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Figure 1.
Flow of Patients Through the Study
Flow of Patients Through the Study
Figure 2.
Individual Patient Values for Systemic Arterial Compliance and Central and Peripheral Pulse Wave Velocities
Individual Patient Values for Systemic Arterial Compliance and Central and Peripheral Pulse Wave Velocities

Squares indicate mean (SEM) values. P values for change in placebo vs change in perindopril were calculated using analysis of covariance with baseline values as covariates (P = .004 for systemic arterial compliance and P < .001 for central and peripheral pulse wave velocities). Systemic arterial compliance measurements were not obtained in 5 patients with aortic regurgitation (2 in placebo group and 3 in perindopril group).

Figure 3.
Individual Patient Values for End-Systole and End-Diastole Aortic Root Diameters
Individual Patient Values for End-Systole and End-Diastole Aortic Root Diameters

Squares indicate mean (SEM) values. P values for change in placebo vs change in perindopril were calculated using analysis of covariance with baseline values as covariates (for end-systole: P = .03 for left ventricular outflow tract diameter, P < .001 for sinuses of Valsalva diameter, P = .001 for supra-aortic ridge diameter, and P = .01 for ascending aorta diameter; and for end-diastole: P < .001 for all).

Figure 4.
Individual Matrix Metalloproteinase (MMP)-2 and MMP-3 Protein Levels
Individual Matrix Metalloproteinase (MMP)-2 and MMP-3 Protein Levels

Squares indicate mean (SEM) values. P < .001 for both plots.

Figure 5.
Individual Transforming Growth Factor β (TGF-β) Plasma Levels
Individual Transforming Growth Factor β (TGF-β) Plasma Levels

Squares indicate mean (SEM) values. P = .01 for latent and P = .02 for active TGF-β comparisons.

Figure 6.
Proposed Effect of ACE Inhibition on Pathogenesis of Aortic Stiffness in Patients With MFS
Proposed Effect of ACE Inhibition on Pathogenesis of Aortic Stiffness in Patients With MFS

Marfan syndrome (MFS) is associated not only with increased transforming growth factor β (TGF-β) signaling through the angiotensin II type 1 receptor (AT1R),10 but also with cystic medial degeneration through the angiotensin II type 2 receptor (AT2R).11 Blockade of the renin angiotensin system with an angiotensin-converting enzyme (ACE) inhibitor rather than an AT1R or AT2R inhibitor does not only inhibit downstream effects of increased TGF-β signaling, such as increased matrix metalloproteinase activity, increased extracellular matrix breakdown, arterial wall fibrosis, and ultimately increased arterial dilatation, but it also leads to a reduction in vascular smooth muscle cell apoptosis, the principle characteristic of cystic medial degeneration. Thus, ACE inhibition provides additional clinical benefit because it attenuates detrimental effects mediated through both the AT1R and AT2R. Dashed pathways indicate that an exact mechanism is not yet known.

