Background
Patients with Duchenne muscular dystrophy (DMD) require frequent imaging to assess left ventricular (LV) function. Poor imaging windows can limit the diagnostic utility of echocardiography. Cardiac magnetic resonance imaging (CMR) is the gold standard for the assessment of LV function but has not been universally adopted in patients with DMD. The study objectives were (1) to evaluate the reproducibility of echocardiographic measures of LV function, (2) to evaluate which echocardiographic methods correlate best with CMR LV ejection fraction (LVEF), and (3) to evaluate whether CMR provides additional value compared with echocardiography.
Methods
Twenty-eight participants with DMD prospectively underwent echocardiography and CMR. Two blinded readers measured fractional shortening from M-mode and two-dimensional images and LVEF using four-chamber, biplane Simpson, 5/6 area-length, and three-dimensional methods. Speckle-tracking echocardiography was used to analyze circumferential strain. Readers subjectively rated function and segmental wall motion. Agreement was assessed using intraclass correlation coefficients, Bland-Altman plots, Spearman correlation, and weighted κ.
Results
Two-dimensional fractional shortening and 5/6 area-length LVEF had the best combination of reproducibility and correlation with CMR LVEF, though both misclassified approximately 20% as either normal or abnormal function. Other measures of LV function were less reproducible, with worse correlations with CMR LVEF. Thirty-seven percent of segments not visible on echocardiography were believed to have wall motion abnormalities by CMR.
Conclusions
Two-dimensional fractional shortening and 5/6 area-length LVEF represent the most accurate and reproducible echocardiographic measures of LV function in patients with DMD. CMR should be considered when neither of these techniques is measurable or when it is necessary to detect more subtle cardiovascular changes.
Highlights
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The authors evaluated the reproducibility of echocardiographic measures of LV function in DMD.
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Echocardiographic measures of LV function were compared with LVEF from contemporaneous CMR.
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In DMD, two-dimensional FS and 5/6 area-length are the most accurate and reproducible methods.
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CMR has added value for wall motion assessment and LGE.
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CMR is preferable when subtle cardiovascular changes must be detected.
Duchenne muscular dystrophy (DMD) affects one in 4,700 live male births and leads to loss of ambulation and cardiomyopathy. Boys with DMD can have rapid progression of left ventricular (LV) dysfunction without symptoms, making accurate assessment of cardiac function integral to their routine care. Current recommendations call for initial cardiac evaluation starting at 6 years of age, with at least biannual evaluation until 10 years of age, then at least annual evaluation with more frequent evaluations after the development of cardiac imaging abnormalities.
Echocardiography is the most frequently used test to assess ventricular function in patients with DMD. However, patients with DMD have notoriously poor acoustic windows in part because of adiposity and scoliosis. Recent evaluations in patients with DMD have demonstrated moderate reproducibility of echocardiographic measures of LV function and a correlation coefficient of only 0.67 between fractional shortening (FS) by echocardiography and LV ejection fraction (LVEF) by cardiac magnetic resonance imaging (CMR). Echocardiography and CMR have been compared in other disease processes, and in patients with myocardial infarction, echocardiography underestimates LV volumes and LVEF and is less sensitive in the detection of focal wall motion abnormalities. CMR provides superior delineation of the border between the blood pool and endocardium, and image quality is not affected by external factors such as body habitus. It also allows accurate volumetric measurements, subjective and objective assessment of wall motion abnormalities, and tissue characterization by methods such as late gadolinium enhancement (LGE). For these reasons, CMR has become the gold standard for the assessment of ventricular function in patients with cardiomyopathy. Citing many of these advantages, a recent DMD cardiovascular working group emphasized the importance of CMR for evaluation of LV function in this population.
Despite the advantages of CMR in patients with DMD, CMR is not available at all centers, and many still support echocardiography as the standard modality for DMD functional imaging. Clinical and research assessments of cardiac function require accurate and precise measures. Given the clinical and research implications of inaccurate LV functional assessment in this population and the known limitations of echocardiography in DMD, a study comparing the accuracy and reproducibility of echocardiography with those of CMR is essential. In addition, the increasing difficulty of obtaining insurance approval for medical testing requires that all medical testing demonstrate “value added” to obtain authorization. Therefore, an evaluation of the reproducibility and accuracy of echocardiographic measures of LV function, and a comparison with CMR, is integral for clinical care and research in patients with DMD. The objectives of this study were the following: (1) to evaluate the reproducibility of multiple echocardiographic measures of LV function in the DMD population, (2) to evaluate which echocardiographic methods correlate best with CMR LVEF, and (3) to evaluate whether CMR provides additional value compared with echocardiography.
