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Early Non-Contrast Biomarkers of Left Ventricular Cardiomyopathy in Children with Duchenne Muscular Dystrophy

ZHAN-QIU LIU¹, Nyasha Maforo², Seraina Dual³, Ashley Prosper⁴, Pierangelo Renella⁴, Nancy Halnon⁵, Holden Wu⁴, and Daniel Ennis³
¹Cardiovascular Institute, Stanford University, Stanford, CA, United States, ²Physics and Biology in Medicine Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, United States, ³Department of Radiology, Stanford University, Stanford, CA, United States, ⁴Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA, United States, ⁵Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States

Synopsis

Left ventricular(LV) peak mid-wall circumferential strain (Ecc) is a sensitive early biomarker for evaluating the subtle and highly variable onset and progression of cardiomyopathy in pediatric subjects with Duchenne muscular dystrophy (DMD). Cine Displacement Encoding with Stimulated Echoes (DENSE) has proven sensitive to changes in Ecc. Using cine DENSE we show a significantly decreased septal Ecc in LGE negative(-) boys with DMD absent identifiable focal fibrosis compared with controls. A binomial logistic regression model that combines septal Ecc, LV pre-contrast T1, and LV ejection fraction can sensitively distinguish LGE(-) boys with DMD from healthy boys without the need for contrast.

Background

Cardiomyopathy is the leading cause of mortality in boys with Duchenne muscular dystrophy (DMD). Reduced left ventricular (LV) ejection fraction (EF<55%) is a widely used marker of cardiac function and outcomes¹, but the decline in LVEF is a relatively late finding among DMD patients. Late gadolinium enhancement (LGE) MRI is the gold standard for detecting focal myocardial fibrosis, but positive LGE is also a late finding in DMD^2,3. We seek to define a sensitive non-contrast biomarker to evaluate cardiac involvement in DMD prior to the decline in LVEF or the appearance of LGE.

Myocardial native pre-contrast T1 (preT1) mapping can be used to evaluate diffuse fibrosis⁴ and can offer insight into early cardiac involvement in DMD⁵. In addition, LV peak mid-wall circumferential strain (Ecc). using tagging is an early biomarker of dysfunction in DMD^6-8, but further validation is needed⁹. Alternatively, Cine Displacement Encoding with Stimulated Echoes (DENSE) is sensitive to changes in Ecc¹⁰. Ecc derived from cine DENSE, however, has not been reported in a DMD cohort. Thus, our objectives were: 1) To characterize regional LV Ecc in healthy boys and LGE negative (-) boys with DMD using cine DENSE; and 2) To evaluate a regression model that includes non-contrast biomarkers (Ecc, preT1 mapping, and LVEF) to distinguish between healthy boys and LGE(-) boys with DMD.

Methods

LGE(-) boys with DMD (N=10, 12.5±3.0 years old) and healthy boys (N=12, 13.0±2.0 years old), were prospectively enrolled in an IRB-approved study, consented, and underwent a 3T (Skyra, Siemens) CMR exam. Single-slice, short-axis, mid-ventricular data was acquired using navigator-gated free-breathing cine DENSE (2.5x2.5x8 mm³, TE/TRes=1.2/15ms, k_e=0.08cycles/mm, Navg=3, ~2.5min/slice)¹¹. Ecc at each voxel was computed from DENSE images using the open-source DENSE analysis tool^12,13. Regional strain analysis was done using a custom DENSE analysis plugin¹⁴. Specifically, a mid-ventricular LV slice was segmented into six segments using the AHA model¹⁵. Then, septal Ecc was averaged over anteroseptal and inferoseptal segments and lateral Ecc was averaged over inferolateral and anterolateral segments. Two expert clinicians calculated LV and RV volumes and function from standard bSSFP cine images. Average LV preT1 values and RV preT1 values (using a one-pixel centerline approach) were recorded. For each group, within-group differences in the biomarkers of interest (BOI) were tested using a Skillings-Mack test followed by pairwise Wilcoxon signed-rank tests. For each wall segment, group-wise differences in the BOI were tested by a Wilcoxon rank-sum test. Data is reported as median (IQR) and p<0.05 was considered significant. A framework was proposed to determine how all predictors contribute to predicting the significant change in Ecc between healthy boys and LGE(-) boys with DMD (Table 3). Lastly, a binomial logistic regression model tested whether Ecc, LV preT1, and LVEF can distinguish between healthy boys and LGE(-) boys with DMD.

