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A landmark study by Habashi et al(1) in 2006 documented for the first time both the prevention and reversal of structural changes in the aorta associated with Marfan syndrome, via pharmacological means. This study, carried out in a rat model, concluded that such results were due to an inhibitor effect by the drug losartan on TGB-β1 (Figure 1). Habashi's paper prompted some physicians, in the absence of human trials, to begin the clinical off-label use of losartan on Marfan patients, arguing that this was justified due to the drug's excellent safety profile. This has caused some controversy. Two significant randomized human trials of losartan in Marfan patients have since been conducted, which contribute different but valuable elements to the debate; the COMPARE trial demonstrated a significantly lower increase in aortic root diameter among study subjects receiving losartan compared with a placebo group after 3 years, although no significant differences were observed in aortic diameter beyond the root itself. A more recently concluded trial by Lacro et al(2) from the Paediatric Heart Network, comparing losartan with atenolol (and no placebo group), appeared to show no comparative benefit with respect to the rate of aortic dilatation over three years among the losartan users compared with study patients given atenolol, with both groups of patients experiencing a similar decrease in the rate of dilatation over the 3 year follow-up. Both studies suggest a positive impact of losartan on aortic dilation in humans with Marfan, but they also highlight a number of important questions that remain unanswered. Further trials are clearly needed in order to assess optimal dosing and to guide timing of therapy, and also to further assess the potential and comparative effectiveness of both losartan and β-blockers, individually and in combination, as therapeutic treatments for aortic protection of different groups of patients with Marfan syndrome.

COMPARE and Pediatric Heart Network Investigator trials: Losartan finally validated in humans with Marfan, but much work remains!