Table 1. 
Baseline Characteristics of the Study Populationa
Baseline Characteristics of the Study Populationa
Table 2. 
Effects of Perindopril on Blood Pressure and Arterial Stiffness Parameters
Effects of Perindopril on Blood Pressure and Arterial Stiffness Parameters
Table 3. 
Effects of Perindopril on Echocardiographic Parameters
Effects of Perindopril on Echocardiographic Parameters
1.
Neptune  ER, Frischmeyer  PA, Arking  DE,  et al.  Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33(3):407-411.
PubMedArticle
2.
Shores  J, Berger  KR, Murphy  EA, Pyeritz  RE.  Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994;330(19):1335-1341.
PubMedArticle
3.
Propanolol Aneurysm Trial Investigators.  Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J Vasc Surg. 2002;35(1):72-79.
PubMedArticle
4.
Lindholt  JS, Henneberg  EW, Juul  S, Fasting  H.  Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms. Int Angiol. 1999;18(1):52-57.
PubMed
5.
Moursi  MM, Beebe  HG, Messina  LM, Welling  TH, Stanley  JC.  Inhibition of aortic aneurysm development in blotchy mice by beta adrenergic blockade independent of altered lysyl oxidase activity. J Vasc Surg. 1995;21(5):792-799.
PubMedArticle
6.
Ahimastos  AA, Natoli  AK, Lawler  A, Blombery  PA, Kingwell  BA.  Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. Hypertension. 2005;45(6):1194-1199.
PubMedArticle
7.
Hackam  DG, Thiruchelvam  D, Redelmeier  DA.  Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study. Lancet. 2006;368(9536):659-665.
PubMedArticle
8.
Liao  S, Miralles  M, Kelley  BJ, Curci  JA, Borhani  M, Thompson  RW.  Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg. 2001;33(5):1057-1064.
PubMedArticle
9.
Nagashima  H, Uto  K, Sakomura  Y,  et al.  An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg. 2002;36(4):818-823.
PubMedArticle
10.
Habashi  JP, Judge  DP, Holm  TM,  et al.  Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117-121.
PubMedArticle
11.
Nagashima  H, Sakomura  Y, Aoka  Y,  et al.  Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan's syndrome. Circulation. 2001;104(12)(suppl 1):I282-I287.
PubMed
12.
Yetman  AT, Bornemeier  RA, McCrindle  BW.  Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005;95(9):1125-1127.
PubMedArticle
13.
Nataatmadja  M, West  M, West  J,  et al.  Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation. 2003;108(suppl 1):II329-II334.
PubMedArticle
14.
Ikonomidis  JS, Jones  JA, Barbour  JR,  et al.  Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation. 2006;114(1)(suppl):I365-I370.
PubMed
15.
De Paepe  A, Devereux  RB, Dietz  HC, Hennekam  RC, Pyeritz  RE.  Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62(4):417-426.
PubMedArticle
16.
Liu  Z, Brin  KP, Yin  FC.  Estimation of total arterial compliance: an improved method and evaluation of current methods. Am J Physiol. 1986;251(3 pt 2):H588-H600.
PubMed
17.
Cameron  JD, Dart  AM.  Exercise training increases total systemic arterial compliance in humans. Am J Physiol. 1994;266(2 pt 2):H693-H701.
PubMed
18.
Mitchell  GF, Izzo  JL  Jr, Lacourciere  Y,  et al.  Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation. 2002;105(25):2955-2961.
PubMedArticle
19.
Kingwell  BA, Berry  KL, Cameron  JD, Jennings  GL, Dart  AM.  Arterial compliance increases after moderate-intensity cycling. Am J Physiol. 1997;273(5 pt 2):H2186-H2191.
PubMed
20.
Roman  MJ, Devereux  RB, Kramer-Fox  R, O'Loughlin  J.  Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol. 1989;64(8):507-512.
PubMedArticle
21.
Perry  GJ, Helmcke  F, Nanda  NC, Byard  C, Soto  B.  Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol. 1987;9(4):952-959.
PubMedArticle
22.
Levine  RA, Stathogiannis  E, Newell  JB, Harrigan  P, Weyman  AE.  Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol. 1988;11(5):1010-1019.
PubMedArticle
23.
Jeremy  RW, Huang  H, Hwa  J, McCarron  H, Hughes  CF, Richards  JG.  Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am J Cardiol. 1994;74(4):369-373.
PubMedArticle
24.
Gott  VL, Greene  PS, Alejo  DE,  et al.  Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med. 1999;340(17):1307-1313.
PubMedArticle
25.
Kornbluth  M, Schnittger  I, Eyngorina  I, Gasner  C, Liang  DH.  Clinical outcome in the Marfan syndrome with ascending aortic dilatation followed annually by echocardiography. Am J Cardiol. 1999;84(6):753-755,A9.
PubMedArticle
26.
Rodríguez-Vita  J, Sánchez-López  E, Esteban  V, Rupérez  M, Egido  J, Ruiz-Ortega  M.  Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism. Circulation. 2005;111(19):2509-2517.
PubMedArticle
27.
Dean  JC.  Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007;15(7):724-733.
PubMedArticle
28.
Cushman  DW, Wang  FL, Fung  WC,  et al.  Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE). Br J Clin Pharmacol. 1989;28(suppl 2):115S-130S.
PubMedArticle
29.
Asmar  RG, London  GM, O'Rourke  ME, Safar  ME.  Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension. 2001;38(4):922-926.
PubMedArticle
30.
Girerd  X, Giannattasio  C, Moulin  C, Safar  M, Mancia  G, Laurent  S.  Regression of radial artery wall hypertrophy and improvement of carotid artery compliance after long-term antihypertensive treatment in elderly patients. J Am Coll Cardiol. 1998;31(5):1064-1073.
PubMedArticle
31.
Pannier  BM, Guerin  AP, Marchais  SJ, London  GM.  Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension. Clin Exp Pharmacol Physiol. 2001;28(12):1074-1077.
PubMedArticle
Preliminary Communication
October 3, 2007

Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan SyndromeA Randomized Controlled Trial

Author Affiliations

Author Affiliations: Alfred and Baker Medical Unit, Baker Heart Research Institute (Drs Ahimastos, White, Dart, and Kingwell, and Mss D’Orsa and Formosa); Department of Cardiology, Royal Melbourne Hospital (Dr Aggarwal); and Murdoch Children's Research Institute and University of Melbourne (Dr Savarirayan), Melbourne, Australia.

JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539
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 β-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 β (TGF-β), 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 β-blocker therapy, possibly through attenuation of TGF-β signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome.

Trial Registration  clinicaltrials.gov Identifier: NCT00485368

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in FBN1, the gene encoding fibrillin 1. Fibrillin 1 is a key component of extracellular matrix elastic fibers and also a negative regulator of the cytokine transforming growth factor β (TGF-β), which contributes to matrix metalloproteinase (MMP) activation and extracellular matrix degeneration.1 The main clinical manifestations of MFS involve the skeletal, ocular, and cardiovascular systems. Progressive aortic stiffening, dilatation, and rupture are the most serious complications and the most common cause of premature death. Based on a single trial2 of propranolol in 32 patients with MFS and 38 controls, β-blockers are currently the standard treatment for MFS. The rationale for the use of β-blockers includes reduction in the rate of pressure change in the aortic root (ie, left ventricular ejection) and heart rate, and therefore aortic wall stress. However, β-blockers may not directly address the underlying pathobiology of aortic wall degeneration35 as effectively as other agents.69

A number of recent studies have implicated the renin-angiotensin system in development of aortic stiffening, dilatation, and rupture in MFS through multiple mechanisms involving both the angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors. In fibrillin 1–deficient mice, enhanced activation of and signaling by TGF-β can be blocked by the AT1 antagonist losartan preventing aortic aneurysm.10 On the other hand, both angiotensin II and AT2 receptor expression are increased in MFS aortas and associated with cystic medial degeneration, which contributes to aortic rupture.11 Angiotensin-converting enzyme (ACE) inhibition and AT2 receptor antagonism also significantly inhibit vascular smooth muscle cell apoptosis in cultured aortic cells from patients with MFS.11 ACE inhibitors are known to reduce large artery stiffness6 and a small nonrandomized clinical study has also reported that ACE inhibitors increase aortic distensibility compared with β-blocker therapy in children and adolescents with MFS.12

Given the efficacy of ACE inhibitors to inhibit the actions of angiotensin II through both the AT1 and AT2 receptors, we hypothesized that such therapy would reduce arterial stiffness and aortic dilatation relative to placebo in adult patients with MFS taking standard β-blocker therapy. We also hypothesized that these aortic changes would be associated with reduction in TGF-β and MMP plasma levels, particularly MMP-2 and MMP-3, which are up-regulated by TGF-β in MFS.13,14

METHODS

Seventeen patients (mean [SD], 33 [6] years; range, 27-40 years) were recruited from the Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia, and completed the trial, which was initiated in January 2004 and completed in September 2006 (Figure 1). All patients gave written informed consent to participate in the study, which was approved by the Alfred Hospital Ethics Committee. Inclusion criteria included (1) positive strict diagnosis of MFS using Ghent criteria,15 (2) age 18 to 40 years, (3) serum creatinine level of less than 1.2 mg/dL (to convert to micromoles per liter, multiply by 88.4), (4) systolic blood pressure of 140/90 mm Hg or less (when measured on β-blocker therapy), and (5) no history of previous aortic surgery. Homocysteinuria was excluded as an alternative diagnosis. All patients were receiving long-term treatment with a β-blocker.

