Results
Cardiac involvement in DMD
The heart is ‘abnormal from the start’ in boys with DMD.12 The main manifestation of cardiac involvement in DMD is left ventricular (LV) systolic dysfunction. As part of early discussions, parents/carers should be made aware that progressive heart muscle weakness is part of the natural history of DMD.13 This is to help them understand why baseline heart checks are advisable soon after diagnosis followed by a schedule of regular checks thereafter. It also prepares them for discussions about the use of prophylactic heart medication from an early age in order to realise their established benefits.
The multidisciplinary dystrophinopathy care team should include, as an integral member, a cardiologist who has expertise in inherited neuromuscular disorders and in heart failure management. He or she should oversee the cardiac management of patients with dystrophinopathy.12 Although remote oversight of cardiac test results, performed to schedule, in younger boys reduces the need to attend a separate cardiology clinic, it is preferable for boys and their families to be familiar with ‘their cardiologist’ well ahead of the time when heart medications are recommended. Families who were consulted through a UK survey and within DMD Care UK’s focus groups reported that they would welcome early, direct contact with the cardiac team to enable them to better understand the cardiac implications of DMD and to have the opportunity to discuss timely introduction of heart therapies. A multidisciplinary outpatient clinic, in which several different specialty assessments can take place on the same day, is probably the ideal arrangement for follow-up, but one that has not been implemented in the UK to date.12
Females with DMD-gene mutations should also be made aware of their risk of developing cardiomyopathy and offered a baseline cardiac assessment at the time of their genetic diagnosis and subsequent ongoing cardiac review.4
Heart surveillance in dystrophinopathy
LV dysfunction is an inevitable consequence of DMD.13 So, it is not a question of whether a patient with DMD will benefit from cardioactive medications but rather one of when they are best deployed in a particular patient. Cardiac symptoms only occur late in the involvement of the heart in DMD and so are a very poor guide to the state of cardiac function, which can only be determined by objective testing.9
A 12-lead ECG should be performed serially to detect inappropriate sinus tachycardia, arrhythmias or atrioventricular block.14 Cardiomyopathy in DMD initially develops with segmental dysfunction affecting inferobasal or basolateral LV regions. So, the earliest changes will not necessarily be detected by semi-qualitative assessments or by measures of LV-fractional shortening alone. Therefore, from as soon as convenient after diagnosis, echo examinations should include both measures of global (ie LV chamber dimensions; fractional shortening, ejection fraction and assess radial and longitudinal function) and regional LV function. The sensitivity of these assessments is further increased by including tissue Doppler measures of LV lateral wall longitudinal function and, if obtainable reliably, global LV-‘strain’ by speckle-tracking.12 15 16 The detection of LV dysfunction should trigger the cascade of cardiac medications summarised in figure 1, acknowledging that some treatments may already have been initiated prophylactically based empirically on age alone. It is now also recognised that the finding of LV dysfunction by echo and tissue-Doppler is a relatively late indicator of cardiac involvement in dystrophinopathy. By the time dysfunction is evident, destructive processes have long been underway in the myocardium.12
Cardiac MRI is an even more sensitive imaging modality which provides detailed structural and functional information about the heart. It is particularly useful in clarifying equivocal findings and in those in whom reliable echo measures cannot be obtained. Furthermore, its ability to provide tissue characterisation allows detection of heart involvement before it has resulted in LV dysfunction.12 15 16 Late-gadolinium enhanced imaging sequences allow detection of diffuse or focal myocardial fibrosis, which generally precedes the development of LV dysfunction. The pattern of sub-epicardial fibrosis seen in dystrophinopathy helps distinguish it from other patterns of unknown significance sometimes seen in scans of healthy young adults.17 Although more sensitive than echo in detecting early abnormalities, cMRI is absolutely contraindicated in some patients (eg. presence of MRI-incompatible metal implants) and may require general anaesthesia or sedation to reduce motion artefacts (eg, in children below age 6 years or in adolescents with learning difficulties or contractures). Some patients do not tolerate the confined space of the MR-scanner (eg. steroid-related obesity or claustrophobia). In practice, the use of sedation or general anaesthesia for cMRI in younger children is rarely justified unless the results are thought likely to change clinical management.
