Baltimore, MD - Use of angiotensin-2-receptor blockers (ARBs) has slowed the rate of progressive aortic root dilation in a small study of patients with Marfan's syndrome [1]. Dr Benjamin S Brooke (Johns Hopkins University School of Medicine, Baltimore, MD) and colleagues report their findings in the June 25, 2008 issue of the New England Journal of Medicine.

Marfan's syndrome is a congenital, autosomal dominant disorder in which progressive enlargement of the aortic root—leading to dissection—is the main cause of premature death.

Brooke et al warn, however, that their study is only a pilot and the results need to be confirmed in an ongoing prospective randomized trial that is being coordinated by the Pediatric Heart Network of the National Heart Lung and Blood Institute (NHLBI), as previously reported by heartwire. "We encourage all eligible patients to enroll in this trial. Until data from this trial are available, evidence for the potential efficacy of ARB therapy in this setting should be considered preliminary," they note.

In an accompanying editorial [2], Dr Reed E Pyeritz (University of Pennsylvania School of Medicine, Philadelphia) agrees. "We all have a stake in supporting this [NHLBI] trial, since it affords perhaps the best chance to validate a crucial hypothesis."

Brooke and colleagues explain that the current medical management of Marfan's syndrome is focused on serial cardiac imaging studies and the use of pharmacologic agents such as beta blockers to reduce hemodynamic stress on the aortic wall.

As previously reported by heartwire, studies in mice models of Marfan's syndrome have shown that the ARB losartan was able to prevent and even reverse three prominent feature of Marfan's syndrome in humans—dilatation of the aortic root, air-space widening, and skeletal myopathy.

Consequently, the researchers followed 18 pediatric patients with Marfan's who had been taking ARBs for 12 to 47 months after other medical therapy had failed. Of the patients, 17 were taking losartan and one irbesartan. They compared the rates of change in aortic-root diameter before and after the initiation of ARB treatment.

The mean rate of change in aortic-root diameter decreased significantly, from 3.54 mm per year to 0.46 mm per year during the ARB therapy (p<0.001). Other relevant measures also improved during ARB therapy, such as the deviation of aortic-root enlargement from normal and the change in diameter of the sinotubular junction.

But Pyeritz warns in his editorial of the dangers of extrapolating from mouse studies to humans and says that the initial studies of ARBs in mice "have drawn widespread and often inappropriately enthusiastic notice in the scientific and lay communities for several years."

Brooke et al agree wholeheartedly: "Despite the encouraging results of this observational study, equipoise is maintained regarding a role for ARB therapy in the treatment of patients with Marfan's syndrome; our findings must be confirmed by a prospective randomized trial that is being coordinated by the . . . NHLBI, comparing losartan with atenolol in patients with Marfan's syndrome," they stress.

Pyeritz says that unfortunately—and probably due to the overenthusiastic media coverage of the mice studies of ARB therapy in Marfan's—"some families and patients have opted not to join the NHLBI trial and have even obtained prescriptions for ARBs from their own physicians.

"We must remain cognizant of the fact that other mouse models of human genetic diseases have suggested beneficial therapies that either have not worked in humans or have been associated with undesirable effects," he cautions. "At this stage, the most appropriate course of action for patients with Marfan's syndrome and their physicians is to give serious consideration to enrolling in this trial."

If, however, patients are not eligible for the trial, an ARB is "a reasonable choice if beta blockade alone is not controlling either blood pressure or dilatation in any region of the aorta," Pyeritz adds.

The NHLBI trial began enrolling in the winter of 2007 and, unless losartan proves to be remarkably beneficial and the study is stopped early as a result, findings are expected to be available in four to five years, he says.

"If the preliminary findings by Brooke et al are confirmed, the treatment of Marfan's syndrome will go down in history as an early triumph of translational medicine," Pyeritz concludes.