Methods
This study was approved by the institutional review board, and all participants signed the appropriate consent or assent documents. DMD participants were prospectively enrolled from the multidisciplinary Neuromuscular-Cardiology Clinic. Inclusion criteria were (1) diagnosis of DMD by clinical phenotype and either skeletal muscle biopsy or genetic testing and (2) age ≥ 8 years and ability to undergo CMR without sedation. Exclusion criteria were (1) muscular dystrophy other than DMD and (2) CMR and echocardiography performed >30 days apart. Consent was obtained directly from participants ≥18 years of age. Those <18 years of age signed age-appropriate assent forms while their parents completed the informed consent documents. Additional pertinent data were recorded.
Echocardiography
All echocardiograms were obtained by one of four research sonographers with experience imaging patients with DMD. Whenever possible, echocardiograms were obtained in a supine position; in a minority of participants unable to transfer to a supine position, echocardiograms were obtained in a reclined wheelchair. Images were deidentified using Showcase version 5.3.0.0 (Trillium Technology, Ann Arbor, MI) and placed into the Digital Imaging and Communications in Medicine viewer with unique study identification numbers.
Blinded analysis was performed on Xcelera workstations (Philips Medical Systems, Best, The Netherlands) by two independent readers (J.H.S. and D.A.P.). Readers were asked to grade the echocardiographic image quality on a scale of 1 to 5 as follows: 1 = inadequate (very poor image quality with inability to visualize endocardial borders or visualize most cardiac structures; no or very little objective data obtainable), 2 = poor (poor image quality with only marginal delineation of endocardial borders in some views and limited assessment of atrial sizes and valves; only some objective data obtainable), 3 = average (average image quality with adequate delineation of endocardial borders in most views and adequate visual assessment of atrial sizes and all valves but the tricuspid valve; approximately half of objective data obtainable), 4 = good (at least adequate delineation of endocardial borders in all views with good delineation of endocardial borders in most views and good visualization of atrial sizes and all valves; all objective data obtainable), and 5 = excellent (excellent delineation of endocardial borders in all views and excellent visualization of all other cardiac structures assessed; all objective data obtainable). A subset of 10 echocardiograms was reanalyzed by one blinded reader (J.H.S.) 3 months after the initial analysis to assess intraobserver variability.
Echocardiographic assessments were performed as described in the American Society for Echocardiography guidelines and included the following: (1) FS measured from M-mode images obtained in either the short-axis or long-axis plane, (2) FS measured from two-dimensional images obtained in the short-axis plane at the level of the papillary muscles, (3) single-plane LVEF measured in the apical four-chamber view, (4) modified Simpson’s biplane LVEF measured in the apical four-chamber view and two-chamber view, (5) 5/6 area-length LVEF measured from the short-axis and apical four-chamber views, and (6) three-dimensional LVEF measured using dedicated software (4D LV Analysis; TomTec Imaging Systems, Unterschleissheim, Germany). When image quality allowed, measurements were averaged over multiple beats. Using the standard American Heart Association 17-segment model, one blinded reader determined which segments were visible and, if visible, which segments had wall motion abnormalities. Last, readers subjectively graded global systolic function on a scale of 0 to 6, ranging from normal to severely depressed ( Table 1 ).
| Subjective score | Corresponding LVEF |
|---|---|
| 0 = normal | ≥55% |
| 1 = borderline depressed | <55% and ≥50% |
| 2 = mildly depressed | <50% and ≥45% |
| 3 = mildly to moderately depressed | <45% and ≥40% |
| 4 = moderately depressed | <40% and ≥35% |
| 5 = moderately to markedly depressed | <35% and ≥30% |
| 6 = markedly depressed | <30% |
Speckle-tracking echocardiography was used to measure peak myocardial circumferential strain (ε cc ) in the short axis at the level of the papillary muscles. Analysis was performed by two blinded readers with expertise in speckle-tracking analysis (J.H.S., M.S.) using dedicated software (Cardiac Performance Analysis; TomTec Imaging Systems). One reader (J.H.S.) repeated analysis of 10 subjects ≥3 months after the initial analysis to assess intraobserver variability.
