Old antidepressant offers promise
in treating heart failure
Reported February 01, 2010
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
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
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
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.
Source : www.gazette.jhu.edu