Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.
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.
Brooke
Benjamin S
BS
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Habashi
Jennifer P
JP
Judge
Daniel P
DP
Patel
Nishant
N
Loeys
Bart
B
Dietz
Harry C
HC
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007223:Infant; D000077405:Irbesartan; D016014:Linear Models; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies; D013777:Tetrazoles / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000077405:Irbesartan; D019808:Losartan