Our study shows Real-world data from a consecutive Adult population with Duchenne Muscular Dystrophy that show only a small proportion of patients enrolled had both diagnostic quality TTE (91%) and CMR (25%) performed successfully. Our study is the first to report on the actual barriers to obtaining an evaluable CMR. The array of barriers to successful imaging which were encountered prove problematic in obtaining accurate diagnostic information on LV function as well as potentially useful prognostic information such as strain rate and fibrosis, which may be important in guiding treatment decisions.
Current evidence for therapeutic strategies based on imaging parameters
As in other forms of heart failure (HF), incident left ventricular (LV) systolic dysfunction in DMD should prompt the introduction of treatment with beta adrenergic blockade, renin-angiotensin activation system inhibition, mineralocorticoid receptor antagonist and sodium-glucose cotransporter 2 inhibitor drugs11, and Ivabradine. Established TTE parameters, such as reduction in LV ejection fraction and fractional shortening, are well studied in the seminal clinical trials of these drug classes12-14. International bodies therefore recommend treatments based on cut-off values in these parameters.
Due to complete penetrance of cardiomyopathy in DMD, however, early intervention with conventional drugs is the currently accepted consensus strategy to prevent or delay the onset of clinical HF. The optimal timing of treatment has yet to be determined, and clinical trials are ongoing to ascertain when these drugs should be initiated before the onset of LV systolic dysfunction15. The emergence of tissue Doppler and strain imaging, which correlate well with subsequent development of DMD HF16, has already seen a role for these parameters in early detection and instigation of treatment. Similarly, CMR parameters such as late gadolinium enhancement of the LV midwall can provide invaluable early prognostic information about the extent of fibrosis, and predict subsequent deterioration in systolic function.
Comparison of modalities: TTE
Despite recent advances in cardiac magnetic resonance imaging (CMR) and computed tomography (CCT), transthoracic echocardiography (TTE) remains the most commonly used imaging modality in the investigation of cardiomyopathy and heart failure, and in their follow-up17. Although the comparatively low cost is likely to be the principal motivation behind its ongoing use in preference to other modalities18, TTE continues to bear certain important advantages over CMR and CCT. The widespread availability of TTE makes it accessible to patients who are too unwell or clinically unstable to undergo other departmental imaging studies. Its portability has unique implications in DMD, where practical issues such as immobility and lack of appropriate transportation can render travel to centres with CCT and CMR capability unfeasible for patients. Moreover, the prevalence of contractures seen in DMD limits entry into the CMR scanner, and this is less problematic with a mobile modality such as TTE.
Factors limiting the diagnostic accuracy and utility of TTE are also encountered frequently. Image quality is often suboptimal in this almost-universally non-ambulatory cohort as correct positioning is infrequently achieved. Neuromuscular scoliosis and chest wall deformity present a further barrier to the acquisition of good acoustic windows in many cases. In addition to the factors limiting image acquisition, TTE interpretation is also highly operator dependent. This presents unique challenges in serial follow-up examinations when monitoring patients for deteriorating LV function. Varying degrees of correlation have been reported in studies comparing CMR with TTE.
Comparison of modalities: CMR
Postmortem histopathological examinations in DMD show a paucity of cardiac myocytes with a distinctive pattern of fibrofatty infiltration with early preponderance for the posterior left ventricular wall19. CMR can detect this myocardial fibrosis using gadolinium contrast enhancement. The extent of late gadolinium enhancing myocardium indicates the degree of fibrosis, and strongly correlates with the risk of subsequent deterioration in LVEF. Consequently, it is useful in screening for early myocardial involvement prior to the onset of LV systolic dysfunction. Unfortunately only 25% of our patients were able to have CMR performed due to the inherent patient-based and system-based obstacles described above.
CMR strain imaging is also increasingly used, and declining circumferential strain even precedes myocardial fibrosis. These technologies are therefore emerging as pre-clinical predictors of earlier and more severe cardiomyopathy, with greater accuracy than conventional TTE imaging. Thus CMR is likely to become much more widespread as a tool to inform risk stratification in DMD. Research is ongoing to investigate how this may guide the timing and optimisation of pre-clinical intervention in cardiomyopathy.
Despite these promising advances, CMR has inherent limitations specific to the DMD population of patients. Its cost and consequent lack of widespread availability means that travel to centres with CMR capability may present an obstacle to patients attending for this investigation, especially with regard to immobility and transport. Neuromuscular contractures resulting in scoliosis and fixed flexion deformity of the hip joints are well described and present a barrier to patients entering the MRI scanner (and precluded scanning in 27% of our study cohort). Additionally, 3% of patients required continuous non-invasive ventilation. These devices are generally incompatible with MRI, and therefore scanning could not be achieved in patients who were fully dependent.
The use of a multi-modality approach increases diagnostic yield, with the finding of early and extensive pattern of fibrosis on CMR prompting intensification of treatment prior to deterioration in systolic function. Despite the clinical value of this diagnostic information, obtaining it can be onerous on patients, causing significant disruption to routine as well as discomfort at times.