CMR
CMR was performed on a 1.5-T Siemens Avanto (Siemens Healthcare Sector, Erlangen, Germany) with an eight-channel cardiac coil. Functional assessment was performed as previously described with breath-held, electrocardiographically gated, balanced steady-state free precession cine imaging obtained in 10 to 16 contiguous slices in the short axis. Myocardial grid tagging was performed with a breath-hold in the short axis at the base, level of the papillary muscles, and apex with typical imaging parameters: field of view, 340 × 350 mm 2 ; matrix size, 256 × 192; slice thickness, 8 mm; voxel size, 1.3 × 1.8 × 8 mm 3 ; minimal echo and repetition times; and parallel imaging (generalized autocalibrating partially parallel acquisitions) with an acceleration factor of 2. LGE imaging was performed 10 min after the injection of gadolinium diethylenetriaminepentaacetic acid contrast (Magnevist [gadopentate dimeglumine]; Bayer Healthcare Pharmaceuticals, Wayne, NJ) through a peripheral intravenous line at a dose of 0.2 mmol/kg. LGE was assessed using single-shot and segmented inversion recovery balanced steady-state free precession imaging with an inversion recovery to optimally null myocardium as well as phase-sensitive inversion recovery balanced steady-state free precession with an inversion time of 300 msec. All patients were able to perform adequate breath-holds for functional analysis; when necessary, slices with respiratory artifacts were repeated as per our standard CMR protocol.
Image Processing
The endocardial and epicardial borders at end-diastole and end-systole were manually contoured and used to calculate LV volumes, LV mass, and LVEF using the Leonardo Workstation (Siemens Healthcare Sector). One reader (J.H.S.) performed all CMR analyses. The same reader who qualitatively assessed for segmental wall motion abnormalities by echocardiography also assessed wall motion abnormalities by CMR. A random subset of 10 CMR studies was reanalyzed by a second reader (D.A.P.) to evaluate interobserver variability. One reader (J.H.S.) repeated analysis in 10 subjects ≥3 months after the initial analysis to assess intraobserver variability. Peak global ε cc was measured in the short axis at the level of the papillary muscles using harmonic phase analysis (Diagnosoft, Morrisville, NC), as previously described. In brief, a mesh was created by contouring the epicardial and endocardial borders of the tagged images. Peak strain values were then generated by the software program. Two readers evaluated LGE sequences independently for presence or absence of LGE in each segment. For segments on which the readers did not agree, the two readers reviewed the images together and formed a consensus.
Statistical Analysis
The choice of statistic used to summarize agreement depended on whether the comparison was being made for variables measured in the same units and whether the variables were continuous or categorical. Intra- and interobserver variability of continuously measured echocardiographic and CMR measures of function was estimated using intraclass correlation coefficients (ICCs), and graphical comparisons were made using Bland-Altman plots. Agreement between readers for subjective evaluation of function on a five-point scale was estimated using a weighted κ statistic. Spearman’s ρ was used to estimate the correlation between measures of FS and CMR LVEF. The correlations between echocardiographic measures of LVEF and CMR LVEF were estimated using ICC and Bland-Altman plots. We used bootstrapping to estimate 95% CIs for the ICC, Spearman’s ρ, and weighted κ.
Analyses were performed with the statistical programming language R version 2.14.1 (R Development Core Team, Vienna, Austria) or IBM SPSS Statistics version 23.0 (IBM, Armonk, NY). Study data were collected and managed using Research Electronic Data Capture, hosted at Vanderbilt University.
Results
Demographics
A total of 28 participants with DMD were enrolled. The average age of participants was 14.7 years ( Table 2 ). The mean LVEF by CMR was 51% ( Table 3 ). On the basis of indexed LV end-diastolic volumes, the majority of participants did not have LV dilation. The median number of days between echocardiography and CMR was 0 (all but three echocardiographic studies were performed the same day as CMR).
