Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial.

Abstract

CONTEXT:

Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness.

OBJECTIVE:

To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome.

DESIGN, SETTING, AND PARTICIPANTS:

A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard beta-blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia.

INTERVENTION:

Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks.

MAIN OUTCOME MEASURES:

Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography.

RESULTS:

Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor beta (TGF-beta), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms.

CONCLUSIONS:

Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard beta-blocker therapy, possibly through attenuation of TGF-beta signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00485368.

• Authors: Anna A Ahimastos, Anuradha Aggarwal, Kellie M D'Orsa, Melissa F Formosa, Anthony J White, Ravi Savarirayan, Anthony M Dart, Bronwyn A Kingwell
• Journal: JAMA (JAMA) Vol. 298 Issue 13 Pg. 1539-47 (Oct 03 2007) ISSN: 1538-3598 [Electronic] United States
• PMID: 17911499 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Adrenergic beta-Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Transforming Growth Factor beta
• Angiotensin II
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 2
• Perindopril

Topics

• Adrenergic beta-Antagonists (therapeutic use)
• Adult
• Angiotensin II (antagonists & inhibitors)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology, therapeutic use)
• Aorta (diagnostic imaging, drug effects, pathology)
• Arteries (diagnostic imaging, drug effects, physiology)
• Blood Flow Velocity
• Blood Pressure
• Double-Blind Method
• Echocardiography
• Female
• Humans
• Male
• Marfan Syndrome (diagnostic imaging, drug therapy, physiopathology)
• Matrix Metalloproteinase 2 (blood)
• Matrix Metalloproteinase 3 (blood)
• Perindopril (pharmacology, therapeutic use)
• Transforming Growth Factor beta (blood)
• Ultrasonography, Doppler
• Vasodilation (drug effects)