Background
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin [1], a protein essential to the integrity of the cytoskeleton of striated muscle. The complete absence of dystrophin seen in DMD [2], and resultant progressive atrophy, manifests clinically as gait disturbance with subsequent loss of ambulation, and ultimately cardiac and respiratory failure [3]. Its prevalence is approximately 4.78 per 100,000 males [4].
The natural history of DMD carries a poor prognosis, with death at a mean age of 14.4 years reported in some studies [5]. The introduction of non-invasive ventilation has increased this by approximately 10 years. Consequently, cardiomyopathy, which is universally apparent by 18 years of age, has become the leading cause of mortality [6].
Monitoring for pre-clinical evidence of cardiomyopathy presents a challenge in this unique cohort of patients. Contractures, chest wall deformities, ventilation abnormalities and scoliosis are some of the barriers to diagnostic quality imaging of patients with DMD which have been alluded to in previous studies [7], [8].While more recent research has highlighted the utility of CMR in the evaluation of patients with muscular dystrophy for the presence of preclinical cardiomyopathy [9], [10], there is a lack of data regarding the extent to which these issues impact on the quality and practicability of cardiac imaging in this group of patients.
Aim
The aim of this study was to evaluate the optimal strategy for cardiac imaging in young adults with DMD with regard to the practicalities of imaging in individual patients, and to review the extent to which these issues impact on the quality and practicability of cardiac imaging in this group of patients. We also sought to report the ECG correlates in a descriptive manner.
Methods
We conducted a prospective cohort study comparing the diagnostic utility of CMR with TTE in patients with DMD. All patients attending a Comprehensive Multidisciplinary Adult DMD clinic over a 4-year period were enrolled. The clinic provided a single “One Stop Visit” with an extensive review with Advanced Specialist Care from Pulmonologist, Cardiologist, Neurologist, Physiotherapist, Occupational Therapist, Nutritionist, and Social Worker.
Patients who attended had a confirmed diagnosis of DMD. Clinical diagnosis was made in all cases by a Pediatrician specializing in Neuromuscular Disorders or a Clinical Geneticist, based on clinical evaluation, family pedigree and confirmatory genetic testing in most cases.
Data collection occurred at baseline and at patients’ most recent clinical review. Parameters gathered were age, time to follow-up, ambulatory status, use of respiratory adjuncts. Each patient had baseline biochemistry, and baseline ECG was analysed, with characteristics reported descriptively.
Findings of continuous 24 h Holter ECG monitoring, overnight oximetry and pulmonary function testing are also reported where conducted. No patient had an implantable loop recorder placed or used a wearable technology for arrhythmia detection. All data collection, storage and reporting was carried out in accordance with local governance procedures, and national and international data protection regulations.
TTE was conducted at baseline and follow-up, with examinations carried out in accordance with British Society of Echocardiography guidance and minimum dataset [11]. All patients were offered referral for CMR. Presence or absence of fibrosis and CMR derived EF were gathered where performed.
In the case of non-attendance for their investigation, we recorded the reason cited by the patient or caregiver. Data were analysed for agreement in LVEF between modalities with results illustrated using a Bland-Altman plot. Differences in non-attendance and non-diagnostic exam rates, and the reason for observed differences between modalities, were reported in a qualitative manner.
Ethical approval
The study protocol was reviewed and ethically approved by the Beaumont Hospital Clinical Audit & Governance Committee (Institutional Review Board reference number CA2023/133).
Results
Baseline characteristics
We enrolled a total of 33 patients consecutively, all of whom were male. Baseline characteristics and medication use are shown in Table 1. The median age was 20 at enrollment, standard deviation 4.3 years.
