A pricey drug used to treat a rare but well-known
genetic disorder may hold wider promise as a
treatment for millions of Americans with potentially
lethal enlarged hearts due mainly to high blood
pressure, a study from Johns Hopkins shows.
The common denominator in both phenylketonuria, or
PKU, and cardiac hypertrophy is the
chemical tetrahydrobiopterin, known as BH4. In PKU, this
enzyme co-worker helps break down the
molecule phenylalanine whose buildup is toxic to the
brain. In the heart, BH4 helps build the chemical
nitric oxide, which is needed for normal heart function
and neutralizing toxic chemicals, called oxygen
free radicals.
Doctors have traditionally used diets excluding
phenylalanine to treat PKU, a so-called inborn
error of metabolism that can lead to irreversible brain
damage; but more recently, they have also
begun to treat the disease with BH4. An estimated 13,000
Americans are living with PKU, and each
year more than 300 newborns are diagnosed with the
disease.
Building on what has been known about BH4's
activities, the Johns Hopkins team, working with
mice, found that treatment with BH4 stabilizes the pumping
function of failing, enlarged hearts and
dramatically shrinks the muscle size in a relatively short
timeframe of just over a month. The team's
findings appear in the May 20 edition of the journal
Circulation.
"Our results show for the first time the pivotal role
played by BH4 in stopping and reversing
the weakening and damage done — even in severe cases
— to the heart muscle as a result of hypertension
and subsequent hypertrophy," said study senior
investigator David Kass, a professor at the School of
Medicine and its
Heart Institute. "This key evidence may help us
develop new therapies that stop and
reverse hypertrophy, preventing the disease from leading
to end-stage heart failure and keeping
affected individuals from needing heart-assist pumps or a
treatment of last resort, the heart
transplant."
Specifically, Kass and Belgian scientist An Moens, a
postdoctoral cardiology research fellow at
Johns Hopkins, fed a daily dose of 5 milligrams of BH4 per
25 grams of body weight to 31 mice whose
hearts had been subjected to prolonged experimental
hypertension created by constricting their
aortas for four weeks.
Before and after treatment, heart function was
monitored by several key tests, such as
echocardiogram and magnetic resonance imaging, as well as
catheters placed within the heart. This
was supplemented by post-treatment tissue analysis.
Results from this group were compared to those
from another group of 25 mice, also subjected to high
blood pressure, who were given placebo instead
of BH4 during the same timeframe.
After induced heart failure and five weeks of
subsequent therapy, researchers found that
BH4-treated mice showed "remarkable improvements,"
according to Kass, when compared to placebo-
treated animals. Ejection fraction measures of heart
pumping function not only stabilized with BH4
but improved, from an average 87 percent before heart
failure to roughly 48 percent at the start of
therapy, then back to 59 percent at the end of study.
Meanwhile, average pumping function in placebo-
treated mice showed a perilous decline, from 87 percent to
48 percent to 35 percent.
Heart weight, as measured by muscle mass, showed
similar results. Pressure stress resulted in
mice hearts growing from an average 100 milligrams to 290
milligrams before therapy and returning to
an average 209 milligrams in the BH4-treated hearts, while
placebo-treated hearts grew increasingly
worse, to an average 330 milligrams.
Improvements with BH4 therapy were almost as dramatic
in at least three other measurements
of organ health, including heart wall thickness, muscle
cell size and fibrosis, and lowered chemical
production of dangerous free radicals.
"Hearts clearly got better from administering the
drug, and our results offer proof of principle
that damage to the left ventricle from hypertrophy can be
stopped and reversed, providing a potential
therapy for the lethal implications of prolonged high
blood pressure," said Moens, now a cardiologist at
the University of Antwerp in Belgium.
Kass expects clinical trials to start within a
year.
Though no harmful side effects have been observed
with BH4 therapy, Kass said, at present
the drug comes with a significant cost drawback.
Technologically complex to manufacture, it is
currently priced at $29 per 100 milligrams, and average
individual treatments for PKU have been
estimated to cost as much as $57,000 per year. (The drug
is currently sold as sapropterin
dihydrochlorid, or Kuvan, by its manufacturer, BioMarin
Pharmaceuticals.)
Researchers say that even before the emergence of
symptoms of heart failure, such as chronic
fatigue and shortness of breath, the heart muscle
contracts more strongly to counteract high blood
pressure. As muscle action increases, the heart grows and
its walls become thicker, taking up space
inside the heart's chambers normally reserved for blood.
And despite harder muscle contractions,
pumping function becomes increasingly weak as the heart
can no longer push sufficient blood around
the body to meet its energy needs.
According to the American Heart Association, more
than 65 million American adults have high
blood pressure, a major risk factor for developing
larger-than-normal hearts. Experts say nearly a
quarter of the adult population worldwide is estimated to
have above-normal blood pressure.
Hypertrophy increases by two to three times an adult's
risk of suffering cardiovascular disease,
including heart failure and sudden cardiac death.
For nearly two decades, Kass and his team have
studied the nitric oxide pathway for clues to its
overall role in causing heart failure in the belief that
improving its function or lowering its production
of oxygen free radicals could prevent or reverse the
course of disease.
The Johns Hopkins team says that BH4, whose tissue
levels are degraded in stressed hearts
from hypertrophy and the muscle's weakened state, works by
recoupling the enzyme nitric oxide
synthase.
Researchers say that this is the only form of the
enzyme that functions normally, making more
nitric oxide rather than free radicals. Testing of another
potent antioxidant, Tempol, did not counter
the effects of hypertrophy like BH4 and failed to recouple
nitric oxide synthase. "This tells us that
BH4's targeted action is key to its benefits," Kass
said.
Researchers next plan to look at combined therapies
that could improve upon the effectiveness
of BH4. Add-on drugs include vitamin C or folic acid, both
of which are known to interact with the so-
called enzyme cofactor, and researchers plan to monitor
closely the effects of combined therapy on
heart function, size and weight.
In related work, Kass and his team have studied
Viagra as a possible treatment for hypertrophy
in its early stages. However, Kass points out that the
Viagra-based research focuses on a different
route, the phosphodiesterase-5 chemical pathway, and how
it is involved in the process of heart
failure. But, he said, BH4 is known to have some effect on
this chemical pathway, so "there could be
some combination from these two therapies" that he also
plans to study.
Funding for the study of BH4 was provided by the
National Institutes of Health and Peter
Belfer Laboratory Foundation, with additional support from
the American Heart Association, Belgian
American Educational Foundations and University of
Antwerp, Belgium.
In addition to Kass and Moens, Johns Hopkins
researchers involved in this study were Eiki
Takimoto, Carlo Tocchetti, Khalid Chakir, Djahida Bedja,
Gianfranco Cormaci, Elizabeth Ketner, Maulik
Majmudar, Kathleen Gabrielson, Marc Halushka, Shyam
Biswal, Nazareno Paolocci and Hunter
Champion. Kass is also the Abraham and Virginia Weiss
Professor of Cardiology at Johns Hopkins.