Computer-generated numbers specified the drug allocation sequence. A tamper-proof randomization process generated by the hospital research center randomly assigned participants to receive either perindopril (2 mg/d for 1 week, 4 mg/d for 2 weeks, and thereafter 8 mg/d for 21 weeks; Coversyl, Servier Laboratories Ltd Pty, Hawthorn Victoria, Australia) or placebo (2 mg/d equivalent for 1 week, 4 mg/d equivalent for 2 weeks, and thereafter 8 mg/d equivalent for 21 weeks) in a parallel-group, double-blind design. All patients reached the 8 mg/d dosage. Both investigators and patients were blinded to drug assignment. Furthermore, investigators did not have access to baseline data when they performed follow-up measurements and patients were not asked which treatment they thought they were receiving. No patient assigned to placebo crossed over to perindopril during the trial or vice versa. The study had 80% power to detect a 10% change in arterial stiffness parameters and a 5% change in aortic diameters with an α=.05.

Resting Blood Pressure

On the morning of testing and 10 hours following the last medication dose, supine resting brachial arterial blood pressure and heart rate were measured 3 times at 3-minute intervals using an automated oscillometric blood pressure monitor (Dinamap Vital Signs Monitor 18465X, Criticon, Florida) following 15 minutes of quiet rest in a temperature-controlled room.

Arterial Stiffness

Arterial stiffness was assessed globally via systemic arterial compliance (carotid tonometry and Doppler velocimetry) and regionally via pulse wave velocity. Systemic arterial compliance was determined noninvasively using calculations based on the area method of Liu et al16 and a 2-element Windkessel model of the arterial system as described previously.16,17 This method has been validated to primarily assess the properties of the large vessels, including the aorta and carotid arteries.18 Pulse wave velocity is related directly to aortic stiffness and was measured centrally between the right carotid and right femoral arteries and peripherally between the right femoral and dorsalis pedis arteries, by simultaneous applanation tonometry (SPT-301; Miller Instruments, Houston, Texas).19 The experienced analyst performing the measurements (A.A.A.) was blinded to treatment allocation.

Echocardiography

Two-dimensional, M-mode, and Doppler echocardiograms were obtained with a commercially available cardiac ultrasound system, using a 2.5-MHz transducer. Aortic root measurements were made in 2-dimensional parasternal long-axis view at end-diastole (peak of R wave on electrocardiogram) and at end-systole (T wave on electrocardiogram) at the level of the left ventricular outflow tract, sinuses of Valsalva, supra-aortic ridge, and proximal ascending aorta 1 to 2 cm above the supra-aortic ridge according to the method of Roman et al.20 All measurements were made using the leading edge technique on up to 5 cycles and averaged. The severity of aortic and mitral regurgitation was graded semiquantitatively using color Doppler jet area criteria.21 Echocardiographic evidence of mitral valve prolapse was evaluated using established echocardiographic criteria.22 A single sonographer blinded to the clinical data and treatment assignment (K.M.D.) performed the analysis, and all echocardiograms were also assessed by 2 experienced cardiologists blinded to patient identity and treatment (A.A. and A.J.W.). Excellent comparability (and no systematic differences) in measures of aortic root diameters both in end-diastole and end-systole between readers was observed (r = 0.88-0.97). Results are expressed relative to body surface area calculated according to Roman et al.20

Biochemical Analyses

Venous blood samples were drawn from each patient at baseline and following 24 weeks of therapy. Samples were subsequently analyzed for active and latent TGF-β using enzyme-linked immunosorbent assay (ELISA, TGF-β Emax ImmunoAssay System, Promega Corporation, Madison, Wisconsin). A fluorokine MAP-Human MMP Base Kit (R&D Systems, Minneapolis, Minnesota) was used to measure MMPs on a BioPlex platform (BioRad Laboratories Inc, Hercules, California); this assay consists of multiplexed sandwich ELISA for the quantitative measurement of MMP-2 and MMP-3. Each sample was assayed twice and averaged. The coefficient of variation between all duplicate assays was less than 5% and therefore results were averaged to obtain a single value for each sample. Unique standard curves were constructed for each bead and sample analyte concentration determined. This approach delivers the sensitivity of ELISA.