| Variable | Value |
|---|---|
| Age (y) | 14.7 ± 4.8 (6.9–27.5) |
| Height (cm) | 149 ± 15 (114–178) |
| Weight (kg) | 54 ± 17 (28–86) |
| Body surface area (m 2 ) | 1.49 ± 0.28 (0.99–2.0) |
| Body mass index (kg/m 2 ) | 24 ± 6.7 (14–39) |
| Ambulatory | 4 (14%) |
| Positive pressure ventilation (nocturnal or continuous) | 7 (25%) |
| Continuous positive pressure ventilation | 3 (11%) |
| Race | |
| Caucasian | 25 (89%) |
| African American | 2 (7%) |
| Asian | 1 (4%) |
| Hispanic/Latino | 4 (14%) |
| Medical therapy at time of CMR | |
| ACE inhibitor | 16 (57%) |
| ARB | 5 (18%) |
| β-blocker | 10 (36%) |
| Corticosteroids | 17 (61%) |
| Mean corticosteroid duration (y) | 4.4 ± 2.8 |
| Variable | Value |
|---|---|
| CMR functional measures | |
| CMR LVEF (%) | 51 ± 9.3 (33–66) |
| CMR indexed LVEDV (mL/m 2 ) | 66 ± 14 (42–104) |
| CMR indexed LVESV (mL/m 2 ) | 33 ± 12 (17–70) |
| CMR RVEF (%) | 54 ± 5.3 (42–66) |
| LGE ( n = 25) | 19 (76%) |
| CMR ε cc (%) | −14.1 ± 3.3 (−7.8 to −20.1) |
| Median days between CMR and echocardiography | 0 (0–22) |
| Mean echocardiographic functional measures | |
| M-mode FS (%) | 27.0 ± 5.3 |
| Two-dimensional FS (%) | 26.5 ± 6.1 |
| Biplane LVEF (%) | 51.1 ± 5.4 |
| Four-chamber LVEF (%) | 47.7 ± 7.4 |
| 5/6 area-length LVEF (%) | 50.8 ± 8.4 |
| Three-dimensional LVEF (%) | 44.5 ± 10.2 |
| Echocardiographic ε cc (%) | −16.2 ± 4.4 (−5.1 to −23.0) |
Image Quality and Intra- and Interobserver Variability
Correlation of subjective assessments of image quality was strong ( r = 0.84, P < .001). Reader 1 rated 60.7% of studies as average or better, while reader 2 rated 64.3% as average or better. The median rating of echocardiographic quality was average for both readers. At least three objective measures of function were measureable by both readers on 18 of the participants’ studies (21 for reader 1 and 20 for reader 2). Echocardiographic quality was negatively correlated with age, with a significant decrease in quality in older participants ( r = −0.63, P < .001). Intra- and interobserver variability is demonstrated in Table 4 . The most reproducible measures were two-dimensional FS (ICC = 0.86; 95% CI, 0.69–0.94), 5/6 area-length LVEF (ICC = 0.87; 95% CI, 0.45–0.97), and three-dimensional LVEF (ICC = 0.88; 95% CI, 0.61–0.96) ( Figure 1 ). Notably, M-mode FS and four-chamber LVEF both had relatively low reproducibility. Intraobserver agreement was >0.8 for most echocardiographic measurements ( Table 4 ). Interobserver agreement was highest for CMR LVEF (ICC = 0.94; 95% CI, 0.85–0.98).
| Variable | ICC | 95% CI |
|---|---|---|
| Interobserver variability | ||
| Echocardiographic measures | ||
| M-mode FS ( n = 22) | 0.66 | (0.18–0.87) |
| Two-dimensional FS ( n = 22) | 0.86 | (0.69–0.94) |
| Biplane LVEF ( n = 12) | 0.77 | (0.47–0.94) |
| Four-chamber LVEF ( n = 17) | 0.60 | (0.09–0.88) |
| 5/6 area-length LVEF ( n = 14) | 0.87 | (0.45–0.97) |
| Three-dimensional LVEF ( n = 14) | 0.88 | (0.61–0.96) |
| ε cc ( n = 20) | 0.84 | (0.61–0.94) |
| CMR | ||
| LVEF ( n = 10) | 0.94 | (0.85–0.98) |
| Intraobserver variability | ||
| Echocardiographic measures ( n = 10) | ||
| M-mode FS | 0.93 | (0.75–0.98) |
| Two-dimensional FS | 0.80 | (0.30–0.96) |
| Biplane LVEF | 0.80 | (0.48–0.93) |
| Four-chamber LVEF | 0.69 | (−0.18 to 0.90) |
| 5/6 area-length LVEF | 0.99 | (0.96–0.99) |
| Three-dimensional LVEF | 0.94 | (0.53–0.97) |
| ε cc | 0.90 | (0.47–0.98) |
| CMR (N = 10) | ||
| LVEF | 0.98 | (0.92–0.99) |
| ε cc | 0.97 | (0.87–0.99) |
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