Mean follow-up period was 3 years, 3 months.Table 1Baseline Characteristics and Medications Use at First & Most Recent Reviews:First Review (33)Most Recent Review (28)Age (median years, StD)20, 4.323.3, 3.9Mean Heart Rate88 bpm72 bpmBeta blocker79 %89 %ACEi75 %96 %MRA50 %96 %SGLT2 Inhibitors0 %61 %Ivabradine0 %11 %Corticosteroid50 %ICD Placement0 %7 %Declined ICD Placement0 %1 %
ECG findings
ECG characteristics are shown in Table 2. Mean HR 88 bpm, sinus rhythm / sinus tachycardia in all cases. P wave duration, PR interval, and QT interval were normal in all cases, as was QRS duration in all but two.
The most common abnormality was pathological Q waves in the inferolateral leads, seen in 21 ECGs. T wave inversion was seen in 6 cases, 3 anterior and 3 inferolateral leads, and correlated with reduced LVEF in all cases.Table 2Baseline ECG characteristics (N = 32).HR (mean, StD)88, 16Sinus rhythm (N, %)32, 100 %P amplitude (mean, StD)0.165, 0.047P duration (mean, StD)75, 15PR (mean, StD)125, 20QRS RAD (N, %)8, 25 %QRS duration (mean, StD)94, 12QRS amplitude (mean, StD)1.7, 0.75Limb QRS amp. sum4.1, 1.76QT interval (mean, StD)340, 37QTc (mean, StD)407, 34Pathological Q (N, %)21, 66 %TerritoryInferolateralInferolateral TWI (N, %)3, 9 %Anterior TWI (N, %)3, 9 %RSr' pattern (N, %)6, 19 %
TTE findings
TTE was conducted in all patients. Table 3 depicts TTE parameters measured for each patient at follow-up, and initial study. Although imaging was reported as “suboptimal” or “limited” in 75 % of cases, only 9 % of studies (N = 3) were considered non-diagnostic.
Patient positioning / immobility was cited as the reason for suboptimal imaging in most cases, making techniques such as speckle tracking, strain, 3d volumetric imaging, and other quantitative assessment impractical (Table 5). Mean EF was 51 % at initial echo and 45 % at follow-up (Fig. 3 – box plot).Table 3TTE parameters (Follow-up, Initial study).Follow-up StudyInitial StudyAge (Median +/- StD years)22 +/-4.718 +/-1LVEF (Mean +/- StD %)46 +/-1251 +/-11LVIVSd (mm)8 +/-2***LVPWd (mm)7 +/-2***LVIDd (mm)44 +/-1***LVIDs (mm)36 +/-1***E/A1.5 +/-0.3***RV dysfunction (N, %)3, 9 %1, 3 %MR mild (N, %)3, 9 %***MR trace (N, %)10, 30 %***LVEF: Left Ventricular Ejection FractionLVIVSd: Left Ventricular Interventricular Septal thickness in diastoleLVPWd: Left Ventricular Posterior Wall thickness in diastoleLVIDd: Left Ventricular Intracavitary Diameter in diastoleLVIDs: Left Ventricular Intracavitary Diameter in systoleE/A: Ratio of early to late diastolic mitral valve inflow velocityRV: Right VentricleMR: Mitral RegurgitationAR: Aortic RegurgitationTR: Tricuspid Regurgitation*** Echo imaging was performed by the Pediatric Cardiologists several years prior to care transfer to the Adult Cardiology Services.
We note that of the 13 patients with any degree of mitral regurgitation (MR), 12 (92 %) had LVEF less than 55 %. Thus the presence of any degree of MR strongly correlates to LVSD in our study cohort. Absence of MR did not correlate well with presence or absence of LVSD, however.
CMR findings
Eight patients (25 %) underwent a diagnostic quality CMR. CMR Results are depicted in Table 4. The remainder were offered or attempted the scan but declined to attend or attended and were unable to have a diagnostic quality scan for the reasons given (Table 5).
