Commonly used blood pressure medication prevents aortic aneurysm in mice with Marfan syndrome
Advances likelihood of clinical treatment for inherited vascular condition and affirms promise of genetic researchScientists 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," says study senior author, Harry (Hal) Dietz, M.D., a professor at the McKusick-Nathans Institute of Genetic Medicine at The Johns Hopkins University School of Medicine.
The Hopkins findings, to be 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," says cardiac geneticist Daniel P. Judge, M.D., an assistant professor at Hopkins and its Heart Institute and co-lead author of the study.
"Until now, surgery has been our main option for repairing an aorta at risk of rupturing," says cardiac surgeon Vincent Gott, M.D., a professor emeritus and former chief of cardiac surgery at Hopkins, who mastered early, life-saving techniques for replacing damaged areas of the Marfan aorta with Dacron grafts and artificial valves. "However, it is comforting to witness the time when medication could prevent this disease, making surgery unnecessary." Gott 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 U.S. 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 notes.
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, says Dietz, a Howard Hughes Medical Institute investigator and director of the William S. Smilow Center for Marfan Syndrome Research at 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, Ph.D., 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, M.D., the renowned 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 two 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 says.
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 tissues 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 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 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, says Judge, 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," says study co-lead author Jennifer Pardo Habashi, M.D., a pediatric cardiology fellow at Hopkins.
Moreover, she says, 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, Habashi says the science of genetics was used to create animal models with the disease, which could then be studied. 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 says.
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 Hopkins researchers involved in this study were Tammy Holm, B.A.; Ronald Cohn, M.D.; Bart Loeys, M.D., Ph.D.; Timothy Cooper, D.V.M.; Loretha Myers, A.A.; Erin Klein, B.A.; Khalid Khan, B.V.M.S.; Guosheng Liu, B.S.; Carla Calvi; Megan Podowski, B.A.; Enid Neptune, M.D.; Marc Halushka, M.D., Ph.D.; Djahida Bedja, B.S.; Kathleen Gabrielson, Ph.D.; and David Huso, D.V.M., Ph.D. Collaborators at other sites included Daniel Rifkin, Ph.D., in New York and Luca Carta, Ph.D., and Francesco Ramirez, Ph.D., in New Brunswick, N.J.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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