Scientists at Johns Hopkins have used a commonly
prescribed blood pressure medicine, losartan (Cozaar), to
prevent a potentially fatal weakening of arteries in mice
with Marfan syndrome.
As a result, efforts are already under way with the
National Heart, Lung and Blood Institute and its affiliated
network of hospitals in the Pediatric Heart Health Network
and The Johns Hopkins Hospital to begin a clinical trial
for people with Marfan syndrome, which is expected to start
in the fall.
"The results of our study in mice greatly increase the
likelihood that losartan will also serve as an effective
treatment in humans, and quickly, because it is already
approved for use in the United States as a safe and
effective treatment for hypertension," said study senior
author Harry "Hal" Dietz, a professor at the
McKusick-Nathans Institute of Genetic Medicine at the
Johns Hopkins School of Medicine.
The Johns Hopkins findings, published in the journal
Science online April 6, are considered a
breakthrough discovery, researchers say, because they are
the first to identify a drug that can prevent Marfan
syndrome's most life-threatening complications from
developing and potentially reverse the damage already done.
Marfan syndrome can lead to a fatal tear or rupture in the
aorta, the body's main blood vessel that carries blood away
from the heart. The disease is often diagnosed in childhood
or early adulthood, when people are still young enough to
consider long-term therapies.
"It is very exciting that an existing medication has
proven capable of not only treating the problems of Marfan
syndrome but also disrupting the biological pathway that
precipitated them," said cardiac geneticist Daniel P.
Judge, an assistant professor at Johns Hopkins and its
Heart Institute and co-lead author of the study.
Cardiac surgeon Vincent Gott, a professor emeritus and
former chief of cardiac surgery at Johns Hopkins, said,
"Until now, surgery has been our main option for repairing
an aorta at risk of rupturing. However, it is comforting to
witness the time when medication could prevent this
disease, making surgery unnecessary," said Gott, who
mastered early life-saving techniques for replacing damaged
areas of the Marfan aorta with Dacron grafts and artificial
valves. He has surgically repaired the aortas in more than
100 Marfan patients.
The National Marfan Foundation estimates that more
than 30,000 Americans have the genetic condition, caused by
a defect in the connective tissue protein fibrillin-1,
which gives blood vessels and other organs their structural
form and strength. The condition is well-known for its
distinctive features, such as abnormal skeletal growth,
including thin and unusually long legs, arms and fingers,
as well as dislocation of the eye lens and, most
significantly, weakening of the aorta.
Losartan, first approved for use in 1995 by the Food
and Drug Administration, is a blood pressure medication
that is often used as an alternative to other medications
in people with chronic renal disease, heart failure and
diabetes.
Beta blockers, also prescribed for hypertension, have
been used to try to forestall the syndrome's arterial
growth. While evidence in people suggests that beta
blockers can slow the rate of aortic growth in Marfan
syndrome, researchers say the drugs neither halt abnormal
growth nor prevent the risk of aortic tear or rupture.
Moreover, the biological effects of these medications,
including propranolol (Inderol), have not been fully
studied, Dietz said.
The medication used in this study, formally known as
losartan potassium, is part of a class of medications
called angiotensin II receptor antagonists, which work by
blocking the angiotensin II molecule from binding to smooth
muscle cells. This, in turn, prevents the arteries from
tightening and raising blood pressure.
The latest studies, said Dietz, a Howard Hughes
Medical Institute investigator and director of the William
S. Smilow Center for Marfan Syndrome Research at Johns
Hopkins, crown more than 16 years of research by his team
into the root causes of the disease, whose genetic origins
they discovered in 1991. It was also Dietz and fellow
scientist Francesco Ramirez who developed and studied mice
with the gene for Marfan syndrome, allowing for much of the
research on the condition to continue to this day. His work
followed directly from that of Victor A. McKusick, the
renowned Johns Hopkins medical geneticist who, in 1955,
pioneered the clinical description of people with Marfan
syndrome and after whom the Institute of Genetic Medicine
is named.
As part of the latest study, 15 young Marfan mice were
given 0.6 grams per liter of losartan, consumed through
their drinking water for a period of six to 10 months.
Another group of 15 mice, also with Marfan syndrome, were
given a placebo. A third group was given a dose of 0.5
grams per liter of propranolol, a beta blocker commonly
used to alleviate the condition's symptoms by lowering
blood pressure within the arteries. A fourth group of mice
without Marfan syndrome served as a healthy comparison
group against which to gauge all treated mice. Mice studied
were approximately 2 months old when therapy was started,
an age equivalent to that of a human teenager, and already
had enlarged aortas.
According to Dietz, a cardiologist and geneticist,
after the mice were treated for six months, examination of
the aorta showed no apparent differences between
losartan-treated Marfan mice and those without the
disease.
"In essence, the cardiovascular system in the Marfan
mice was cured, while treatment with the beta blocker
simply slowed the rate of aortic growth but did not prevent
aortic pathology," he said.
Echocardiographic measurements of aortic growth showed
nothing abnormal in losartan-treated mice. Treated Marfan
mice showed the same average rate of growth as normal mice
during a six-month period, at 0.18 millimeters and 0.2
millimeters, respectively, while propanolol-treated mice
had growth of 0.36 millimeters. Untreated mice had three
times the growth rate, at 0.66 millimeters.
In the losartan-treated group, average aortic wall
thickness was 62 micrometers, essentially the same width as
in normal mice, at 63 micrometers. But untreated Marfan
mice had an abnormal average wall thickness of 92
micrometers, which was not significantly different from
that seen in propranolol-treated mice.
When aortic tissue samples were examined under the
microscope and scored on a four-point scale of
fragmentation, as an increasing measure of structural
breakdown of the aorta, losartan-treated mice had an
average score of 1.7. This was comparable to that of normal
mice, at 1.5, while untreated mice and propranolol-treated
mice had scores greater than 3.
The Johns Hopkins team was led to investigate losartan
after initial experiments, also part of the Science study,
showed that many problems in Marfan syndrome are caused by
excessive activity of a signaling protein called
transforming growth factor beta, or TGF-beta, and could be
prevented by blocking this molecule.
Previous studies showed that losartan inhibits the
activity of TGF-beta, and research by the Johns Hopkins
team in 2003 showed that overstimulation of TGF-beta in the
lungs and heart valve was triggered by a deficiency of
fibrillin-1, the underlying genetic origin of the
syndrome.
To show that excessive signaling by TGF-beta was also
responsible for progressive weakening in the aorta, the
disease's most serious complication, the researchers tested
various doses of neutralizing antibodies to see if reducing
the growth factor's signaling had any impact on aortic
growth. Ten Marfan mice were injected over an eight-week
period with a dose of 1 milligram per kilogram of
neutralizing antibody to TGF-beta, while another group of
Marfan mice was given a dose of 10 milligrams per kilogram,
and a third group was given a placebo.
Previous research into the syndrome, Judge said, had
shown that the rate of increased growth in the aortic root
and its diameter were directly related to the chances of
suffering a serious tear in the blood vessel.
When researchers examined ultrasound images and tissue
samples, they found that treated mice showed significant
improvement in aortic wall architecture, aortic root growth
and vessel wall thickness. Indeed, the average width of
the aorta in untreated Marfan mice was abnormally high, at
2.4 millimeters. In mice that received a low-dose antibody
treatment, it was reduced to 1.86 millimeters, while in
those that received high-dose therapy, it was 1.8
millimeters, which was indistinguishable from that of
normal mice.
"These findings proved that TGF-beta overstimulation
was driving the disease in the aorta, very similar to what
was found in the lungs and heart valve," said study co-lead
author Jennifer Pardo Habashi, a pediatric cardiology
fellow at Hopkins.
Moreover, she said, the studies connected the dots in
the disease from its genetic origins to its mechanistic or
biological pathways and finally to its treatment.
In the latest experiments, which took three years to
complete, the science of genetics was used to create animal
models with the disease, which could then be studied,
Habashi said. The disease was then broken down into its
individual steps or biological mechanisms, allowing the
identification of a medicine that could break the chain of
events.
"If molecular-based therapy can lead to a cure for
Marfan syndrome, there is increased optimism that it holds
similar promise in the quest for treatments of other
diseases in the future," she said.
Funding for this study was provided by the William S.
Smilow Center for Marfan Syndrome Reseach; the National
Institute of Arthritis and Musculoskeletal and Skin
Diseases, and the National Heart Lung and Blood Insitute,
both members of the National Institutes of Health; the
National Marfan Foundation; the Victor A. McKusick
Professorship; and the Dana and Albert "Cubby" Broccoli
Center for Aortic Diseases.
Besides Dietz, Judge and Habashi, other Johns Hopkins
researchers involved in this study were Tammy Holm, Ronald
Cohn, Bart Loeys, Timothy Cooper, Loretha Myers, Erin
Klein, Khalid Khan, Guosheng Liu, Carla Calvi, Megan
Podowski, Enid Neptune, Marc Halushka, Djahida Bedja,
Kathleen Gabrielson and David Huso. Other collaborators
were Daniel Rifkin, in New York, and Luca Carta and
Francesco Ramirez, in New Brunswick, N.J.
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