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Rationale and design of a randomized clinical trial of β-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome

Published on Oct 1, 2007in American Heart Journal4.023
· DOI :10.1016/j.ahj.2007.06.024
Ronald V. Lacro29
Estimated H-index: 29
(Harvard University),
Harry C. Dietz90
Estimated H-index: 90
(Johns Hopkins University)
+ 15 AuthorsLynn Mahony30
Estimated H-index: 30
(UTSW: University of Texas Southwestern Medical Center)
Abstract
Background Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1 -targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. Methods The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area–adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. Conclusion This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.
  • References (34)
  • Citations (198)
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References34
Newest
Objective To test the hypothesis that chronic beta-blocker therapy in pediatric patients with Marfan syndrome alters the rate of aortic root dilation. Beta-blockade has been advocated as preventive therapy for Marfan syndrome based on reports indicating a decreased rate of aortic root dilation in treated patients. Study design Patients with Marfan syndrome (n = 63) followed at Children’s Hospital of Pittsburgh or Children’s Hospital of New York-Presbyterian who had ≥18 months of echocardiographi...
57 CitationsSource
#1Jennifer Habashi (Johns Hopkins University)H-Index: 13
#2Daniel P. Judge (Johns Hopkins University)H-Index: 40
Last. Harry C. Dietz (Johns Hopkins University)H-Index: 90
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Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor–β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β–neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, lo...
1,230 CitationsSource
#1Lynn Mahony (UTSW: University of Texas Southwestern Medical Center)H-Index: 30
#2Lynn A. SleeperH-Index: 70
Last. G. D. Pearson (UTSW: University of Texas Southwestern Medical Center)H-Index: 1
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Most contemporary diagnostic and treatment strategies for pediatric patients with cardiovascular disease are not supported by evidence from clinical trials but instead are based on expert opinion, single-institution observational studies, or extrapolated from adult cardiovascular medicine. In response to this concern, the National Heart, Lung, and Blood Institute established the Pediatric Heart Disease Clinical Research Network (PHN) in 2001. The purposes of this article are to describe the init...
61 CitationsSource
#1Ryan R. Davies (Yale University)H-Index: 28
#2Amy Gallo (Yale University)H-Index: 11
Last. John A. Elefteriades (Yale University)H-Index: 55
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337 CitationsSource
#1Bart Loeys (Johns Hopkins University)H-Index: 56
#2Junji Chen (Johns Hopkins University)H-Index: 1
Last. Harry C. Dietz (Johns Hopkins University)H-Index: 90
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1,147 CitationsSource
#1Daniel P. Judge (Johns Hopkins University)H-Index: 40
#2Harry C. Dietz (Johns Hopkins University)H-Index: 90
Summary Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mou...
708 CitationsSource
#1Anji T. Yetman (Anschutz Medical Campus)H-Index: 24
#2Renee A. Bornemeier (University of Arkansas for Medical Sciences)H-Index: 9
Last. Brian W. McCrindle (U of T: University of Toronto)H-Index: 88
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Despite variable clinical results, β blockers have become the primary therapy for prevention of aortic dilation in patients with the Marfan syndrome. This study examines the use of the angiotensin-converting enzyme inhibitor enalapril for treatment of these patients. We sought to examine the effects of enalapril versus β-blocker therapy in patients with the Marfan syndrome and noted improved aortic distensibility (3.0 ± 0.3 vs 1.9 ± 0.4 cm 2 dynes −1 ; p
131 CitationsSource
#1Connie M. Ng (Johns Hopkins University)H-Index: 2
#2Alan Cheng (Johns Hopkins University)H-Index: 34
Last. Harry C. Dietz (Johns Hopkins University)H-Index: 90
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Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to ...
471 CitationsSource
#1Gijs J. NollenH-Index: 10
#2Maarten GroeninkH-Index: 31
Last. Barbara J.M. MulderH-Index: 62
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Aim Patients with Marfan syndrome may develop dissection due to progressive dilatation in the entire aorta, which is not always predictable by mere anatomic assessment of the aortic diameter, especially of the descending aorta. The aim of this study was to identify the predictive value of aortic stiffness on the occurrence of dissection and progressive aortic dilatation. Methods and results In 78 non-operated patients with Marfan syndrome (mean age 31±8 years, mean aortic root diameter 43±6 mm, ...
219 CitationsSource
#2Nan M. LairdH-Index: 100
Last. James H. Ware (Harvard University)H-Index: 74
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Preface.Acknowledgments.PART I: INTRODUCTION TO LONGITUDINAL AND CLUSTERED DATA.1. Longitudinal and Clustered Data.2. Longitudinal Data: Basic Concepts.PART II: LINEAR MODELS FOR LONGITUDINAL CONTINUOUS DATA.3. Overview of Linear Models for Longitudinal Data.4. Estimation and Statistical Inference.5. Modelling the Mean: Analyzing Response Profiles.6. Modelling the Mean: Parametric Curves.7. Modelling the Covariance.8. Linear Mixed Effects Models.9. Residual Analyses and Diagnostics.PART III: GEN...
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#1Fabian Emrich (Stanford University)H-Index: 8
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#2Kim A. Eagle (UM: University of Michigan)H-Index: 115
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#1Michael Thomas (Roseman University of Health Sciences)H-Index: 1
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