1. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Flow of Patients Through the Study Figure Legend:

2. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Individual Patient Values for Systemic Arterial Compliance and Central and Peripheral Pulse Wave VelocitiesSquares 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 Legend:

3. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Individual Patient Values for End-Systole and End-Diastole Aortic Root DiametersSquares 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 Legend:

4. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Individual Matrix Metalloproteinase (MMP)-2 and MMP-3 Protein LevelsSquares indicate mean (SEM) values. P <.001 for both plots. Figure Legend:

5. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Individual Transforming Growth Factor β (TGF-β) Plasma LevelsSquares indicate mean (SEM) values. P =.01 for latent and P =.02 for active TGF-β comparisons. Figure Legend:

6. Date of download: 6/3/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial JAMA. 2007;298(13):1539-1547. doi:10.1001/jama.298.13.1539 Proposed Effect of ACE Inhibition on Pathogenesis of Aortic Stiffness in Patients With MFSMarfan syndrome (MFS) is associated not only with increased transforming growth factor β (TGF-β) signaling through the angiotensin II type 1 receptor (AT 1 R), but also with cystic medial degeneration through the angiotensin II type 2 receptor (AT 2 R). Blockade of the renin angiotensin system with an angiotensin-converting enzyme (ACE) inhibitor rather than an AT 1 R or AT 2 R 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 AT 1 R and AT 2 R. Dashed pathways indicate that an exact mechanism is not yet known. Figure Legend: