Heterogeneous aortic response to acute β-adrenergic blockade in Marfan syndrome

Haouzi, Annick; Berglund, Hans; Pelikán, P.; Maurer, Gerald; Siegel, Robert J.

doi:10.1016/s0002-8703(97)70248-5

Cited by 79 publications

(44 citation statements)

References 15 publications

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“…14 Management with ␤-blockers retards aortic root dilatation and improves survival in patients with Marfan syndrome. 36,37 The present study shows that aortic root dilatation in both males and females with BAV occurs in the absence of hemodynamically significant aortic valve disease. The aortic root dimensions in the BAV group, however, were not markedly enlarged or aneurysmal, suggesting subclinical disease.…”

Section: Discussionsupporting

confidence: 50%

Bicuspid Aortic Valve Associated With Aortic Dilatation

Nkomo

Enríquez-Sarano

Ammash

et al. 2003

ATVB

180

102

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Objective-This study was undertaken to examine the association between bicuspid aortic valve (BAV) and aortic dilatation in the community. The association between BAV and aortic dilatation has been reported predominantly in retrospective studies in patients mostly with valvular dysfunction or selected surgical patients from tertiary referral centers. An independent association of BAV and aortic dilatation in a community-based study has not been demonstrated. Pϭ0.16). These differences were maintained when the groups were stratified by sex and blood pressure. The relationship between bicuspid aortic valve and aortic dilatation was maintained when adjusting for factors related to fluid mechanics and hemodynamics such as systolic blood pressure, diastolic blood pressure, left ventricular ejection time, and peak aortic valve velocity. Methods and Results-In Conclusions-In

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Section: Discussionsupporting

confidence: 50%

Bicuspid Aortic Valve Associated With Aortic Dilatation

Nkomo

Enríquez-Sarano

Ammash

et al. 2003

ATVB

180

102

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“…89 In patients with Marfan syndrome a heterogeneous response (normalizing or worsening) has been observed in both the aortic stiffness index and distensibility to -adrenergic blockade, with possible implications for their prognosis. 90,91 These data are in accordance with the fact that -blockers do not inhibit aortic root dilatation in all patients with Marfan syndrome. Long-term folic acid treatment showed no major effect on carotid artery stiffness in chronic dialysis patients using a noninvasive vessel wall movement detector system.…”

Section: Therapeutic Interventionssupporting

confidence: 84%

Noninvasive Ultrasound Techniques for the Assessment of Atherosclerosis in Coronary Artery Disease

Neunteufl

Maurer

2003

Circ J

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“…13 Short-term administration of propranolol or metoprolol resulted in an increased stiffness and dilatation of ascending aorta. 11,14 In patients after entire aortic replacement, the use of atenolol or labetalol did not decrease aortic pressure, and, with atenolol increased, wave reflection was observed. 12 A metaanalysis has even suggested no clinical benefit from ␤-blockade therapy in MFS.…”

Section: Discussionmentioning

confidence: 99%

“…10 Several studies have shown that short-term ␤-blockers may not produce the desired hemodynamic effects in patients with marked dilation of the aortic root, resulting in increased aortic diameter, stiffness index, and wave refection. [11][12][13][14] A heterogeneous response to ␤-blockers has been reported, [13][14][15] and a metaanalysis even showed no evidence of clinical benefit from ␤-blockade therapy. 16 Our recent studies using a well-characterized mouse model of MFS demonstrated that the progression of thoracic aortic aneurysm (TAA) is associated with an upregulation of matrix metalloproteinase (MMP)-2 and -9, which is concomitant with extensive degeneration of elastic fibers, endothelium dysfunction, and reduction of smooth muscle contractility.…”

mentioning

confidence: 99%

Long-Term Doxycycline Is More Effective Than Atenolol to Prevent Thoracic Aortic Aneurysm in Marfan Syndrome Through the Inhibition of Matrix Metalloproteinase-2 and -9

Chung

Yang

Radomski

et al. 2008

Circulation Research

206

164

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Abstract-␤-Blockers, eg, atenolol, are the cornerstone therapy for thoracic aortic aneurysm (TAA) in patients with Marfan syndrome; however, continued aortic dilatation has been reported. We have demonstrated that matrix metalloproteinase (MMP)-2 and -9 were upregulated during progression of TAA in Marfan syndrome, accompanied with degenerated elastic fibers and vasomotor dysfunction. We hypothesized that doxycycline, a nonspecific inhibitor of MMPs, would ameliorate TAA by attenuating elastic fiber degeneration and improving vasomotor function. A well-characterized mouse model of Marfan syndrome (Fbn1 C1039G/ϩ ) was used. Mice were untreated (nϭ40), given doxycycline (0.24g/L, nϭ30), or given atenolol (0.5g/L, nϭ30) in drinking water at 6 weeks of age. The Fbn1 ϩ/ϩ mice served as control (nϭ40). At 3, 6, and 9 months, aortic segments from the ascending, arch, and descending portions were used to obtain the "average" value of the whole thoracic aorta. TAA was prevented in the doxycycline group, whereas mild aneurysm was evident in the atenolol group. Doxycycline improved elastic fiber integrity, normalized aortic stiffness, and prevented vessel weakening. The impairment of vasocontraction and endothelium-dependent relaxation in the untreated and atenolol groups were improved by doxycycline. The upregulation of transforming growth factor-␤ in the Marfan aorta was suppressed by doxycycline. Doxycycline augmented expression ratios of tissue inhibitors of MMP to MMPs. Intraperitoneally injected neutralizing antibodies against MMP-2 and -9 yielded similar effects to doxycycline. We concluded that long-term treatment with doxycycline, through the inhibition of MMP-2 and -9, is more effective than atenolol in preventing TAA in Marfan syndrome by preserving elastic fiber integrity, normalizing vasomotor function, and reducing transforming growth factor-␤ activation. (FBN-1). 1-3 Fibrillin-1 negatively regulates transforming growth factor (TGF)-␤, and the augmented TGF-␤/ Smad2-signaling in MFS contributes to the prominent clinical manifestations in the cardiovascular, ocular, skeletal, and pulmonary systems. 4 -7 Fibrillin-1 is a structural component of microfibrils, which are crucial in the formation, maturation, and stabilization of elastic fibers. Elastic fibers provide much of the physiological recoil of the aorta during systole. Abnormality in the formation and integrity of elastic fibers in MFS causes weakening of the aorta, making it vulnerable to dilatation and dissection. 3 Aortic rupture is the major cause of death in patients with MFS. If untreated, it significantly shortens the lifespan of affected individuals; half will succumb in their late 20s or early 30s. 8 ␤-Adrenoceptor blockade has been advocated as preventive therapy to decrease the rate of aortic root dilation and progression to dissection in patients with MFS. 9 ␤-Adrenoceptors are classified as ␤1 and ␤2, and atenolol is a selective ␤1 inhibitor, which effectively reduces contractility and slows the heart rate. Although ␤-blocker therapy is pres...

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Heterogeneous aortic response to acute β-adrenergic blockade in Marfan syndrome

Cited by 79 publications

References 15 publications

Bicuspid Aortic Valve Associated With Aortic Dilatation

Bicuspid Aortic Valve Associated With Aortic Dilatation

Noninvasive Ultrasound Techniques for the Assessment of Atherosclerosis in Coronary Artery Disease

Long-Term Doxycycline Is More Effective Than Atenolol to Prevent Thoracic Aortic Aneurysm in Marfan Syndrome Through the Inhibition of Matrix Metalloproteinase-2 and -9

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