Correspondence

Angiotensin II Blockade in Marfan's Syndrome

N Engl J Med 2008; 359:1732-1734October 16, 2008

Article

To the Editor:

Brooke et al. (June 26 issue),1 report a reduced rate of aortic-root dilation among pediatric patients with Marfan's syndrome after treatment with angiotensin II–receptor blockers (ARBs) as compared with previous medical therapy alone. This finding may be related to the inhibition of excessive transforming growth factor β (TGF-β) signaling2 and the subsequent inhibition of matrix metalloproteinases, thus reducing extracellular-matrix degeneration and aortic dilation.3 We recently reported the results of a randomized, placebo-controlled trial, which showed that an angiotensin-converting–enzyme (ACE) inhibitor, perindopril, reduced aortic dilation in adult patients with Marfan's syndrome after only 6 months.4 The article by Brooke et al. prompted us to present further analyses showing significant correlations between the change from preintervention to postintervention (with placebo or perindopril) in the aortic diameter at the sinuses of Valsalva and the change in plasma levels of both latent and active TGF-β, matrix metalloproteinase 2, and matrix metalloproteinase 3 (Table 1Table 1Univariate Correlations between Changes in Aortic Diameter and TGF-β, MMP-2, and MMP-3 in Plasma.).

Collectively, these data1,4 provide support for the concept that therapies targeting TGF-β and downstream pathways may have efficacy in reducing aortic dilation in Marfan's syndrome. The emerging role of TGF-β in abdominal aortic aneurysms5 also suggests broader applications for these therapies.

Anna A. Ahimastos, Ph.D.
Anthony M. Dart, D.Phil.
Bronwyn A. Kingwell, Ph.D.
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia

5 References

1
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC III. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med 2008;358:2787-2795
Full Text | Web of Science | Medline

2
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121
CrossRef | Web of Science | Medline

3
Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003;33:407-411
CrossRef | Web of Science | Medline

4
Ahimastos AA, Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA 2007;298:1539-1547
CrossRef | Web of Science | Medline

5
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N Engl J Med 2006;355:788-798
Full Text | Web of Science | Medline

To the Editor:

Compelling evidence indicates that mutations in the gene encoding fibrillin-1 (FBN1) in Marfan's syndrome result in excessive TGF-β signaling, causing many of the clinical features of this disease, including aortic dilation. Besides the classic pathway of TGF-β signal transduction, alternative protein cascades modulate the effects of TGF-β. Among these, a pathway initiated by the angiotensin II type 1 (AT1) receptor appears to play a crucial role in Marfan's syndrome. Brooke et al. report that blocking AT1 with losartan exerted a strikingly protective effect in patients with Marfan's syndrome. Nevertheless, the precise mechanism whereby losartan exerts its protective effect remains to be defined. Furthermore, in the studies of patients, there was variation in the therapeutic response, suggesting that other approaches may be useful.

Recently, an alternative TGF-β–initiated, Smad-independent signaling pathway that activates the nonreceptor tyrosine kinase, c-ABL, was defined.1 Imatinib mesylate effectively inhibits c-ABL and may be effective in the treatment of TGF-β–mediated diseases.2 Since affected tissues in Marfan's syndrome may have variable responses to losartan, imatinib mesylate could prove to be beneficial in this setting.

Sergio A. Jiménez, M.D.
Thomas Jefferson University, Philadelphia, PA 19104
sergio.jimenez@jefferson.edu

Joel Rosenbloom, M.D., Ph.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19107

2 References

1
Wilkes MC, Leof EB. Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J Biol Chem 2006;281:27846-27854
CrossRef | Web of Science | Medline

2
Rosenbloom J, Jimenez SA. Molecular ablation of transforming growth factor beta signaling pathways by tyrosine kinase inhibition: the coming of a promising new era in the treatment of tissue fibrosis. Arthritis Rheum 2008;58:2219-2224
CrossRef | Web of Science | Medline

To the Editor:

Losartan, an ARB, prevents aortic aneurysms in fibrillin-1–mutant (C1039G/+) mice by antagonizing increased TGF-β signaling.1 Brooke et al. confirm this beneficial effect of ARBs in 18 pediatric patients with Marfan's syndrome, raising hope for nonsurgical cardiovascular treatment in this syndrome. However, two important questions remain. First, are ARBs beneficial in Marfan's syndrome irrespective of the underlying FBN1 mutation? Second, are ARBs beneficial in cases of Marfan's syndrome that are caused by mutations in other genes? We hypothesize that the usefulness of losartan depends on the TGF-β signaling status. More than 800 different FBN1 mutations are known2; these may differentially affect TGF-β signaling. Decreased TGF-β signaling in Marfan's syndrome due to mutations in the gene encoding TGF-β receptor 2 has been reported,3 suggesting a possible adverse effect of ARBs.

