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Intra-Exam Repeatability of CINE DENSE Strain in Duchenne Muscular Dystrophy1Bioengineering, University of California, Los Angeles, CA, United States, 2Radiological Sciences, University of California, Los Angeles, CA, United States, 3Physics and Biology in Medicine, University of California, Los Angeles, CA, United States, 4Stanford University, Stanford, CA, United States, 5Pediatrics (Cardiology), University of California, Los Angeles, CA, United States, 6Radiology, Stanford University, Stanford, CA, United States
Synopsis
Heart failure leads the causes of mortality in Duchenne Muscular Dystrophy (DMD), the most common fatal genetic disorder. Circumferential strain (Ecc) is a promising biomarker for improved diagnosis and evaluation of therapy, but its repeatability has not been evaluated in a DMD cohort. The objective was to quantify the intra-exam repeatability of peak mid-wall circumferential (Ecc) strain derived from CINE DENSE in boys with DMD (N=11) compared to age-matched controls (N=10). Intra-scan repeatability was high, with a smallest detectable change in strain of 0.005, well under the previously reported 0.013±0.015 decrease in Ecc/year reported in boys with DMD.
Background
Duchenne Muscular Dystrophy (DMD) is the most common fatal inherited genetic disorder (1 in 3800 boys) and heart failure is the leading cause of mortality. The most commonly used cardiac MRI (cMRI) biomarkers (LV ejection fraction, LVEF, and LGE-positivity) are primarily effective at detecting late-stage disease and are highly variable1, 2. There exists a clinical need to identify and validate cMRI biomarkers of early cardiac disease in this cohort to improve diagnosis and evaluate the efficacy of novel therapeutics.
Recently, peak systolic circumferential strain (Ecc) in the LV derived from MRI tagging has been reported to effectively distinguish DMD patients and normal volunteers despite no significant differences in LVEF3,4,5. However, patients with DMD can have difficulty with the breath-holding required for tagged images. CINE DENSE is a free-breathing method for measuring myocardial strain with notable imaging and post-processing advantages6. While previous studies have assessed the segmental reproducibility of CINE DENSE7 in adult patients and volunteers, none have considered pediatric patients. In fact, CINE DENSE strain in a DMD cohort has not been reported. Defining the intra-exam repeatability of strain with CINE DENSE in this cohort is important in quantifying longitudinal disease progression. Consequently, the objective was to quantify the intra-exam repeatability of peak mid-wall circumferential (Ecc) strain derived from CINE DENSE in boys with DMD compared to age-matched healthy controls.
Methods
Study Population: In this IRB-approved prospective study, boys with DMD (N=11, age=13±.40 years) and age-matched healthy volunteers (N=10, age=13±0.8 years) underwent a cMRI examination after obtaining informed consent.
MRI Protocol: A conventional cMRI exam also included a single, ECG-triggered, navigator gated, mid-ventricular LV short-axis slice acquired with balanced 3-point encoding, 2.5x2.5x8mm, TE/TR=1.04/15, Ke=0.06cycles/mm, Navg=3, spiral interleaves=10, scan time=2min/slice. The lower bound on intra-exam repeatability was evaluated by repeated acquisitions without patient repositioning.
Data Processing and Statistical Analysis: All CINE DENSE data were imported into custom software8 used to extract the x, y, and z Lagrangian displacements that ultimately compute Ecc. The intra-class correlation coefficient (ICC) measured agreement between repeated scans and was used to compute the standard error of measurement (SEM) and the smallest detectable change (SDC) in strains where $$$ SEM = SD×√(1-ICC)$$$ and $$$SDC = 1.96×SEM×√2$$$ 9. SDC provides a threshold above which a change in measurement exceeding the threshold is true and reliable at a 95% confidence interval, not simply measurement error. Bland-Altman analysis was used to assess and visualize bias and limits-of-agreement between repeated exams.
Results
Table 1 summarizes strain values in boys with DMD and age-matched volunteers and provides descriptive statistics of strain measurements between repeated exams. In both patients and volunteers, the intra-class correlation coefficient is high (93.6% and 91.0%), and the standard error of measurement is quite low (0.0019 and 0.0019 for Ecc). The smallest detectable change was 0.0052 and 0.0054 Ecc, respectively. Bland-Altman analysis (Figure 1) shows good agreement between repeated scans, with a mean difference and limits of agreement (1.96xSD) of 0.0025±0.014 and -0.0048±0.0126 for patients with DMD and volunteers respectively. Figure 2 provides representative repeated CINE DENSE scans from a DMD patient.Discussion & Conclusion
This data suggests that peak midwall Ecc measured with navigator-gated CINE DENSE has high intra-scan reproducibility and can be used to measure changes in Ecc as low as 0.005. Previous reports using MRI tagging suggest that peak systolic Ecc decreases uniformly amongst DMD patients at a rate of 0.013±0.015 strain per year5 and that the smallest detectible change (considering inter-study error) in mid-ventricular Ecc as measured by MRI tagging is an absolute decrease of 0.02710. The intra-exam SDC of CINE DENSE is capable of resolving this change and is well below the tagged SDC.
The characterization of repeatability of CINE DENSE Ecc is novel both in a pediatric cohort and in a DMD population, and provides insight with regards to quantifying longitudinal progression of disease and response to therapy. While this study did not assess intra or inter-observer variability or inter-study repeatability, intra-scan repeatability without repositioning is important because it provides a reasonable lower bound on our confidence in Ecc measured with CINE DENSE and in quantifying the repeatability of the measurement itself. Future investigation into other sources of variability and into regional-sub analysis is on-going.
Acknowledgements
Support from: NIH/NLHIB HL131975References
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