Study Design and Population

Patients with World Health Organization group I PAH were recruited prospectively from the pulmonary hypertension clinic at the University of Chicago for same-day TTE and CMR, the latter of which was used as a reference standard. Recruitment specifically focused on patients who had expressed interest in ongoing research or had participated in prior clinical trials. Patients with contraindications to noncontrast CMR, such as inability to comply with breath-hold instructions, severe claustrophobia, or implanted ferromagnetic devices, were excluded. Patients were not screened for 2D transthoracic echocardiographic image quality before inclusion. CMR and transthoracic echocardiographic image acquisitions were separated by no more than 2 hours to minimize potential changes in RV size and function. On the same day, blood was drawn for N-terminal pro–brain natriuretic peptide (NT-proBNP) assessment, and 6-min walk testing was performed. The University of Chicago Institutional Review Board approved the study protocol. All patients provided written informed consent before study enrollment.

Echocardiographic Equipment, Image Acquisition, and Analysis

Transthoracic echocardiographic images were acquired using standard ultrasound equipment (iE33 system and S5 transducer; Philips Medical Systems, Andover, MA) connected to a specialized console by a transducer attachment and used with a magnetic field generator, located underneath the patient’s bed (VentriPoint Diagnostics Ltd., Seattle, WA). Before each study, the optimal ultrasound depth for the visualization of all relevant structures was determined and preset in the specialized console. Patients remained entirely stationary in the left lateral decubitus position throughout the imaging protocol. A series of standard and nonstandard transthoracic echocardiographic views were obtained, including the following: parasternal long-axis, parasternal short-axis at the papillary muscle level and at the apex, RV inflow, RV inflow-outflow, standard apical four-chamber, and focused RV apical ( Figure 1 ). Each acquisition consisted of two or three beats, and all images were acquired during breath holds. End-inspiratory acquisitions were preferred, but for patients with severe dyspnea, end-expiratory breath holds were permitted. All images were acquired by two sonographers (L.W. and M.Y.) trained in equipment use and image analysis.

Transthoracic echocardiographic images with points placed to define anatomic landmarks and borders of 3D model superimposed ( yellow outlines ). (A) Parasternal long-axis view. (B) Parasternal short-axis view at the level of the papillary muscles. (C) RV inflow view. (D) RV inflow-outflow view. (E) Standard apical four-chamber view. (F) Focused RV apical view. To obtain this view, the transducer is placed slightly medial relative to a standard apical view and angulated laterally. Colors of points are as follows: red, RV endocardium; cyan, interventricular septum; green, RV septal edge; violet, tricuspid annulus; blue, conal septum; orange, pulmonic annulus; brown, basal bulge; light pink, RV apex.

Image analysis was performed on the specialized console. End-diastole was selected manually for each acquisition by visual determination of the time point at which RV volume was largest. End-systole was selected on an apical four-chamber view. The same end-diastole–to–end-systole interval was automatically applied to all other acquisitions. Points corresponding to several anatomic landmarks were placed on transthoracic echocardiographic images at end-diastole ( Table 1 ), with a minimum of nine points per patient. RV endocardial points were placed at the base of trabeculations. End-diastolic images were then submitted to a secure server and processed within seconds by a proprietary algorithm, KBR (VentriPoint Diagnostics Ltd.), created from a catalog of CMR and 2D transthoracic echocardiographic images from >100 patients with pulmonary hypertension. A 3D model of the right ventricle at end-diastole was then displayed for review on the console ( Figure 2 ). Transthoracic echocardiographic images with superimposed outlines of the 3D model were then reviewed to assess alignment ( Figure 3 ). Points were added and deleted as needed, and the images were reprocessed to optimize border alignment. On transthoracic echocardiographic images with obvious border misalignment, suggesting shifts in patient position, all points were deleted, effectively excluding these images from the model ( Figure 3 ). The same process of point placement, image processing, and model editing was performed at end-systole. Finally, a nested view of the end-diastolic and end-systolic models was reviewed to confirm appropriate alignment of tricuspid and pulmonic annular planes ( Figure 4 ). All transthoracic echocardiographic studies were analyzed by a single observer (N.M.B.) with formal training in software use, who was blinded to CMR results.

Three-dimensional model of the right ventricle at end-diastole, with endocardial points placed during multiplane initialization.

(A) Border of 3D model superimposed on parasternal long-axis transthoracic echocardiographic image. Note that the model border lies inside the ventricle rather than along the true endocardium, resulting in an underestimated RV volume. Placement of an additional endocardial point, as shown in red, will redraw the border closer to its correct position. (B) Obvious misalignment of 3D model border with transthoracic echocardiographic image in a different patient. In this instance, the patient changed position during imaging. Because no points have been placed on this image, it is effectively excluded from the model.

Nested view of end-diastolic and end-systolic models, confirming appropriate alignment of the pulmonic ( arrow ) and tricuspid ( arrowhead ) valve planes.

CMR Image Acquisition and Analysis

CMR images were acquired using a 1.5-T scanner (Achieva; Philips Medical Systems, Best, The Netherlands) and a five-element phased-array cardiac coil. Retrospectively gated cine images were obtained with a steady-state free precession sequence (repetition time, 2.9 msec; echo time, 1.5 msec; flip angle, 60°; temporal resolution, ∼40 msec). A stack of short-axis slices (8-mm thickness, 2-mm gap) from the base to the apex of the entire heart was acquired. Short-axis cine slices were used to measure ventricular volumes and EFs using Simpson’s method of disks. All measurements were made by a single observer (see Acknowledgments), who was blinded to echocardiographic results.

Interobserver and Intraobserver Variability

All transthoracic echocardiographic studies were reanalyzed by a second observer (L.W.), who used the same end-diastolic and end-systolic frames and excluded the same misaligned images as the original observer. The second observer was blinded to the original observer’s end-diastolic volume (EDV), end-systolic volume (ESV), and EF measurements. For intraobserver variability assessment, the original observer (N.M.B.) performed repeat analyses ≥24 hours after the initial analyses. Interobserver and intraobserver variability was quantified using intraclass correlation coefficients and coefficients of variation, the latter of which were defined as the absolute difference between repeated measurements as a percentage of their mean.

Statistical Analysis

The relationship between TTE-derived and CMR-derived RV volumes and EFs was evaluated using linear regression analysis with Pearson’s correlation coefficient. In addition, Bland-Altman analysis was performed to assess agreement between the two imaging modalities in terms of bias and 95% limits of agreement.