Angiotensin II Blockade and Aortic-Root Dilation in Marfan's Syndrome

Brooke, Benjamin S.; Habashi, Jennifer; Judge, Daniel P.; Patel, Nishant; Loeys, Bart; Dietz, Harry C.

doi:10.1056/nejmoa0706585

Cited by 758 publications

(549 citation statements)

References 25 publications

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“…This is in contrast to the pathological role of TGF-␤ in the aortic aneurysms that form in MS, 6 as assessed by the efficacy of TGF-␤ blockade in both preventing aneurysms in the murine model of MS and slowing disease progression in patients with MS. 7 In marked contrast to the MS model, our data suggest that with an inflammatory stimulus, loss of elastin is prevented by induction of TGF-␤ and PAI-1-mediated repression of MMP-9 activation by plasmin. An unexpected observation is that TGF-␤ signaling is essential during this postnatal window of coronary artery development because TGF-␤ inhibition caused marked coronary wall thinning and dilation.…”

Section: Discussioncontrasting

confidence: 66%

“…In the murine model of MS, TGF-␤ blockade with either a neutralizing antibody (nAb) or the angiotensin-II receptor antagonist, losartan, effectively prevented aortic dilation and induced regression of established disease. 6 Furthermore, in a clinical study 7 in pediatric patients with MS, losartan therapy was effective in decreasing the rate of aortic root dilation. As a result of these studies, there has been speculation that increased TGF-␤ activation is related to non-MS aneurysm formation, leading to interest in extrapolating the use of TGF-␤ blockade to treat conditions such as abdominal aortic aneurysm and KD.…”

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confidence: 99%

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Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira

Guignabert

Kim

et al. 2011

The American Journal of Pathology

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Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) ␤ increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-␤ would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-␤ signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-␤ by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-␤ suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-␤, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

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Section: Discussioncontrasting

confidence: 66%

mentioning

confidence: 99%

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira

Guignabert

Kim

et al. 2011

The American Journal of Pathology

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“…In a mouse model of aortic dilation, treatment with losartan proved to be more effective than propranolol in reducing and reverting aortic wall disarray. 27 In agreement with this finding, two clinical trials recently demonstrated that the inhibition of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors 28 or angiotensin receptor blockers 29 reduced the rate of aortic enlargement in patients affected by Marfan's syndrome.…”

Section: Discussionmentioning

confidence: 62%

Aortic size index enlargement is associated with central hemodynamics in essential hypertension

et al. 2010

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The aim of this study was to evaluate the association between brachial and central blood pressure (bBP and cBP) levels and aortic root dilatation (ARD) in essential hypertensive patients. A total of 190 untreated and treated essential hypertensive patients (mean age, 55±11 years) were considered for this analysis. We measured pulsatile hemodynamics and the proximal aortic diameter directly using tonometry, ultrasound imaging (echocardiography) and Doppler. Ninety-one hypertensive patients had an ARD (defined as aortic size index (ASi)42 cm/m 2 ). Central hemodynamic variables were significantly associated with ASi. Patients with increased ASi were significantly older (60 ± 10 vs. 50 ± 11 years, Po0.0001) and had higher levels of the augmentation index (AIx; 28±10 vs. 21±10 Po0.0001), augmentation pressure (AP; 13±6 vs. 8±5 mm Hg, Po0.0001), and central pulse pressure (cPP; 44 ± 10 vs. 39 ± 8 mm Hg, Po0.0001) compared with patients with normal ASi. In a logistic regression analysis, the AIx was the only significant predictor of ASi. In hypertensive patients, the AIx and cBP were associated with ARD, whereas the bBP was not. Patients with an increased ASi may lose part of the elastic properties of the aorta, demonstrating a strict correlation between ASi and central hemodynamic indexes, in particular, the cPP and AIx.

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“…For patients with thoracic aortic aneurysm, it is reasonable to reduce blood pressure with beta blockers and angiotensin-converting enzyme inhibitors 103 or angiotensin receptor blockers 104,105 to the lowest point patients can tolerate without adverse effects. [100][101][102] (Level of Evidence: B) 2.…”

Section: Class Iiamentioning

confidence: 99%

“…An angiotensin receptor blocker (losartan) is reason able for patients with Marfan syndrome, to reduce the rate of aortic dilatation unless contraindicated. 105,112 (Level of Evidence: B)…”

Section: Class Iiamentioning

confidence: 99%

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

Hiratzka

Bakris

Beckman

et al. 2010

Cathet Cardio Intervent

280

105

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Angiotensin II Blockade and Aortic-Root Dilation in Marfan's Syndrome

Abstract: ConclusionsIn 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.

Cited by 758 publications

References 25 publications

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Aortic size index enlargement is associated with central hemodynamics in essential hypertension

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

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