Statistical Analysis

Demographic and hemodynamic indices at baseline were compared in the perindopril and placebo groups by χ2 tests (categorical variables) and unpaired t tests (continuous variables). Replicates were meaned to obtain a single value for each patient at each time point (baseline and postintervention). All data are presented as mean (SEM) except age, which is mean (SD). The change in all arterial stiffness indices and echocardiographic parameters from baseline to 24 weeks was compared between the perindopril and placebo groups using an analysis of covariance model. Although groups were matched for all baseline parameters, these were included in all covariate analyses. In addition, because the change in mean arterial pressure was greater in the perindopril group compared with the placebo group, this variable was also included in covariate analyses. P values did not change when change in mean arterial pressure was included as a covariate except as otherwise noted. All statistical analyses were performed by using SPSS version 15.0 (SPSS Inc, Chicago, Illinois). P<.05 was considered to be significant. The statistician performing the analyses was blinded to treatment group.

RESULTS

The perindopril and placebo groups were similar in age, body mass index, body surface area, and other cardiovascular risk factors (Table 1). The presence of mild aortic regurgitation, mitral valve prolapse, and mitral valve regurgitation was comparable between the 2 groups. The type and dose of β-blocker did not vary between groups. In the perindopril group, 5 patients were taking 200 mg/d of atenolol, 3 patients were taking 100 mg/d of atenolol, 1 patient was taking 240 mg/d, and 1 patient was taking 200 mg/d of propranolol. In the placebo group, 3 patients were taking 200 mg/d of atenolol, 2 patients were taking 100 mg/d of atenolol, 1 patient was taking 240 mg/d, and 1 patient was taking 160 mg/d of propranolol. None of the above doses were changed during the trial. One patient in the perindopril group and 2 patients in the placebo group were taking lipid-lowering therapy. None of the patients were taking any other cardiovascular-active drugs. No adverse events were reported throughout the trial.

Blood Pressure and Arterial Stiffness

Perindopril therapy increased mean systemic arterial compliance by 0.2 (SEM, 0.1) mL/mm Hg and was significantly different from placebo (–0.01 [0.03] mL/mm Hg, P = .004) (Table 2 and Figure 2). Consistent with these findings, perindopril also reduced central pulse wave velocity (–1.6 [0.2] m/s for perindopril vs 0.4 [0.1] m/s for placebo, P < .001) and peripheral pulse wave velocity (–2.2 [0.2] m/s for perindopril vs 0.2 [0.1] m/s for placebo, P < .001) (Table 2 and Figure 2).

In young healthy individuals, central systolic and pulse pressure are normally lower than the corresponding brachial pressure; however, due to the increase in arterial stiffness in MFS,23 this differential was not evident. Relative to placebo, perindopril significantly reduced both carotid and brachial systolic blood pressure as well as brachial diastolic blood pressure; however, these changes were small (reduction of 1-4 mm Hg from baseline, P < .001 vs placebo) (Table 2). Although brachial pulse pressure was unaffected by the perindopril intervention, carotid pulse pressure was reduced compared with placebo (P = .03). The reduction in mean arterial pressure was small but significant (mean [SEM], –1 [1] mm Hg for perindopril vs 1 [1] mm Hg for placebo; P = .004). Importantly, the observed changes in arterial stiffness parameters remained significant (P = .001-.006) when mean arterial pressure was included as a covariate. There was no significant difference in resting heart rate between the 2 groups (Table 2).