Results

LGE(-) boys with DMD were significantly shorter, resulting in significantly smaller BSA compared to healthy controls (Table 1). 4 out of the 10 LGE(-) boys with DMD presented with reduced LVEF (< 55%) and 3 out of the 10 presented with reduced RVEF (<50% ¹⁶). Shown in Table 2, LGE(-) boys with DMD had significantly lower RVEDV and RVESV compared to healthy controls. LGE(-) boys with DMD also demonstrated significantly elevated preT1 in LV lateral wall [1336(77) vs 1282(62), p=0.030] and RV wall [1569(184) vs 1434(81), p = 0.008] compared to healthy controls. Depicted in Figure 1, both groups of boys had significantly lower septal Ecc and significantly higher lateral Ecc compared to the Ecc in other segments. LGE(-) boys with DMD exhibited significantly reduced septal Ecc [-0.13(0.01) vs -0.16(0.03), p = 0.019] compared to healthy boys. Table 3 illustrates that LVEF predicts septal Ecc in controls, but not in LGE(-) boys with DMD; while LVEDV and RVEDV predict septal Ecc in LGE(-) boys with DMD, but not in controls. Figure 2 reveals that a combination of septal Ecc, lateral LV preT1, and LVEF best distinguished between LGE(-) boys with DMD and healthy boys, followed by septal Ecc plus LVEF, septal Ecc, and lateral LV preT1 (AUC = 0.92, 0.83, 0.80, and 0.79), respectively.

Discussion & Conclusion

LGE(-) boys with DMD and healthy boys both exhibited lower septal Ecc relative to the higher lateral Ecc. Similar findings have been previously observed using tagging in control subjects and DMD patients^17,18. The regional heterogeneity in Ecc is likely attributed to regional differences in loading conditions. Similarly, the optimal regression models reveal that decreased LVEDV and RVEDV predict the significantly reduced Ecc in LGE(-) boys with DMD compared with controls, indicating the impaired septal shortening is likely due to a shift in end-diastolic loading conditions for both the LV and RV. Functional changes in the respiratory system owing to DMD may affect the biventricular end-diastolic loading conditions. For distinguishing LGE(-) boys with DMD from healthy boys, septal Ecc outperformed the other individual biomarkers and the combination of septal Ecc, lateral LV preT1, and LVEF outperformed the other biomarker combinations. This combination may provide an early, non-contrast biomarker for detecting the onset of LV cardiac involvement in boys with DMD.

Acknowledgements

The authors thank all of the study coordinators, MRI technicians, study participants, and their families. This study was supported by NIH R01 HL131975 to DBE and NSF DGE 1650604 to NGM.

References

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Figures

Table 1: Demographics of healthy controls and LGE(-) boys with DMD.

Table 2: Summary of LV and RV volume, function, and pre-contrast T1 values, as well as differences between LGE(-) patients with DMD and healthy controls.

Table 3: Framework for finding out all predictors contribute to predicting the septal Ecc in healthy boys and LGE(-) boys with DMD.

Figure 1: Global and Regional Ecc in Healthy Boys and LGE(-) boys with DMD. Septal Ecc was significantly lower than anterior, lateral, and inferior Ecc and the lateral Ecc was significantly higher than septal, anterior, and inferior Ecc for both the controls or LGE(-) DMD patients. Furthermore, the LGE(-) DMD patients had significantly reduced septal Ecc compared to healthy volunteers. * p-value ≤ 0.05 is significant for a comparison within either controls or LGE(-) boys with DMD. # p-value ≤ 0.05 is significant for a comparison between controls and LGE(-) patients with DMD.

Figure 2: Receiver Operator Characteristic (ROC) curves for septal Ecc, lateral LV pre-contrast T1, and LVEF from a binomial logistic regression classifier for distinguishing between LGE(-) boys with DMD from healthy boys. Larger area under the curve (AUC) values indicate better classifier performance. Regarding differentiating LGE(-) boys with DMD from healthy boys, septal Ecc outperforms each individual biomarker and the combinaiton of septal Ecc, lateral LV pre-contrast T1, and LVEF outperforms the other biomarker combinations.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)

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