Echocardiographic methods, quality review, and measurement accuracy in a randomized multicenter clinical trial of Marfan syndrome

Abstract

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 ROOTmaxZ 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 R(2) = 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 ROOTmaxZ 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 ROOTmaxZ scores < 4.5.

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

Figure 1

Proximal aortic measurements in the parasternal long-axis view. The maximum and minimum measurements were taken from inner edge to inner edge: (1) aortic valve “annulus” at the hinge points of the leaflets; (2) aortic root at the largest diameter within the sinuses of Valsalva; (3) sinotubular junction at the transition point from sinus to tubular aorta; (4) ascending aorta at the level of the right pulmonary artery (RPA). AO, Aorta; LA, left atrium; LV, left ventricle.

Figure 2

Bland-Altman plots for interobserver agreement for all maximum (A) and minimum (B) aortic root measurements using absolute dimensions and percentage error. The Bland-Altman plots graph the difference in absolute dimension or the percentage difference between primary and secondary readers (primary minus secondary reader) versus the mean across readers. The shaded 95% confidence bands are typically accepted as the range of “clinical equivalence.” Agreement is considered very good if all data points are within these bands. These plots emphasize the systematic bias, with values obtained from the primary reader consistently lower than those from the secondary reader. STJ, Sinotubular junction.

Figure 3

Bland-Altman plots for intraobserver agreement for minimum and maximum aortic root measurements at the level of the sinuses of Valsalva.