In mice genetically engineered to have Marfan's, the angiotensin II type 1 receptor inhibitor Cozaar (losartan) prevented two separate clinical manifestations of the syndrome -- weakening and lengthening seen in the aorta and flawed development of the lungs, according to Harry Dietz, M.D., of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins.
The evidence is sufficiently compelling that a clinical trial in humans affected by the genetic syndrome 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," Dr. Dietz said in a statement. Such a treatment could be available relatively soon, he added, because the drug is already approved for use in hypertension, even in children.
Mice with Marfan's syndrome, when treated with Cozaar starting at seven weeks of age, developed lungs and arteries that were essentially the same as those seen in wild-type mice, Dr. Dietz and colleagues reported in the April 7 issue of Science.
Many of the symptoms of the syndrome, they reported, are caused by excessive signaling by the transforming growth factor-beta (TGF-beta) family of cytokines. Blocking TGF-beta, either with specific neutralizing antibodies or with Cozaar, prevented the development of the syndrome.
Dr. Dietz and colleagues were the first to pin down the cause of Marfan's, whose clinical manifestations include long bone overgrowth, lens dislocation, emphysema, thickening and dysfunction of the mitral valve, and aortic aneurysm with a predisposition for vascular rupture and sudden death.
The syndrome is caused, they reported in 1991, by defects in the gene for fibrillin-1, a protein required during development to make elastic fibers in a range of tissues. That suggested, Dr. Dietz said, "that people with Marfan's are born without a proper quotient or quality of elastic fibers."
On the basis of that idea, the researchers expected that the lungs of their mutant mice would show signs of progressive destruction, as the tissues -- weaker than they should be because of the lack of fibrillin-1 -- slowly disintegrated. Instead, the early signs of emphysema were present almost from birth.
The implication was that some basic developmental signal was going awry, causing the lungs to develop abnormally. In 2003, the researchers showed that a deficiency in fibrillin-1 led to an over-production of TGF-beta, which was associated with all of the tissue abnormalities in the syndrome.
In the current study, which focused mainly on the aortic aneurysm issue, 15 young Marfan mice were given 0.6 grams per liter of Cozaar in their drinking water for six to 10 months, while another group of 15 mice was given a placebo. A third group got a beta-blocker, which is sometimes used in human Marfan's patients to reduce their blood pressure and therefore the risk of an aneurysm. Wild-type mice served as controls.
All the mice were seven weeks old when the study started -- roughly equivalent to a human teenager -- and the Marfan's mice already had enlarged aortas. After six months, there were no apparent differences between the aortas of the Cozaar-treated mice and wild-type animals.
"In essence, the cardiovascular system in the Marfan mice was cured," Dr. Dietz said. Treatment with the beta-blocker slowed the rate of aortic growth but did not prevent the development of pathological tissue.
Specifically, echocardiographic measurements of aortic growth showed:
- Over six months, Cozaar-treated Marfan mice had an average aortic growth of 0.18 millimeters, while the control mice had growth of 0.2 millimeters -- a difference that was not statistically significant.
- Mice treated with the beta-blocker had aortic growth of 0.36 millimeters, which was significantly greater than either the Cozaar-treated or wild-type mice, at P<0.02.
- The untreated Marfan mice had aortic growth of 0.66 millimeters, which was significantly greater than the Cozaar-treated or wild-type mice, at P<0.0001.
At the same time, the architecture of the aorta was normal in the Cozaar-treated and wild-type mice, both in terms of thickness of the vessel wall and in terms of fragmentation, a measure of structural breakdown. However, the mice getting the placebo and the beta-blocker both had thicker vessel walls and greater fragmentation, with no significant differences between the latter two groups.
The mice that got Cozaar "had normal aortic root growth, normal aortic root size and normal aortic wall thickness and architecture," Dr. Dietz said.
Cardiac surgeon Vincent Gott, M.D., former chief of cardiac surgery at Hopkins, said "until now, surgery has been our main option for repairing an aorta at risk of rupturing." Indeed, Dr. Gott -- one of the pioneers of replacing damaged areas of the Marfan's aorta grafts and artificial valves -- has repaired the aortas in more than 100 Marfan patients.
"However," Dr. Gott said in a statement, "it is comforting to witness the time when medication could prevent this disease, making surgery unnecessary."
The current Science paper also showed that Cozaar restores alveolar separation, preventing the emphysema seen in Marfan's mice and in humans with the condition.
Also, the researchers showed that pre-natal administration of the drug can prevent some of the aortic symptoms from ever appearing. However, that's unlikely to be a useful approach in humans, Dr. Dietz said, because the drug is contraindicated during pregnancy.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
ScienceSource Reference: Jennifer P. Habashi et al. "Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome." Science 2006;312:117-121.