Reversing Heart Failure

Pharmaceuticals often come with warnings of potentially hazardous side effects, but researchers have found that for one antidepressant a potential side effect is the reversal of heart failure.

In a new study published in Science Translational Medicine, researchers at the Center for Translational Medicine at Temple University’s School of Medicine in Philadelphia concluded the antidepressant paroxetine improved cardiac function in mice and, in some instances, even reversed some signs of heart failure.

The fact that paroxetine worked so well at reversing heart failure in this model was surprising, said study co-author Walter Koch, Ph.D., a pharmacology professor at Temple University’s School of Medicine.

About 5.1 million people have heart failure in the United States, and about half of the people who develop the disease die from it within five years, according to the Centers for Disease Control and Prevention.

GRK2, a protein, is unregulated in the failing human heart, and the researchers noted that it appeared to play a critical role in heart failure.

Paroxetine has been shown to inhibit GRK2, and the study showed that, by treating mice for four weeks with the antidepressant, it was actually possible to improve left ventricle function and structure.

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Specifically, researchers tested the drug in mice that had experienced a heart attack and found it improved the left ventricle’s ability to pump blood. It also protected the heart from scar formation and fibrosis.

To confirm the drug worked independent of its effects as an antidepressant, researchers tested the drug on genetically modified mice.

Before the study, researchers were not sure that the required dose to reach plasma and tissue levels would be high enough to inhibit GRK2. In mice, at least, it is.

“We came up with this idea not from the perspective of paroxetine but because we have shown over the last two decades that GRK2 is a pathological enzyme in the failing heart,” Koch said.

Antidepressant

A few years ago, the Temple University researchers, along with John Tesmer, Ph.D., at the University of Michigan, discovered that paroxetine inhibits GRK2.

“This is new because previously GRK2 had been only genetically inhibited,” Koch said.

Genetic blocking of GRK2 has also been shown to reverse signs of heart failure.

“Our study proves that small molecule pharmacological inhibitors of GRK2 would be truly innovative and … may offer new hope for heart failure therapy,” he said.

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However, the use of paroxetine to inhibit GRK2 in humans is unlikely. The dose needed would probably be too high, Koch said.

Nonetheless, this study points to a new pathway for treating heart failure. New compounds derived from paroxetine that are more targeted to GRK2 without affecting serotonin (an operative agent in depression) can be developed. Those could have great potential for treating heart failure.

“We are certainly trying to come up with these compounds because heart failure is a disease where new drugs are needed,” Koch said.

When researchers have new, more potent compounds to try, they will move on to a large animal study. They may still try a large animal study with paroxetine.

Researchers are currently looking at available clinical data where heart failure patients were treated with paroxetine to see if they can uncover existing data where paroxetine did improve cardiac pump function.

In the meantime, there’s an additional silver lining. If a heart failure patient is clinically depressed, why not try paroxetine?

“It may have extra benefits and actually improve heart function,” Koch said.

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