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


METHODS
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.


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


METHODS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00485368.
Ahimastos
Anna A
AA
Alfred and Baker Medical Unit, Baker Heart Research Institute, Central Melbourne, Victoria, Australia.
Aggarwal
Anuradha
A
D'Orsa
Kellie M
KM
Formosa
Melissa F
MF
White
Anthony J
AJ
Savarirayan
Ravi
R
Dart
Anthony M
AM
Kingwell
Bronwyn A
BA
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D001158:Arteries / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D001783:Blood Flow Velocity; D001794:Blood Pressure; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020913:Perindopril / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000097:blood; D018608:Ultrasonography, Doppler; D014664:Vasodilation / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020913:Perindopril