February 1, 2010

Old antidepressant offers promise in treating heart failure

A team of researchers from Johns Hopkins and elsewhere have found in animal experiments that an antidepressant developed more than 40 years ago can blunt and even reverse the muscle enlargement and weakened pumping function associated with heart failure.

In a report published in the Jan. 8 edition of Circulation Research, U.S. and Italian heart experts describe in a dozen key laboratory experiments in rodents how the antidepressant clorgyline, which is no longer in use in humans, blocks the action of enzyme monoamine oxidase-A, or MAO-A, and stops its breakdown of a key neurohormone. Norepinephrine, as it is called, controls the pace of blood pumping and makes the heart pump harder and faster in response to stress.

The latest study results are believed to be the first evidence showing how elevated MAO-A activity biochemically drives heart failure and that its dangerous downstream effects can be stalled by drug therapy.

“Our study helps describe heart failure as a vicious chemical circle of stimulant norepinephrine overload and breakdown, and it offers a disease blueprint with monoamine oxidase-A as the target for drugs similar to clorgyline to rein in the disease,” said cardiologist Nazareno Paolocci, senior study investigator. “When norepinephrine is not properly stored and released from the nerves directed to the heart, monoamine oxidase-A breaks it down, generating dangerous chemical species in the nerves and the heart muscle. These toxic free radicals produce the same deleterious effects on heart muscle size and pumping function long observed in heart failure,” he said.

Paolocci, an assistant professor at the Johns Hopkins School of Medicine and its Heart and Vascular Institute, and at the University of Perugia in Italy, cautions that the studies with clorgyline are initial proof of an important principle but that the drug is far from being used to treat heart disease in humans. He says that newer drugs in the same class, such as moclobemide (sold as Aurorix or Manerix, and already approved by the U.S. Food and Drug Administration), will have to be tested first, citing numerous and potentially lethal drug effects with clorgyline that prevent it from being prescribed.

Notable side effects from clorgyline, Paolocci said, include insomnia and agitation, and high blood pressure after ingesting foods containing the amino acid tyramine, a protein building block that stimulates a surge of stored stimulatory hormones, specifically, norepinephrine. Patients who have taken clorgyline, whose chemical binding to MAO-A is irreversible, had to carefully avoid such tyramine-rich foods as red wine, chocolate, certain beans, meat and especially aged cheeses.

It was previous observations of this norepinephrine surge and accelerated breakdown that led logically, the team reported, to seeing if inhibitor drugs—preferably those already on the shelf—could stop or reverse the damage.

Among the study’s first findings was that after six weeks, mice with failing hearts responded to concurrent low-dose clorgyline treatment, with restoration of normal heart function and only half the harmful changes seen in untreated mice over the same time period.

Heart muscle cell death rates were normal in clorgyline-treated mice but three and a half times higher in untreated mice. Heart muscle chamber expansion also slowed in the clorgyline-treated group, returning to an average chamber dimension of 1.2 mm when the heart was contracting. Hearts in the untreated group expanded to an average of 3 mm. In addition, depleted stores of the hormone norepinephrine were replenished in treated mice but not at all in untreated mice.

The team said it believes that when norepinephrine is not properly stored in the nerves, it overflows into the heart, accelerating the hormone’s breakdown by MAO-A. This in turn leads to the buildup inside the heart of harmful reactive oxygen species, such as hydrogen peroxide, that strain normal muscle cell contraction.

“Now that we know clorgyline works, we can focus future drug testing on newer, safer MAO-A inhibitors, such as moclobemide, whose chemical bindings are reversible, unlike those of clorgyline,” Paolocci said.

Lead study investigator Nina Kaludercic, a postdoctoral fellow at Johns Hopkins and the University of Padova in Italy, said that researchers had long known that the buildup of hydrogen peroxide was dangerous, but no one knew that MAO-A was a major source due to the elevated breakdown of norepinephrine or how MAO-A’s action spurred heart failure.

In other experiments in live heart cells taken from mice and rats, Kaludercic and her colleagues clarified MAO-A’s connection to the muscle-enlarging effects of catecholamines, of which norepinephrine is one. They found that incubating the cells with norepinephrine for a day triggered increased MAO-A enzyme activity, generating hydrogen peroxide and muscle cell expansion, much like what happens in humans with failing hearts. Again, subsequent clorgyline treatment, at a single low dose of 2 micromoles per liter, reversed the damage.

Another key finding was that the overflow of norepinephrine did not just lead to raised activity of the muscle’s alpha and beta receptors, which trigger the heart to beat harder and faster, but also led to upped activity of MAO-A.

Kaludercic said that these experiments “deepen our understanding” of the close ties between the brain and the heart, and of how problems with nerve-muscle interaction can influence key organ failure.

Researchers next plan to analyze medical records from people who have taken MAO-A inhibitors to determine if their drug therapy offered any protection or lower risk of developing heart failure or other kinds of cardiovascular disease. They also plan experiments in animals to assess if clorgyline therapy can reverse heart failure at later stages of the disease, and at what dose. In addition, the team has proposed studies to evaluate other MAO-A inhibitors, including moclobemide, and what effects, if any, they have on failing hearts.

Some 5.7 million American men and women suffer from chronic heart failure, which caused an estimated 290,000 deaths in 2005. A majority of sufferers have high blood pressure, the leading risk factor for the disease.

Funding for the study, which took three years to complete, was provided by the American Heart Association and the National Institutes of Health. Clorgyline remains in use for scientific research and is sold by many different suppliers. The clorgyline used in this study was manufactured by Sigma-Aldrich. Moclobemide is manufactured by Roche.

In addition to Paolocci and Kaludercic, researchers involved in this study were Eiki Takimoto, Ning Feng, Takahiro Nagayama, Djahida Bedja, Kathleen Gabrielson and David Kass, all of Johns Hopkins; Edwin Lai and Karel Pacak, of the National Institute on Chemical Dependency; Randy Blakely, of Vanderbilt University; Kevin Chen and Jean C. Shih, of the University of Southern California; and Fabio Di Lisa, of the University of Padova.