There are also safety concerns about patients having serial cMRIs which include administration of a gadolinium contrast agent (ie nephrogenic systemic fibrosis, potential neuro-toxicity). Therefore, if cMRIs are performed serially, some will not include assessment of myocardial fibrosis to minimise the risk of these adverse effects.18 19
The cardiac biomarker, N-terminal pro-brain natriuretic peptide (pro-BNP) is not sensitive enough to guide early treatment of cardiac dystrophinopathy because measures only become abnormally elevated when LV dysfunction is well advanced.20 However, it may have a role in helping distinguish heart failure from respiratory insufficiency and assessing response to therapy at more advanced stages of cardiomyopathy. In the future, it may become possible to use serial measures of highly sensitive DMD-specific biomarkers in peripheral blood to guide cardiac management throughout the course of DMD.21
Contemporary echo and/or cMRI allow detection of cardiac abnormalities at an earlier stage and at a younger age than was possible for the previous generation of patients. Today’s patients have the potential to benefit from more sensitive heart assessments through the earlier introduction and escalation of drugs aimed at preserving LV function for as long as possible.
Justification for heart imaging in more advanced cardiomyopathy
The justification for performing regular cardiac tests after the initiation of therapies to preserve LV function is sometimes questioned, since this is not routine practice, for patients with idiopathic forms of cardiomyopathy (IDCM), for example. However, the course of these two conditions differs in several key respects. Unlike in IDCM, the multisystem implications of DMD and particularly the severity of immobility, mean that cardiac symptoms occur very late in the course of LV dysfunction, providing no guide for either patient or cardiologist about the progression of cardiomyopathy or its response to treatment. Objective testing is, therefore, needed to help optimise therapy and dosing and to provide feedback to patients regarding the function of their heart. Crucially, the cardiomyopathy of DMD is progressive, meaning that serial testing is required to assess for other changes that only occur later in the course of the condition. Imaging then is to detect atrial dilatation as a forerunner to possible atrial arrhythmias, right ventricular dysfunction and the presence of LV dyssynchrony or thrombus; standard and Holter-ECGs to screen for tachy-arrhythmias or brady-arrhythmias of prognostic importance.
Rationale for introducing heart medications
Despite the increased sensitivity of cardiac imaging techniques in detecting cardiac involvement in recent years, recognition of the way in which dystrophin-deficiency affects the myocardium ‘from the beginning’12 is justification for recommending empiric use of an ACEi therapy prophylactically no later than age 10 years to preserve cardiac function.9 Recognition of the progressive nature of cardiac dystrophinopathy means that the finding of myocardial fibrosis on cMRI, if the test is performed, confirms that LV dysfunction will shortly follow, even if not already detectable. This justifies addition of a mineralocorticoid receptor antagonist (MRA) to inhibit the myocardial scarring process. Confirmation of LV dysfunction should prompt further escalation to maximum tolerated doses and addition of any medications not already deployed.
It is common for boys with DMD to develop a resting sinus tachycardia with faster rates observed at serial attendances (eg, 100–130 bts/min)— sometimes even before there is echoevidence of LV dysfunction. A persistently fast heart rate acts as an additional cardiac stressor accelerating decline in function. Although evidence for the use of rate slowing medications such as a beta-blocker or ivabradine prophylactically is lacking, slowing the heart rate in the context of persistent tachycardia is desirable and coherent with established recommendations for optimising heart rate in patients at more advanced stages of cardiomyopathy in other contexts.22–24
Figure 1 summarises current best practice recommendations in the cardiac care of paediatric patients with cardiac dystrophinopathy, including the need for observations and checks of renal function and biochemistry.9–68 The three-drug combination outlined may have to be reduced or suspended temporarily during serious illness such as sepsis, but it should be restarted during convalescence.
It is rare for children with cardiac dystrophinopathy to have developed advanced LV dysfunction (eg. LV ejection fraction <40%) but it can occur— particularly in those with very large deletions and early onset of cardiomyopathy or following a super-added episode of viral myocarditis. Although typically only relevant for older patients with DMD, figure 2 has been included to summarise drug and device options that can be considered for patients at any age with advanced LV dysfunction.9 11 12 54 56–63 65 67 68
Figure 2Management options for advanced cardiac dystrophinopathy at any age ACE. ACEi, ACE inhibitor; ARB, angiotensin II receptor blocker; AV, atrioventricular; BB, beta-blocker; BP, blood pressure; CRT, cardiac resynchronisation pacing device (P)±defibrillator capability (D); DDD, dual chamber pacemaker; DMD, Duchenne muscular dystrophy; DOAC, direct oral anticoagulant; DVT, deep venous thrombosis; EF%, (left ventricular) ejection fraction; HF, heart failure; Holter (ECG), continuous ECG recording; ICD, implantable cardioverter-defibrillator; LBBB, left bundle branch block; LV, left ventricular; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Failure Classification; PE, pulmonary embolism; QoL, quality of life; SGLT2-inhibitor, sodium-glucose co-transporter-2 inhibitor.
