Cardiomyopathy in Becker muscular dystrophy

Article written and reviewed by Dr Luca Moretti

Becker muscular dystrophy is an X-linked dystrophinopathy caused by pathogenic variants in the DMD gene that, in most cases, allow production of at least partially functional dystrophin. Compared with Duchenne muscular dystrophy, the protein is not completely absent and the skeletal phenotype is, on average, later in onset and more variable. This distinction does not, however, make the heart relatively protected: dystrophin cardiomyopathy can be severe, progressive and sometimes disproportionate to muscle weakness.

The most characteristic cardiac phenotype is a non-ischemic cardiomyopathy that begins with regional fibrotic lesions, often inferolateral, and may progress to dilation, reduced systolic function and heart failure. Fibrosis can be detected by cardiac magnetic resonance before symptoms appear or ejection fraction is clearly reduced. The preclinical phase therefore represents a true therapeutic interval, not a period in which the myocardium is still unaffected.

Presentation is extremely heterogeneous. Some men preserve ambulation and independence into adulthood but develop dilated cardiomyopathy early; others have more evident muscle impairment and an initially stable heart. Heterozygous women may also develop fibrosis or heart failure in the absence of skeletal symptoms. Cardiomuscular dissociation prevents strength, CK or walking ability from being used as reliable surrogates of cardiac status.

Modern management requires comprehensive molecular diagnosis, serial imaging, timely cardioprotective treatment and independent assessment of arrhythmic risk. In patients with advanced disease, mild weakness and preserved respiratory function often make ventricular assist devices and transplantation feasible, provided assessment begins before multiorgan damage develops. A dedicated cardiology pathway must accompany the natural history of Becker muscular dystrophy rather than intervening only when edema or dyspnea appears.

DMD gene, residual dystrophin and phenotypic variability

The DMD gene, located at Xp21.2 and composed of 79 exons, produces several tissue-specific isoforms. Muscle dystrophin links the actin cytoskeleton to the dystrophin-glycoprotein complex of the sarcolemma and, through it, to the extracellular matrix. It is not merely a mechanical tether, because it organizes signaling proteins and contributes to membrane stability. Cytoskeleton-matrix continuity is particularly important in the cardiomyocyte, which is continuously subjected to tension and shortening.

The reading-frame rule explains much of the difference between Duchenne and Becker muscular dystrophy. Deletions that preserve the reading frame, defined as in-frame, generally allow synthesis of a shorter but present dystrophin; out-of-frame variants instead introduce premature termination and frequently result in almost complete absence of the protein. The in-frame rule is probabilistic, not absolute: variant location, splicing, transcript quantity and integrity of functional domains can produce clinically important exceptions.

The amount of residual dystrophin and the quality of the protein have different effects. A shortened molecule may localize to the sarcolemma but transmit force poorly, whereas a very low amount of relatively intact protein may not withstand the load of the adult heart. Missense variants, duplications, splicing abnormalities and complex rearrangements can also cause Becker muscular dystrophy. Residual protein function therefore cannot be inferred from the number of deleted exons alone.

Correlations between specific regions of DMD and cardiac risk have been described, but they do not allow deterministic prediction for an individual patient. Variants associated with a mild skeletal phenotype may leave the myocardium exposed for decades to a cumulative defect and lead to severe failure. Genetic modifiers, hemodynamic load, lifestyle and mosaicism contribute further. The genotype does not replace longitudinal surveillance with direct cardiac measurements.

Cardiomyocyte injury and fibrotic remodeling

When dystrophin is insufficient, the membrane becomes vulnerable to cyclical stress. Microinjury and altered mechanotransduction promote calcium influx, protease activation, oxidative stress and mitochondrial dysfunction; the cell progressively loses its ability to recover after each contraction. Sarcolemmal injury does not necessarily cause clinically overt myocarditis, but rather a chronic sequence of necrosis and incomplete repair.

Adult myocardium has far less regenerative capacity than skeletal muscle. Lost cardiomyocytes are replaced by extracellular matrix and adipose tissue, creating mechanically inefficient regions and slowing electrical conduction. Initially, preserved segments compensate by increasing their workload; as scar extends, wall stress and neurohormonal activation drive further remodeling. Fibro-adipose replacement links mechanical progression and arrhythmic vulnerability.

The initial inferolateral distribution is not fully explained. Regional differences in stress, perfusion, fiber orientation and sympathetic activity may make the subepicardium of the free wall more vulnerable. Injury then expands toward deeper layers and contiguous segments, eventually involving the left ventricle diffusely; the right ventricle may also dilate or lose function. The regional pattern is recognizable but not exclusive to dystrophinopathies.