Echocardiographic Data

At the initial examination, all echocardiographic variables were comparable between the 2 groups (Table 3). Aortic root diameters during systole increased during the placebo intervention, and this increase was significantly attenuated in the perindopril group for all diameters (Table 3 and Figure 3). During diastole, aortic root diameters increased marginally in the placebo group, while perindopril therapy led to a reduction (1.2-3.0 mm/m2) in end-diastolic diameters compared with the placebo group (Table 3 and Figure 3). The differences in changes in aortic diameters remained significant (P < .001) when mean arterial pressure was included as a covariate.

MMP-2, MMP-3, and TGF-β Levels

Perindopril reduced total MMP-2 protein levels (mean [SEM], 157 [14] ng/mL at baseline to 135 [14] ng/mL at 24 weeks; decrease of 22 [6] ng/mL in the perindopril group vs increase of 8 [3] ng/mL in the placebo group, P < .001) and total MMP-3 proteins levels (18 [1] ng/mL at baseline to 13 [1] ng/mL at 24 weeks; decrease of 5 [1] ng/mL in the perindopril group vs increase of 2 [1] ng/mL in the placebo group, P < .001) (Figure 4). Perindopril also reduced latent TGF-β levels (59 [6] ng/mL at baseline to 45 [3] ng/mL at 24 weeks; decrease of 14 (4.5) ng/mL), which was significantly different from placebo (51 [8] ng/mL at baseline to 54 [7] ng/mL at 24 weeks; increase of 2 [2.3] ng/mL, P = .01) (Figure 5). Active TGF-β levels were also reduced following perindopril therapy (46 [2] ng/mL at baseline to 42 [1] ng/mL at 24 weeks; decrease of 4 [1] ng/mL in the perindopril group vs increase of 3 [1] ng/mL in the placebo group, P = .02) (Figure 5).

COMMENT

The major novel finding of our study was that perindopril therapy for 24 weeks reduced aortic diameters relative to placebo in both systole and diastole in patients with MFS taking standard β-blocker therapy. In systole, perindopril reduced the progression of aortic dilatation observed in the placebo group. However, in diastole, perindopril actually reduced aortic diameters below baseline levels by an average of between 1.2 and 3.0 mm/m2. Aortic root dilatation and associated aortic regurgitation, dissection, and rupture is the major life-threatening complication of MFS. Prophylactic repair of the aorta with a composite valve and graft is effective therapy once the ascending aorta becomes widely dilated.24 The current indication for surgery is an aortic root diameter of 50 mm.25 However, even after surgery, approximately 10% of patients develop complications of the residual aorta.24 In addition, some patients will have a major complication (ie, dissection or rupture), even though the aortic root dimension is less than 50 mm.25 Postoperatively, the patient is required to remain on life-long warfarin treatment and has the risk of prosthetic valve endocarditis. Thus, there is a great deal of interest in medical therapy for MFS, which protects the aorta and prevents or delays surgery. The current use of β-blockers as standard therapy may not directly address the underlying pathobiology of aortic wall degeneration.35

In MFS, there is good evidence that angiotensin II is increased11 and that signaling through both the AT110 and AT211 receptor pathways contributes to aortic degeneration. Specifically, in a mouse MFS model, the AT1 receptor antagonist losartan reduced aortic growth rate and prevented elastic fiber degeneration, presumably through hemodynamic actions and effects on TGF-β signaling.10 Angiotensin II also stimulates Smad-2 dependent signaling in vascular smooth muscle cells and vessel wall fibrosis in a mouse model by an AT1 receptor-dependent but TGF-β–independent mechanism.26 In addition, AT2 receptor mechanisms are associated with cystic medial degeneration in MFS and contribute to aortic rupture.11 As ACE inhibitors reduce angiotensin II production, they act via both AT1 and AT2 dependent pathways (Figure 6). The effect of inhibiting both pathways in the context of MFS was unknown27 before the current study.

Our data indicate that adjunct therapy with the ACE inhibitor perindopril reduced large artery stiffness and aortic diameter in patients with MFS taking standard β-blocker therapy. This likely occurred by reducing signaling through both the AT1 and AT2 receptors (Figure 6). The observed reduction in TGF-β and MMP-2 and MMP-3 are probably secondary to reduced AT1 receptor signaling.10 Reduction in AT2 receptor signaling may provide additional benefit through protection from cystic medial degeneration.11 Based on our data and previous literature, we therefore suggest that ACE inhibition will provide greater efficacy in aortic root protection in MFS than specific blockade of either of the angiotensin II receptors alone.