Brooke et al. performed FBN1 mutation analysis in 6 of 18 patients without giving specifics. The specific gene mutation in these and other patients enrolling in an ARB trial4 is an important variable that should be included in the analysis.

Fleur S. van Dijk, M.D.
Hanne Meijers-Heijboer, M.D., Ph.D.
Gerard Pals, Ph.D.
VU University Medical Center, 1081 HV Amsterdam, the Netherlands

4 References

1
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121
CrossRef | Web of Science | Medline

2
Faivre L, Collod-Beroud G, Loeys BL, et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007;81:454-466
CrossRef | Web of Science | Medline

3
Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 2004;36:855-860
CrossRef | Web of Science | Medline

4
Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007;154:624-631
CrossRef | Web of Science | Medline

Author/Editor Response

Ahimastos and colleagues pose important research questions that have the potential to affect the clinical care of patients with Marfan's syndrome and related disorders. Although it appears that both ARBs (e.g., losartan) and ACE inhibitors (e.g., perindopril) may modulate the expression or activity of TGF-β and matrix metalloproteinases and reduce aortic-root enlargement in Marfan's syndrome, the mechanism (or mechanisms), relative potency, and duration of protection associated with each class of medication remain to be elucidated. The recent demonstration that beta-adrenergic blockers (e.g., atenolol) and matrix metalloproteinase inhibitors (e.g., doxycycline) can reduce TGF-β and the activity of matrix metalloproteinase in mouse models of Marfan's syndrome1 highlights the possibility of cross-talk between protective pathways that are both dependent on and independent of blood-pressure lowering. The potential for synergism between therapeutic agents and the usefulness, if any, of circulating markers for tailoring therapies can be efficiently investigated with the use of established animal models.

Jiménez and Rosenbloom correctly emphasize that TGF-β can initiate multiple downstream signaling cascades, including both canonical and noncanonical (Smad-independent) pathways.2 Although TGF-β–mediated activation of c-ABL has been implicated in tissue fibrosis and warrants investigation in Marfan's syndrome, other noncanonical pathways are receiving equal emphasis for further investigation.

We strongly support further research to identify genetic determinants of therapeutic response in Marfan's syndrome and related disorders; this position is shared by van Dijk and colleagues. Given that a deficiency of extracellular fibrillin-1 occurs in the full spectrum of patients with Marfan's syndrome and that few (if any) FBN1 genotype–phenotype correlations with high predictive value have emerged, despite the description of close to 1000 mutations, we anticipate that the investigation of variants in other genes (e.g., those that regulate TGF-β or angiotensin signaling) will prove to be more informative. Ancillary studies supported by the National Marfan Foundation will address these issues in the ongoing, randomized trial of losartan versus atenolol.3

In our experience,4,5 patients with mutations in either of the two genes that encode the TGF-β receptor (TGFBR1 or TGFBR2) can routinely be distinguished from patients with classic Marfan's syndrome on the basis of distinguishing features in the craniofacial, skeletal, cutaneous, and cardiovascular systems and the absence of eye-lens dislocation. The analysis of tissue specimens obtained from patients revealed the consistent finding of increased TGF-β signaling in the vessel wall in patients with this condition. We conclude that losartan and other agents that can antagonize TGF-β signaling also hold promise for the treatment of this syndrome and perhaps other forms of genetically imposed aortic aneurysm.

Benjamin S. Brooke, M.D.
Harry C. Dietz, III, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21205
hdietz@jhmi.edu

5 References

1
Chung AW, Yang HH, Radomski MW, van Breemen C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res 2008;102:e73-e85
CrossRef | Web of Science | Medline

2
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-584
CrossRef | Web of Science | Medline

3
Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007;154:624-631
CrossRef | Web of Science | Medline

4
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-281
CrossRef | Web of Science | Medline

5
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N Engl J Med 2006;355:788-798
Full Text | Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Matt Peter, Eckstein Friedrich. (2012) Novel pharmacological strategies to prevent aortic complications in Marfan syndrome. Journal of Geriatric Cardiology 8:4, 254-257
CrossRef
2
Seamus C. Harrison, Anastasia Z. Kalea, Michael V. Holmes, Obi Agu, Steve E. Humphries. (2012) Genomic Research to Identify Novel Pathways in the Development of Abdominal Aortic Aneurysm. Cardiology Research and Practice 2012, 1-8
CrossRef
3
Seamus C. Harrison, Michael V. Holmes, Obi Agu, Steve E. Humphries. (2011) Genome wide association studies of abdominal aortic aneurysms—Biological insights and potential translation applications. Atherosclerosis 217:1, 47-56
CrossRef
4
Teun van der Bom, Paul Luijendijk, Berto J Bouma, Dave R Koolbergen, Joris R de Groot, Barbara JM Mulder. (2011) Treatment of congenital heart disease: risk-reducing measures in young adults. Future Cardiology 7:2, 227-240
CrossRef