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Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.
N Engl J Med. 2008 Jun 26; 358(26):2787-95.NEJM

Abstract

BACKGROUND

Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement.

METHODS

We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs.

RESULTS

The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy.

CONCLUSIONS

In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

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Authors+Show Affiliations

Brooke BS
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Habashi JP
No affiliation info available
Judge DP
No affiliation info available
Patel N
No affiliation info available
Loeys B
No affiliation info available
Dietz HC
No affiliation info available

MeSH

AdolescentAdrenergic beta-AntagonistsAngiotensin II Type 1 Receptor BlockersAngiotensin-Converting Enzyme InhibitorsAortaBiphenyl CompoundsBlood PressureCalcium Channel BlockersChildChild, PreschoolDrug Therapy, CombinationFemaleHeart RateHumansInfantIrbesartanLinear ModelsLosartanMaleMarfan SyndromeProspective StudiesTetrazolesTransforming Growth Factor beta

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18579813

Clinical Trial Links

Generation of Marfan Syndrome and Fontan Cardiovascular Models Using Patient-specific Induced Pluripotent Stem Cells

Citation

Brooke, Benjamin S., et al. "Angiotensin II Blockade and Aortic-root Dilation in Marfan's Syndrome." The New England Journal of Medicine, vol. 358, no. 26, 2008, pp. 2787-95.
Brooke BS, Habashi JP, Judge DP, et al. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008;358(26):2787-95.
Brooke, B. S., Habashi, J. P., Judge, D. P., Patel, N., Loeys, B., & Dietz, H. C. (2008). Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. The New England Journal of Medicine, 358(26), 2787-95. https://doi.org/10.1056/NEJMoa0706585
Brooke BS, et al. Angiotensin II Blockade and Aortic-root Dilation in Marfan's Syndrome. N Engl J Med. 2008 Jun 26;358(26):2787-95. PubMed PMID: 18579813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. AU - Brooke,Benjamin S, AU - Habashi,Jennifer P, AU - Judge,Daniel P, AU - Patel,Nishant, AU - Loeys,Bart, AU - Dietz,Harry C,3rd PY - 2008/6/27/pubmed PY - 2008/7/2/medline PY - 2008/6/27/entrez SP - 2787 EP - 95 JF - The New England journal of medicine JO - N Engl J Med VL - 358 IS - 26 N2 - BACKGROUND: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. METHODS: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. RESULTS: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. CONCLUSIONS: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial. SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/18579813/Angiotensin_II_blockade_and_aortic_root_dilation_in_Marfan's_syndrome_ L2 - https://www.nejm.org/doi/10.1056/NEJMoa0706585?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -