heart failure and paroxetine is the starting point for a novel small molecule," Koch said. "We're looking at a totally new class of drugs for ."

More information: "Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction," Science Translational Medicine, stm.sciencemag.org/lookup/doi/ … scitranslmed.aaa0154

Journal information: Science Translational Medicine
Provided by Temple University
Citation: Common antidepressant may hold the key to heart failure reversal (2015, March 4) retrieved 28 March 2024 from https://medicalxpress.com/news/2015-03-common-antidepressant-key-heart-failure.html
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