Activation of the renin-angiotensin-aldosterone and adrenergic systems temporarily supports blood pressure and cardiac output but increases oxygen consumption, fibrogenesis and arrhythmias. Functional dilation of the valve annuli causes mitral or tricuspid regurgitation, while elevated filling pressures impair the lungs, kidneys and liver. Secondary remodeling becomes partially treatable even though the primary dystrophin defect persists.

Cardiomuscular dissociation and natural history

Weakness in Becker muscular dystrophy may begin in childhood, adolescence or adulthood, with proximal involvement, calf hypertrophy and elevated CK. The heart, however, follows its own trajectory: subclinical cardiomyopathy can be documented in young people who are still fully ambulatory, and the incidence of abnormalities increases with age. Independent progression requires a cardiology baseline at diagnosis regardless of muscle function.

In some men, dyspnea, an arrhythmia or dilated cardiomyopathy is the first manifestation that leads to DMD investigation. Persistently elevated CK, cramps, prominent calves or mild difficulty rising may only be recognized after the cardiac event. The picture approaches X-linked dilated cardiomyopathy and demonstrates that a heart-dominant presentation belongs to the dystrophinopathy spectrum.

Ejection fraction may remain preserved while CMR shows scar and strain worsens. Increased volumes, thinning of the lateral wall, regional hypokinesia and global systolic decline subsequently appear. Failure may progress slowly for years or accelerate after infections, arrhythmias, procedures or loss of neurohormonal compensation. The individual trajectory is more informative than the mean age derived from heterogeneous cohorts.

Reduced activity due to myopathy often masks cardiac exercise intolerance. A patient who walks little may never reach the workload required to develop an anginal equivalent or dyspnea, while edema, orthopnea and fatigue are attributed to muscle disease. Paucity of symptoms is not reassuring and makes serial objective measurements essential.

Clinical manifestations, electrocardiogram and arrhythmias

Heart-failure manifestations include new fatigue, reduced independence relative to the patient's own level, dyspnea, orthopnea, weight gain and peripheral congestion. In the low-output phase, cold extremities, hypotension, hyponatremia and renal deterioration may occur. Respiratory and cardiac signs overlap, so natriuretic peptides, imaging and ventilatory assessment must be interpreted together. Change from baseline matters more than comparison with a person without disability.

ECG may show relatively tall R waves in the right precordial leads, deep Q waves in lateral leads, repolarization abnormalities, sinus tachycardia or intraventricular conduction abnormalities. No finding confirms the diagnosis, and a minimally abnormal ECG does not exclude fibrosis. Progressive QRS widening may reflect remodeling and, with systolic dysfunction, create a potential substrate for resynchronization. Serial ECG interpretation is more useful than searching for a pathognomonic signature.

Ventricular ectopy, nonsustained ventricular tachycardia and, in advanced stages, sustained tachycardia arise on the scar substrate. Atrial fibrillation or flutter may accompany atrial dilation and elevated pressures. Syncope, presyncope or prolonged palpitations require immediate monitoring, because attributing them to weakness or dehydration may delay diagnosis. Arrhythmic risk increases with fibrosis and dysfunction but is not completely represented by ejection fraction alone.

Advanced sinus-node and atrioventricular conduction disease is less characteristic than in laminopathies or Emery-Dreifuss muscular dystrophy, although it may occur. This difference guides diagnosis when early bradycardia dominates the presentation. There is no validated Becker-specific calculator integrating LGE, ectopy and genotype. Personalized stratification uses general criteria, consensus on neuromuscular diseases and the documented course in the individual case.

Echocardiography and cardiac magnetic resonance

Echocardiography remains the most accessible method for measuring dimensions, biventricular function, pressures, valves and treatment response. Acoustic windows are often better in Becker muscular dystrophy than in non-ambulatory stages of Duchenne, but scoliosis, obesity or chest-wall deformity may still limit them. Ejection fraction should be accompanied by volumes, right ventricular function and regurgitation assessment. Longitudinal strain may reveal dysfunction before conventional systolic decline.

Cardiac magnetic resonance provides reproducible measurements independent of acoustic windows and characterizes tissue. Late gadolinium enhancement identifies replacement fibrosis, often subepicardial or midwall in the basal inferolateral wall, with progressive anterior, apical and transmural extension in advanced stages. Fibrosis on CMR may precede dilation and symptoms, changing the threshold for starting or intensifying treatment.

LGE indicates a focal increase in extracellular space but does not measure all diffuse injury. Native T1 mapping and extracellular volume may identify less confluent abnormalities; T2 may help assess edema or active injury, although values and reproducibility depend on sequence and center. Multiparametric characterization is more informative when repeated with comparable protocols and interpreted together with function.

Avoiding gadolinium may be necessary in advanced renal failure or when contrast is inappropriate. Cine CMR, strain and native mapping retain value, but an examination without LGE is not fully equivalent for scar quantification. Sedation is rarely necessary in adults with Becker muscular dystrophy, whereas claustrophobia, devices and ability to remain supine require preparation. Protocol selection should answer the clinical decision rather than become an automatic sequence.