Extensive midwall fibrosis was reported in 100 % of studies where IV contrast was administered (N = 7). Contrast evaluation was not performed in N = 1 due to difficulty obtaining IV access, however T1 mapping was suggestive of midwall fibrosis in this case also. Of those with confirmed fibrosis, 14 % (N = 1) exhibited normal LVEF.
The extent of fibrosis was reported in a semi-quantitative manner, with “significant” or “extensive” fibrosis reported in all 8 cases. Fig. 1 depicts a flowchart showing the number of patients who underwent CMR, as well as reasons not undertaken.Table 4Cardiac MR Parameters.LVEF (median)43 %Normal LVEF (N, %).1, 14 %Extensive midwall fibrosis (N, %)7, 100 %**Contrast not administered in N = 1Regional wall motion abnormality (N, %)4, 50 %Table 5Evaluation of Imaging Quality, Patient Reported & Environmental Barriers to Adequate Imaging.CMR (n = 33)Echo (n = 33)Completed Evaluation8/33 (24 %)33/33 (100 %)Non Diagnostic0(9 %)Suboptimal1 (13 %)(73 %)Patient Based Obstacles (N, %)**Unable to Lay Flat5 (15 %)0Fixed Hip Flexion Deformities7 (21 %)0“Could not Tolerate”4 (12 %)0Continuous Non Invasive Ventilation1 (3 %)0Chest Wall Deformities07 (21 %)Scoliosis02 (6 %)Additional common observationsDisruption of RoutineYesYesDiscomfortEnvironmental FactorsPatient Positioning / Immobility28 (85 %)IV Access for Gadolinium1 (3 %)0Additional common observationsTravel DifficultiesYesYesCost of TravelYesYesProposed systems failures responsible for obstacles citedLack of Additional HCA Support at Imaging Centre to Aid PositioningYesYesLack of Specific Training for Imaging Staff / Sonographers in Dealing with Individuals with DisabilitiesYesYesHCA: Health Care Assistant.**Note Patients experienced more than one obstacle to imaging.Fig.
1Flowchart depicting whether CMR done, or reason not done.
More than one obstacle was cited in most cases (Table 5). The primary reason for non-completion of CMR was recorded as “patient unable to lie flat” or “could not tolerate” due to contractures in all cases except for 1, where “poor IV access” was cited. One patient requiring continuous non-invasive ventilation when lying recumbent was unable to attempt scanning for this reason also.
Difficulties encountered with travel were an obstacle to further imaging described frequently by patients and caregivers in our study cohort, however these difficulties were not cited as the reason for failure to complete a scan in any case. Table 5 summarises all the reported patient-based and environmental obstacles to completion of imaging as well as reasons reported for suboptimal imaging.
Correlation of TTE with CMR findings
Despite the difficulties encountered with both imaging modalities, it is notable that our study found a high degree of correlation between TTE and CMR derived measurement of LV ejection fraction. We used the Bland-Altman plot to assess for clinically acceptable agreement between modalities rather than calculating a correlation coefficient, given the inherent limitations of correlation as a surrogate for agreement in statistical analysis, as well as the lack of any standardised acceptable limits for agreement in LVEF between modalities. We found that there was a high level of agreement between TTE and CMR, with a mean difference in reported LVEF between modalities of 1.625 % (95 % CI −9.0–––5.8).
Fig. 2 depicts the results recorded on the Bland-Altman plot.Fig. 2Bland-Altman Plot for agreement in EF between CMR and TTE.Fig.
3Box and whisker plot comparing range of TTE derived EF at enrolment and follow-up.
Outcomes
During follow-up, three patients died, two due to respiratory failure and one due to multiorgan failure. A total of three had admissions for respiratory failure and one for the evaluation of rapid weight loss and nausea. The list of medications and follow-up management are outlined in Table 1[12].
Two patients no longer attend our clinic. Betablockers, ACE inhibitors and aldosterone antagonists were well tolerated in most patients and were up-titrated to maximimally tolerated doses. Hypotension was the limiting factor.