Female carriers of DMD-gene variants
Care arrangements for females carrying a variant in the DMD-gene are even less well established and more variable around the UK than for boys with DMD. Although the majority experience neither signs nor symptoms at any stage, some develop progressive skeletal myopathy or cardiomyopathy or have cognitive impairment.4 69 70 Because of the diversity in clinical effects, it seems timely to discard the older terminology of ‘DMD/BMD carrier’ to describe these girls/women and replace it with a more accurate term, ‘dystrophinopathy carrier’. Furthermore, even the term ‘carrier’ seems inadequate to describe those with clinical signs or symptoms. It is preferable, therefore, to limit the use ‘carrier’ to describing those without clinical effects (ie. no skeletal or cardiac signs or symptoms on testing, no cognitive effects and normal creatine kinase levels).69 Those with signs or symptoms should be considered to have a dystrophinopathy and managed accordingly as for affected males.
Even in the absence of skeletal muscle manifestations, females with DMD-gene variations have an estimated 7.3%–16.7% lifetime risk of developing cardiomyopathy, from which symptoms typically only occur when LV dysfunction is well advanced.69 70 Detecting cardiomyopathy requires surveillance, using the same heart imaging techniques as outlined for males with DMD. A baseline cardiac assessment, comprising 12-lead ECG and echocardiography, should be undertaken once carrier status is confirmed genetically. Assessments should follow a standard echo-imaging protocol, to provide measures of global and regional LV function that allow for serial comparisons— similar to that outlined above for boys with DMD. Results of this initial assessment provide the basis for decision-making and future comparisons. If initial results are reassuring, repeat testing can usually be undertaken at 3 yearly intervals, modifying the schedule if needed in discussion with families/patients for the very young and elderly. Equivocal findings on echo require repeat testing after a shorter interval or cMRI to clarify uncertainties. As for males with DMD, the finding of clinically significant myocardial fibrosis on cMRI or any degree of regional or global LV dysfunction on echo or cMRI justifies the same schedule of cardiac medications as outlined for males with cardiac dystrophinopathy. The finding of myocardial fibrosis in the typical DMD distribution indicates that LV dysfunction will follow, even if not already present. Management of cardiac involvement in females with cardiac dystrophinopathy comprises introducing an ACEi or ARB, up-titrating to the maximum tolerated dose and adding an MRA for its additional anti-fibrosis benefits. Females with cardiac dystrophinopathy seldom develop the resting sinus tachycardia seen in boys with DMD during early cardiomyopathy and so rate slowing medications (ie, beta-blocker or ivabradine) are less often indicated initially. The overarching aim of therapy is to prevent progressive loss of cardiac function. For women of childbearing age who may become pregnant or who are planning pregnancy, the cardiac drug regimen will need to be modified.71 72 Figure 2 outlines additional drug and/or non-pharmacological options that may be considered in the management of those with advanced cardiac dystrophinopathy.
Box 1Self-assessment minimum cardiac care standards audit for boys with Duchenne muscular dystrophy (DMD)
Does a dedicated cardiologist supervise the cardiac care of boys with DMD?
What evidence can you provide to show that parents/carers have been made aware that cardiomyopathy is almost invariably part of DMD?
What percentage of boys with DMD had their first echo assessment before their 6th birthday?
What percentage of boys with DMD undergo echo and ECG annually from age 10 years?
What percentage of boys under follow-up have been prescribed an ACE-inhibitor or angiotensin-receptor blocker by age 10 years?
What percentage of boys with left ventricular dysfunction are on ‘triple-therapy’ (ie, ACE inhibitor (ACEi)+beta-blocker (BB)+mineralocorticoid receptor antagonist (MRA)-blocker)?
What was your ‘child not brought to appointment’ rate for boys >10 years last year?
Self-assessment cardiac-care standards audit for females with DMD-gene variations
What was your ‘failure to reattend for scheduled cardiac review’ rate for females aged 30–60 years with DMD-gene variations in the last 12 months?
What percentage of females with confirmed cardiac dystrophinopathy are taking combination cardiac medications (ie, ACEi+MRA; ACEi+BB or similar)?