It is noted that patients with DMD and their caregivers cite numerous difficulties in attending appointments, due to considerations around wheelchair-accessible travel arrangements, distance to travel and time constraints. Therefore, as the use of imaging increases, it may necessitate tailoring the use of different modalities to clinical need, with due regard to the patient’s ambulatory state, severity of contractures and dependence on respiratory support, as well as other practical considerations not limited to transportation and the availability of caregiver support.
Image Concordance
Although image quality was suboptimal in a large proportion of TTE studies, it is noteworthy that there was a high level of agreement in LVEF reported on TTE compared with CMR, which is at odds with some previous studies20 where more heterogeneity was observed. We found that LVEF agreed to within +/- 5% in 88% of patients who underwent both TTE and CMR. This was deemed to be a very satisfactory level of agreement to guide clinical decision making, and further supports the use of TTE as the first line of diagnostic imaging in patients with significant mobility impairment.
Technical considerations
Although the technical expertise of radiographers and sonographers is beyond the scope of this article, it is acknowledged that a significant skill set is employed in performing high quality studies on patients with significant mobility impairment. At the time of writing, a literature search for training of cardiac sonographers in imaging patients with disabilities did not yield any relevant published results. Specialist training for operators in the practical considerations of this unique patent cohort may well improve imaging yield. Given the frequent citing by our technicians of difficulty with patient positioning as a major factor in suboptimal TTE image quality, it is postulated that additional resourcing of TTE units with healthcare staff to aid with positioning may help to further optimise acoustic windows.
A Single Multidisciplinary Team Clinical Review
Patients with DMD are almost entirely non-ambulatory and dependent on wheelchairs for mobility, as well as carers for assistance with transport and personal care. Specialised equipment is required to aid with transportation, as well as various devices for respiratory support which require trained operators to be present. This results in a significant stress for patients as well as high demand on their caregivers when numerous different appointments are necessary. The recent establishment of tertiary referral centres such as ours is done with the intention of honing advanced clinical skill from multi-disciplinary services resulting in a broad range of specialised services being made available to patients with DMD in a “one-stop-shop” setting. The aim is to cater for all of the patient’s specialist care needs in one sitting, averting the need for multiple attendances. This also results in continuity of care, with staff being familiar with the particular needs of this group of patients attending over time. Management of challenging discussions around ICD device considerations are best made in this setting, with multiple inputs from the team, patient and carers.
Although not cited as a reason for non-attendance for any diagnostic investigation by our cohort, the additional challenge with off-site CMR imaging is that patients are required to attend a further appointment, with repetition of the full set of obstacles that these patients are required to overcome when travelling for medical and care needs. The provision of dedicated on-site CMR slots would negate this further challenge, however this may be logistically and financially challenging in a publicly funded healthcare setting.
The high level of agreement between TTE and CMR in our study, and the acquisition of diagnostic quality images in the large majority of patients, supports the argument to continue the use of TTE as the standard of care imaging modality in this clinical context. Furthermore, its widespread availability, low cost and portability makes TTE a more convenient test than CMR in patients with DMD. Noting that extensive fibrosis was seen in 88% of patients who underwent CMR in this study, in addition to the complete penetrance of DMD cardiomyopathy seen in other studies, there is an argument for empirical and aggressive medical treatment for all patients with DMD regardless of imaging findings. This is the approach undertaken in our Centre. This would largely negate the need for CMR, especially in patients on whom high quality TTE imaging could be obtained. Regardless of whether CMR data is deemed necessary, it seems rational based on current evidence that all patients should undergo TTE imaging, with CMR being utilised as an adjunctive modality.
The range of difficulties reported with diagnostic imaging by both operators and patients and caregivers related largely to mobility, positioning and discomfort. These issues are universally apparent in this unique cohort of patients, and the natural history of DMD is such that improvements in patient factors are likely to be minimal. Therefore difficulties with imaging should be regarded primarily as difficulties specific to the imaging centre rather than the patient. Increased resourcing of imaging centres to cater to the particular mobility and care needs of these patients is likely to result not only in improved care delivery but also in better quality diagnostic imaging.
Limitations:
This single centre study provides useful information on the barriers to obtaining diagnostic imaging in DMD. The small sample size and the fact that the data presented are only representative of a single centre cohort may affect generalisability of results, however this tertiary referral centre caters to a large catchment area serving urban and rural populations with broad variation in socioeconomic conditions. Therefore data should reflect a reasonably diverse cohort.
Incomplete quantitative measurements in TTE studies were noted, especially missing LV diameter, wall thickness, and occasionally diastology. Assessment of RV function was missing in cases where the RV was not well visualised. As a consequence there was heterogeneity in reports and comparison of data. This was often due to difficulties cited in the discussion above in relation to acquisition of TTE images, however there was also inter-operator variability in reporting of these parameters. A standardised format of quantitative measurement and reporting would likely strengthen the TTE data presented here.
This study evaluated young adult patients with DMD after transition to the adult healthcare system. Due to current legislative and local regulations regarding sharing of patient data, access to historical imaging was limited to reports brought voluntarily by patients to the adult clinic. Thus the comparison of TTE findings over time is limited by a short mean follow-up time.