Just over 60 % were taking an SGLT2i. Two patients were unable to tolerate the SGLT2i agents, others didn’t commence the SGLT2i due to other medications dose adjustments, or UTI’s or patient/family preferences. ARNIs were not prescribed.
Two patients underwent placement of an Implantable Cardioverter Defibrillator (ICD). No shocks for ventricular arrhythmias were delivered to date. One patient and family declined an ICD.
Ivabradine was used in addition to betablockers where additional betablockers doses were not well tolerated, but the heart rates were greater than 75–80 bpm.
Discussion
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 drugs [13], 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 classes [14], [15], [16]. 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 dysfunction [17]. The emergence of tissue Doppler and strain imaging, which correlate well with subsequent development of DMD HF [18], 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), transthoracic echocardiography (TTE) remains the most commonly used imaging modality in the investigation of cardiomyopathy and heart failure, and in their follow-up [19]. Although the comparatively low cost is likely to be the principal motivation behind its ongoing use in preference to other modalities [20], TTE continues to bear certain important advantages over CMR Imaging. The widespread availability of TTE makes it accessible to patients who are too unwell or clinically unstable to undergo other 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 CMR capability not feasible for patients. Moreover, the prevalence of fixed flexion 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. Hence due to poor quality imaging, strain analysis was not reliably available.
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 wall [21]. 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 [22]. 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 21 % of our study cohort) Table 5.
Additionally, 1 patient (3 %) 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 Health Care Assistant to provide support with positioning.
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 studies [23] 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 Assistants are required to aid with positioning may help to further optimize 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. Specialized 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 specialized 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, family and carers.
Although not cited as a reason for non-attendance for any diagnostic investigation by our cohort, the additional challenge of 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 same day 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 generalizability 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 visualized. 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 standardized 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 (Table 3).
Conclusion
We describe the characteristics of a cohort of young adults with Duchenne muscular dystrophy attending a “One-Stop” multidisciplinary clinic, their most prevalent ECG findings and their correlation with reduced LVEF. Our cohort demonstrates LV midwall fibrosis in all patients undergoing CMR, adding support to the hypothesis that cardiomyopathy has universal penetrance in this condition. We highlight the common practical barriers to treatment, such as medication intolerance, and to successful diagnostic imaging in adult patients with Duchenne Muscular Dystrophy cardiomyopathy.
While high rates of suboptimal TTE imaging were observed alongside high rates of failure to carry out CMR, there was good agreement between modalities when both were undertaken. The obstacles included muscular contraction deformity, inability to lie flat, reliance on respiratory and other support devices, and difficulty with positioning for TTE scanning. Transportation and logistic considerations were also cited as an additional challenge by patients and caregivers.
In some cases, we observed opportunities to enable patients to participate more fully in diagnostic imaging. Trained staff to aid with positioning during scanning and assistance with transportation were two key areas where we identified modifiable interactions between impairment and environment which could aid in facilitation of diagnostic imaging for patients. The use of multimodality imaging, namely TTE and CMR, not only contributes important prognostic data on the progression of this universally penetrant cardiomyopathy, but also offers two distinct prospects to obtain sufficient diagnostic data to guide management.
Therefore, we highlight the importance of offering multimodality imaging to patients with DMD, and promoting practical strategies to support patients in modifying and overcoming environmental challenges to diagnostic quality imaging.
Data availability statement
The data underlying this article will be shared on reasonable request to the corresponding author, in aggregate form in order to protect the privacy of the individual study participants.
There are no grants, contracts or other sources of funding associated with this research.
The authors takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
CRediT authorship contribution statement
Peter C. Murray: Writing – review & editing, Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Data curation. Ailis Pollock: .
Katie Hewitt: . Jenna O’Sullivan: . Aoife Sheahan: Data curation, Formal analysis, Investigation, Validation.
Richard Sheahan: Writing – review & editing, Validation, Supervision, Project administration, Formal analysis, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.