Clinical Investigation
Marfan Syndrome
Echocardiographic Methods, Quality Review, and Measurement Accuracy in a Randomized Multicenter Clinical Trial of Marfan Syndrome

https://doi.org/10.1016/j.echo.2013.02.018Get rights and content

Background

The Pediatric Heart Network is conducting a large international randomized trial to compare aortic root growth and other cardiovascular outcomes in 608 subjects with Marfan syndrome randomized to receive atenolol or losartan for 3 years. The authors report here the echocardiographic methods and baseline echocardiographic characteristics of the randomized subjects, describe the interobserver agreement of aortic measurements, and identify factors influencing agreement.

Methods

Individuals aged 6 months to 25 years who met the original Ghent criteria and had body surface area–adjusted maximum aortic root diameter (ROOTmax) Z scores > 3 were eligible for inclusion. The primary outcome measure for the trial is the change over time in ROOTmax Z score. A detailed echocardiographic protocol was established and implemented across 22 centers, with an extensive training and quality review process.

Results

Interobserver agreement for the aortic measurements was excellent, with intraclass correlation coefficients ranging from 0.921 to 0.989. Lower interobserver percentage error in ROOTmax measurements was independently associated (model R2 = 0.15) with better image quality (P = .002) and later study reading date (P < .001). Echocardiographic characteristics of the randomized subjects did not differ by treatment arm. Subjects with ROOTmax Z scores ≥ 4.5 (36%) were more likely to have mitral valve prolapse and dilation of the main pulmonary artery and left ventricle, but there were no differences in aortic regurgitation, aortic stiffness indices, mitral regurgitation, or left ventricular function compared with subjects with ROOTmax Z scores < 4.5.

Conclusions

The echocardiographic methodology, training, and quality review process resulted in a robust evaluation of aortic root dimensions, with excellent reproducibility.

Section snippets

Patients

Subjects enrolled in this trial2 were individuals aged 6 months to 25 years who met the original Ghent criteria for MFS,4 with a body surface area (BSA)–adjusted ROOTmax Z score > 3 and absolute ROOTmax < 5 cm. Patients with prior aortic surgery were excluded. A total of 608 subjects were enrolled between February 2007 and February 2011. The study protocol was approved by the institutional review board or institutional ethics board at each participating center, and informed consent and assent

Results

Imaging of the aortic root was graded as excellent in 203 (33%), good in 357 (59%), and fair in 47 (8%) patients. ROOTmax was measurable at least once in all echocardiograms and in triplicate in 95%.

Discussion

Aortic root size is a major determinant in the clinical diagnosis of MFS13 and is the best predictor of cardiovascular outcome.14 Varying methods to assess aortic root size by echocardiography have been reported, including M-mode versus 2D imaging, systolic versus diastolic measurements, and leading edge–to–leading edge versus inner edge–to–inner edge measurements.6, 15, 16, 17 Most adult echocardiography laboratories use the leading edge–to–leading edge method in diastole, as recommended by

Conclusions

The echocardiographic methodology, training, and quality review process used in this multicenter randomized clinical trial resulted in a robust evaluation of aortic root dimensions with excellent reproducibility despite the challenges of a multicenter study design and the imaging difficulties common in patients with MFS. This will optimize our ability to detect differences in treatment effects between atenolol and losartan in children and young adults with MFS.

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    This study was supported by U01 grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, and HL085057 from the National Heart, Lung, and Blood Institute (Bethesda, MD) and the US Food and Drug Administration Office of Orphan Products Development (Silver Spring, MD). Additional support was provided by the National Marfan Foundation (Port Washington, NY), Merck & Co., Inc. (Whitehouse Station, NJ), and Teva Canada Limited (Mirabel, QC, Canada). The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of National Heart, Lung, and Blood Institute or the National Institutes of Health.

    The authors have no conflict of interest to disclose.

    Benjamin W. Eidem, MD, FASE served as Guest Editor on this article.

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