The current study provides early evidence suggesting that the addition of losartan or another ARB to the traditional regimen used to treat aortic aneurysm in patients with Marfan’s syndrome may be beneficial. The initiation of ARB therapy resulted in a significant reduction in the rate of change in aortic-root diameter as compared with beta-blocker therapy alone. The therapeutic effect extended to the sinotubular junction, a site also affected by Marfan’s syndrome. In comparison, aortic segments not typically affected in Marfan’s syndrome (e.g., the ascending aorta above the sinotubular junction) continued to show an annual rate of change in diameter that was appropriate for age and body size. Together, these findings suggest that ARBs do not arrest aortic growth but specifically reduce the pathologic rate of increase in the diameter of aortic segments that are already of sufficient size to accommodate the physiologic demands of the tissues for blood flow.
Losartan and irbesartan belong to the ARB class of antihypertensive medications that work by selectively blocking the angiotensin II type 1 (AT1) receptor within the renin–angiotensin–aldosterone system.16
In addition to antihypertensive and other effects, AT1-receptor blockade induces a clinically relevant decrease in TGF-β
This antagonism results in reduced plasma levels of free TGF-β
, reduced tissue expression of TGF-β
–responsive genes, and reduced levels of intracellular mediators within the TGF-β
signaling cascade, such as phosphorylated Smad2. In a prospective study of renal-transplant recipients, treatment with normal antihypertensive doses of losartan decreased plasma levels of TGF-β
by more than 50% within 2 weeks.18
The effects of angiotensin II are mediated by two receptors, the AT1 receptor and the angiotensin II type 2 (AT2) receptor.16
AT1-receptor signaling can increase the production of TGF-β
ligands and receptors, as well as activators such as thrombospondin-1.19
Cellular events observed in the tissues of persons with Marfan’s syndrome, including proliferation of vascular smooth-muscle cells, fibrosis, and increased expression of matrix metalloproteinases 2 and 9, are plausibly attributable to increased TGF-β
In contrast, the AT2 receptor is thought to induce cellular effects opposite to those of the AT1 receptor, including antiproliferative and antiinflammatory effects that are beneficial in aortic-wall homeostasis.20
Given these mechanisms, the beneficial effects of ACE inhibitors and ARBs in this setting might be expected to differ. ACE inhibitors limit the production of angiotensin II and hence limit signaling through both the detrimental AT1-receptor pathway and the potentially protective AT2-receptor pathway and would not influence alternative mechanisms for angiotensin II production, such as the activity of mast-cell chymase. In contrast, ARBs cause selective blockade of the AT1 receptor, resulting in overactivation of the AT2-receptor pathway.10
In keeping with these mechanistic hypotheses, Daugherty and colleagues observed that AT1-receptor–blocking agents could prevent abdominal aortic aneurysms induced by the infusion of angiotensin II in apolipoprotein E–deficient mice, whereas selective AT2-receptor antagonists increased both the incidence and the severity of abdominal aneurysms in this model.21,22
On balance, however, it seems possible that the benefit of AT1-receptor antagonism achieved with ACE inhibitors could outweigh the potential negative influence of AT2-receptor blockade. A small, randomized, controlled trial of the ACE inhibitor perindopril as compared with placebo in adult patients with Marfan’s syndrome who were receiving beta-blockers showed a reduced rate of change in aortic-root diameter that correlated with decreased circulating TGF-β
levels over a relatively short period of follow-up (24 weeks).23
Nevertheless, our recent observation of accelerated aortic-root enlargement in fibrillin-1–deficient mice after targeted disruption of the gene encoding the AT2 receptor further supports our hypothesis that selective AT1-receptor antagonists will provide superior protection in preventing aneurysmal dilation of the aortic root (unpublished data).
There are several limitations of our study. This was a nonrandomized, retrospective, observational study that evaluated only a small subgroup of pediatric patients with Marfan’s syndrome who had evidence of severe aortic-root enlargement or rapid increase in aortic diameter. Selection bias may have resulted in the identification of patients who were more adherent to, and therefore more likely to have a response to, ARB therapy, although it could also be hypothesized that patients with established severe disease would be less likely to have a response to ARB therapy than would patients with milder disease. Although all patients in this study had a reduction in the rate of change of aortic-root diameter while receiving ARB therapy, there was variability in this therapeutic response (, and Table 2 in the Supplementary Appendix) that may be correlated with the pre-existing degree of pathologic change or other individually specific factors, such as genotype. This variability may alter the effectiveness of TGF-β antagonism, which was not assessed in this study. It is also possible that up-regulation of AT1 receptors in response to chronic receptor antagonism may limit the long-term therapeutic effect of ARBs.
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. A trial coordinated by the Pediatric Heart Network of the National Heart, Lung, and Blood Institute, comparing losartan with atenolol in patients with Marfan’s syndrome, began enrolling patients in the winter of 2007, and we encourage all eligible patients to enroll in this trial.24,25
Until data from this trial are available, evidence for the potential efficacy of ARB therapy in this setting should be considered preliminary.