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.

[1]  M. Entman,et al.  Angiotensin II Blockade Reverses Myocardial Fibrosis in a Transgenic Mouse Model of Human Hypertrophic Cardiomyopathy , 2001, Circulation.

[2]  R E Pyeritz,et al.  Revised diagnostic criteria for the Marfan syndrome. , 1996, American journal of medical genetics.

[3]  A. Daugherty,et al.  Antagonism of AT2 receptors augments Angiotensin II‐induced abdominal aortic aneurysms and atherosclerosis , 2001, British journal of pharmacology.

[4]  D. Milewicz,et al.  Treatment of aortic disease in patients with Marfan syndrome. , 2005, Circulation.

[5]  B. Gelb.  Marfan's syndrome and related disorders--more tightly connected than we thought. , 2006, The New England journal of medicine.

[6]  B. McCrindle,et al.  Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. , 2005, The American journal of cardiology.

[7]  M. Burnier,et al.  Angiotensin II Type 1 Receptor Blockers , 2001, Circulation.

[8]  R. Alexander,et al.  Angiotensin II type 1 receptor: relationship with caveolae and caveolin after initial agonist stimulation. , 1998, Hypertension.

[9]  D. Judge,et al.  Marfan's syndrome , 2005, The Lancet.

[10]  M. Iwai,et al.  Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury , 2001, Circulation.

[11]  D. Arking,et al.  Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome , 2003, Nature Genetics.

[12]  K. Berecek,et al.  Thrombospondin 1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions. , 2006, Biochemical and biophysical research communications.

[13]  F. Oppenheimer,et al.  Role of transforming growth factor‐ β1 in the progression of chronic allograft nephropathy , 2001 .

[14]  A. Aggarwal,et al.  Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome A Randomized Controlled Trial , 2008 .

[15]  Ada Hamosh,et al.  Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene , 1991, Nature.

[16]  D. Judge,et al.  TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome , 2004 .

[17]  S. Colan,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. , 2007, American heart journal.

[18]  M. Roman,et al.  Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. , 1999, The American journal of cardiology.

[19]  E. Murphy,et al.  Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. , 1994, The New England journal of medicine.

[20]  Marc K. Halushka,et al.  Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome , 2006, Science.

[21]  H. Dietz,et al.  Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. , 1995, Human molecular genetics.

[22]  T. Ogihara,et al.  [Angiotensin II type 1 receptor gene]. , 2000, Nihon rinsho. Japanese journal of clinical medicine.

[23]  S. Ledbetter,et al.  Neutralization of transforming growth factor-β attenuates hypertension and prevents renal injury in uremic rats , 2005, Journal of hypertension.

[24]  A. Daugherty,et al.  Role of the Renin‐Angiotensin System in the Development of Abdominal Aortic Aneurysms in Animals and Humans , 2006, Annals of the New York Academy of Sciences.

[25]  S. Colan,et al.  Theoretical and empirical derivation of cardiovascular allometric relationships in children. , 2005, Journal of applied physiology.

[26]  K Y Liang,et al.  Longitudinal data analysis for discrete and continuous outcomes. , 1986, Biometrics.