Whether our findings represent an effect specific to perindopril or a more broad class effect cannot be determined. ACE inhibitors vary in lipophilicity, tissue binding, duration of action, and metabolism, which may contribute to variable efficacy with regard to arterial actions.28 An extensive literature exists regarding the beneficial effects of perindopril on large artery properties2931; however, whether perindopril has greater efficacy than other ACE inhibitors due to its relative lipophilicity or other properties will require direct comparisons.

This study was limited because of its small sample size and relatively short duration. However, it provides a valid basis for further investigation in a larger clinical trial.

In conclusion, therapy with perindopril reduced both aortic stiffness and aortic root diameter in patients with MFS taking standard β-blocker therapy. These findings warrant further investigation in a larger, longer-term clinical trial.

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Article Information

Corresponding Author: Bronwyn A. Kingwell, PhD, Alfred and Baker Medical Unit, Baker Heart Research Institute, PO Box 6492, St Kilda Rd, Central Melbourne, Victoria, 8008 Australia (bronwyn.kingwell@baker.edu.au).

Author Contributions: Drs Ahimastos and Kingwell had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Aggarwal, Savarirayan, Kingwell.

Acquisition of data: Ahimastos, D’Orsa, Formosa, White.

Analysis and interpretation of data: Ahimastos, D’Orsa, White, Dart, Kingwell.

Drafting of the manuscript: Ahimastos, Dart, Kingwell.

Critical revision of the manuscript for important intellectual content: Ahimastos, Aggarwal, D’Orsa, Formosa, White, Savarirayan, Dart, Kingwell.

Statistical analysis: Ahimastos, Kingwell.

Obtained funding: Kingwell.

Administrative, technical or material support: D’Orsa, Formosa.

Study supervision: Aggarwal, Savarirayan, Dart, Kingwell.

Financial Disclosures: None reported.

Funding/Support: This work was funded by a grant from the National Health and Medical Research Council of Australia. Servier Laboratories Ltd, Australia, provided the perindopril and matching placebo drugs.

Role of the Sponsor: The National Health and Medical Research Council of Australia and Servier Laboratories Ltd had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: Christopher Reid, BA, Dip Ed, MSc, PhD, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, provided expert advice on all statistical analyses reported in the manuscript. Dr Reid did not receive any compensation for his contribution.

