This prospective controlled study reported, for the first time, the existence of a left ventricular regionalized mechanical dyssynchrony in children with DMD with a normal LV systolic function. Indeed, using 2D-STE analysis, all three mechanical dyssynchrony criteria evaluated in this study were significantly higher in the DMD group than in healthy matched subjects: (1) basal inferoseptal to basal anterolateral opposing-wall delay and mid inferoseptal to mid anterolateral opposing-wall delay, (2) modified Yu index, and (3) most of time-to-peak delays, especially in basal and mid anterolateral segments.
Interestingly, this study found a segmental LV mechanical dyssynchrony before the onset of DMD-related cardiomyopathy or any clinical symptoms, as no patient with LV systolic dysfunction or LV dilatation was enrolled. LV mechanical dyssynchrony was more pronounced in the basal and mid anterolateral segments, which is concordant with LV 2D-strain anomalies previously observed in similar segments [6, 7].
Indeed, selective damage in those segments may be related to regional myocardial scar, which has been found to be higher in lateral than in septal segments, even with a preserved LV systolic function. Hor et al. have previously reported that LV mechanical dyssynchrony in DMD with end-stage cardiac dysfunction was associated with extensive infero- and anterolateral fibrosis . Using cardiac magnetic resonance imaging, Bilchick et al. have also shown that myocardial scar affected the LV anterolateral segment eight times more than the septal wall, regardless of LV systolic function . Furthermore, analyses on anatomopathology, electrocardiograms, and vectorcardiograms in DMD patients have suggested that fibrosis would start from the epimyocardial portion of the LV lateral wall, then reach the septal wall, and finally extent to the entire thickness of the myocardial wall . DMD-related fibrosis has been associated with myocardial stiffness, reduced myocyte compliance and increased susceptibility to stretch-mediated calcium overload, inducing cell necrosis . Moreover, LV mechanical dyssynchrony could modify myocardial gene expression and aggravate heart failure, as described in mouse models of cardiac remodeling . However, the reason why fibrosis first involves this specific ventricular region remains unknown.
In this pediatric cohort, 2D-STE dyssynchrony analyses have shown good feasibility and reproducibility, as previously reported in children without any cardiac disease . Indeed, in our study, analyses were technically possible in more than 80% of children in both DMD and healthy subjects, which is the line with the STAR study in adult heart failure . Overall, reproducibility was good to excellent, especially in segments where mechanical LV dyssynchrony was observed.
Other ultrasound methods have been used to measure mechanical LV dyssynchrony . However, M-mode and tissue Doppler imaging (TDI) do not provide simultaneous sampling in multiple segments. Color-coded tissue Doppler, tissue synchronization imaging and 3D-echocardiography provide simultaneous sampling of multiple segments, but require high-end ultrasound equipment and are difficult to use in current practice . 2D-STE analysis is little affected by translational and tethering motions [41, 42], and is not angle dependent. Moreover, 2D-STE semi-automated processing improves reproducibility and provides a global assessment of LV wall deformations, with easier use than other methods .
In this study, no electrical dyssynchrony was observed in children with DMD. Indeed, QRS intervals were similar between DMD and healthy subjects, using both raw values and pediatric Z-scores. This result is in line with the study from Hor et al., using cardiac magnetic resonance imaging in children with DMD and finding that the existence of a LV mechanical dyssynchrony did not involve electrical dyssynchrony in the DMD population . Therefore, measuring QRS intervals remains insufficient for assessing cardiac damage in patients with DMD.
Currently, cardiomyopathy prevention represents one of the most challenging clinical research issues in children with DMD . Conventional echocardiography parameters have failed to determine drugs’ efficacy (angiotensin-converting enzyme inhibitors, β-blockers, corticosteroids) on DMD cardiomyopathy onset and progression rate [5, 44–47]. Moreover, available tools to evaluate cardiac function may not be very specific (biological blood tests), difficult to perform in pediatric patients (cardiac magnetic resonance imaging), or too invasive (myocardial biopsy). Therefore, using mechanical dyssynchrony as a novel non-invasive cardiac biomarker in current (phosphodiesterase-5 inhibitors, COX-inhibiting nitric oxide donators, poloxamer 188) or future pediatric DMD drug trials would be of great interest.
The results of this study evidently question the interest of cardiac resynchronization therapy (CRT) in the DMD population. In adult symptomatic heart failure with impaired systolic LV function and LV mechanical dyssynchrony, CRT may improve symptoms and LV reverse remodeling, regardless of QRS width [48, 49]. However, in adult ischemic heart disease, the existence of inferior fibrosis reaching more than 50% wall thickness is associated with a nonresponse to CRT . LV pacing may reduce the progression of DMD-related cardiomyopathy, by decreasing ventricular work at each heartbeat, and therefore reducing damage to the myocyte membrane [34, 36]. By analogy, we may hypothesize that CRT could prevent LV mechanical dyssynchrony at an early stage of the cardiomyopathy, inducing a clinical benefit for the patient. Nevertheless, more evidence is necessary to support that CRT is useful in the DMD population free from heart failure.
The original study was not designed to use mechanical dyssynchrony as a primary outcome . As a result, the population from this post-hoc study included a small number of patients and controls. No subgroup analyses could be performed, however all three mechanical dyssynchrony criteria reached statistical significance.
No cut-off values to define LV electrical or mechanical dyssynchrony have been established in the pediatric population. As a result, we used a case-control study design to compare DMD patients to age-matched healthy subjects. Further studies are needed to define LV dyssynchrony thresholds in pediatrics.
The cross-sectional design of this study limits the use of LV mechanical dyssynchrony as a prognostic marker of LV dysfunction. Indeed, further longitudinal cohort studies will need to determine whether LV mechanical dyssynchrony can be used as a surrogate outcome for heart failure in the DMD population.