References
1.
Neptune  ER, Frischmeyer  PA, Arking  DE,  et al.  Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33(3):407-411.
PubMedArticle
2.
Shores  J, Berger  KR, Murphy  EA, Pyeritz  RE.  Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994;330(19):1335-1341.
PubMedArticle
3.
Propanolol Aneurysm Trial Investigators.  Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J Vasc Surg. 2002;35(1):72-79.
PubMedArticle
4.
Lindholt  JS, Henneberg  EW, Juul  S, Fasting  H.  Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms. Int Angiol. 1999;18(1):52-57.
PubMed
5.
Moursi  MM, Beebe  HG, Messina  LM, Welling  TH, Stanley  JC.  Inhibition of aortic aneurysm development in blotchy mice by beta adrenergic blockade independent of altered lysyl oxidase activity. J Vasc Surg. 1995;21(5):792-799.
PubMedArticle
6.
Ahimastos  AA, Natoli  AK, Lawler  A, Blombery  PA, Kingwell  BA.  Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. Hypertension. 2005;45(6):1194-1199.
PubMedArticle
7.
Hackam  DG, Thiruchelvam  D, Redelmeier  DA.  Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study. Lancet. 2006;368(9536):659-665.
PubMedArticle
8.
Liao  S, Miralles  M, Kelley  BJ, Curci  JA, Borhani  M, Thompson  RW.  Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg. 2001;33(5):1057-1064.
PubMedArticle
9.
Nagashima  H, Uto  K, Sakomura  Y,  et al.  An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg. 2002;36(4):818-823.
PubMedArticle
10.
Habashi  JP, Judge  DP, Holm  TM,  et al.  Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117-121.
PubMedArticle
11.
Nagashima  H, Sakomura  Y, Aoka  Y,  et al.  Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan's syndrome. Circulation. 2001;104(12)(suppl 1):I282-I287.
PubMed
12.
Yetman  AT, Bornemeier  RA, McCrindle  BW.  Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005;95(9):1125-1127.
PubMedArticle
13.
Nataatmadja  M, West  M, West  J,  et al.  Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation. 2003;108(suppl 1):II329-II334.
PubMedArticle
14.
Ikonomidis  JS, Jones  JA, Barbour  JR,  et al.  Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation. 2006;114(1)(suppl):I365-I370.
PubMed
15.
De Paepe  A, Devereux  RB, Dietz  HC, Hennekam  RC, Pyeritz  RE.  Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62(4):417-426.
PubMedArticle
16.
Liu  Z, Brin  KP, Yin  FC.  Estimation of total arterial compliance: an improved method and evaluation of current methods. Am J Physiol. 1986;251(3 pt 2):H588-H600.
PubMed
17.
Cameron  JD, Dart  AM.  Exercise training increases total systemic arterial compliance in humans. Am J Physiol. 1994;266(2 pt 2):H693-H701.
PubMed
18.
Mitchell  GF, Izzo  JL  Jr, Lacourciere  Y,  et al.  Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation. 2002;105(25):2955-2961.
PubMedArticle
19.
Kingwell  BA, Berry  KL, Cameron  JD, Jennings  GL, Dart  AM.  Arterial compliance increases after moderate-intensity cycling. Am J Physiol. 1997;273(5 pt 2):H2186-H2191.
PubMed
20.
Roman  MJ, Devereux  RB, Kramer-Fox  R, O'Loughlin  J.  Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol. 1989;64(8):507-512.
PubMedArticle
21.
Perry  GJ, Helmcke  F, Nanda  NC, Byard  C, Soto  B.  Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol. 1987;9(4):952-959.
PubMedArticle
22.
Levine  RA, Stathogiannis  E, Newell  JB, Harrigan  P, Weyman  AE.  Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol. 1988;11(5):1010-1019.
PubMedArticle
23.
Jeremy  RW, Huang  H, Hwa  J, McCarron  H, Hughes  CF, Richards  JG.  Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am J Cardiol. 1994;74(4):369-373.
PubMedArticle
24.
Gott  VL, Greene  PS, Alejo  DE,  et al.  Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med. 1999;340(17):1307-1313.
PubMedArticle
25.
Kornbluth  M, Schnittger  I, Eyngorina  I, Gasner  C, Liang  DH.  Clinical outcome in the Marfan syndrome with ascending aortic dilatation followed annually by echocardiography. Am J Cardiol. 1999;84(6):753-755,A9.
PubMedArticle
26.
Rodríguez-Vita  J, Sánchez-López  E, Esteban  V, Rupérez  M, Egido  J, Ruiz-Ortega  M.  Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism. Circulation. 2005;111(19):2509-2517.
PubMedArticle
27.
Dean  JC.  Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007;15(7):724-733.
PubMedArticle
28.
Cushman  DW, Wang  FL, Fung  WC,  et al.  Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE). Br J Clin Pharmacol. 1989;28(suppl 2):115S-130S.
PubMedArticle
29.
Asmar  RG, London  GM, O'Rourke  ME, Safar  ME.  Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension. 2001;38(4):922-926.
PubMedArticle
30.
Girerd  X, Giannattasio  C, Moulin  C, Safar  M, Mancia  G, Laurent  S.  Regression of radial artery wall hypertrophy and improvement of carotid artery compliance after long-term antihypertensive treatment in elderly patients. J Am Coll Cardiol. 1998;31(5):1064-1073.
PubMedArticle
31.
Pannier  BM, Guerin  AP, Marchais  SJ, London  GM.  Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension. Clin Exp Pharmacol Physiol. 2001;28(12):1074-1077.
PubMedArticle
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