Coronary artery disease can coexist with dystrophinopathy, especially in adults with risk factors. Subendocardial enhancement in a vascular territory, a new regional abnormality or compatible pain requires ischemic evaluation rather than automatic attribution to Becker muscular dystrophy. Myocarditis, sarcoidosis and other cardiomyopathies can produce similar non-ischemic LGE. A suggestive pattern strengthens a molecular diagnosis but does not eliminate differential reasoning.

Molecular diagnosis and differential diagnosis

Diagnosis is based on the phenotype and identification of a pathogenic or likely pathogenic DMD variant. Because deletions and duplications of one or more exons are common, copy-number analysis should be combined with sequencing of exons and splice junctions; RNA analysis, long-read sequencing or other methods may resolve deep variants and complex rearrangements. Complete molecular characterization is also required for family counseling and potential eligibility for targeted studies.

A variant of uncertain significance does not confirm Becker muscular dystrophy and should not be used for predictive testing. Segregation, reading-frame effect, transcripts, and dystrophin distribution and quantity may provide additional evidence. Muscle biopsy with immunohistochemistry and Western blot retains a role when genetics does not explain a convincing phenotype, but is not required in every resolved case. Variant classification should be updated as new evidence emerges.

X-linked dilated cardiomyopathy due to DMD may present with minimal or absent skeletal involvement. Tissue-specific promoter and splicing abnormalities may relatively preserve muscle while impairing the heart; in other families, very mild Becker muscular dystrophy is recognized only after targeted examination. Men with early DCM, elevated CK or transmission through women should be tested for DMD. The X-linked continuum is clinically more useful than rigid boundaries between labels.

Laminopathies, desminopathies, sarcoglycanopathies, LMNA-related disease and other neuromuscular cardiomyopathies enter the differential diagnosis. Early atrioventricular block and contractures suggest Emery-Dreifuss muscular dystrophy; myotonia and cataracts suggest myotonic dystrophy; neuropathy or metabolic abnormalities suggest other genes. In common DCM, moderately elevated CK may also result from exercise or non-genetic muscle injury. Multisystem phenotyping selects the correct test without overinterpreting a single biomarker.

Distinguishing Becker from Duchenne muscular dystrophy cannot rely solely on age at assessment. Prolonged ambulation, present dystrophin and a compatible variant favor Becker, whereas early functional loss and nearly absent protein favor Duchenne; intermediate phenotypes exist. Cardiac involvement in both shares lateral-wall fibrosis, but in Becker the heart may become the dominant problem precisely because skeletal muscle retains greater independence. Becker specificity lies in the relationship between residual protein and organ dissociation.

Cardiology surveillance and risk assessment

At diagnosis, family history, physical examination, blood pressure, ECG, echocardiography and rhythm assessment are indicated, supplemented by CMR when feasible. A normal examination does not end surveillance because cardiac penetrance increases with age. In young people without abnormalities, follow-up is generally repeated every one or two years; in adolescents, adults or those with fibrosis and dysfunction, it is often annual or more frequent. Follow-up frequency follows risk and rate of change.

Comparison should use volumes, ejection fraction, strain, right ventricular function, amount and distribution of LGE, ECG and arrhythmic burden. Natriuretic peptides may remain relatively low early, while troponin may rise episodically; neither replaces imaging. Weight, creatinine, potassium and blood pressure are also needed to titrate drugs. A multidimensional baseline helps distinguish measurement variability from true progression.

Periodic Holter monitoring is particularly useful with fibrosis, dysfunction, palpitations or syncope. Duration is chosen according to symptom frequency, moving from 24-48 hours to prolonged patches or loop recorders when events are rare but important. Isolated ectopy does not automatically indicate an ICD, whereas sustained tachycardia requires urgent assessment. Proportionate monitoring seeks arrhythmias capable of changing treatment.

Cardiopulmonary exercise testing or submaximal assessments describe reserve, but the result combines cardiac and muscle limitations. Low oxygen consumption cannot automatically be attributed to pump failure; blood-pressure response, oxygen pulse, ventilation and comparison with neuromuscular capacity aid interpretation. Right-heart catheterization is reserved for discordant data, advanced heart failure or transplant evaluation. Integrated physiology avoids penalizing the patient for a known peripheral limitation.

Drug treatment and timing of initiation

Treatment aims to slow remodeling and fibrosis before cardiomyocyte loss becomes irreversible. An ACE inhibitor or ARB is started when reduced function, dilation, abnormal strain or fibrosis appears; Becker-specific observational data indicate better outcomes when ACE inhibition begins already with ejection fraction below 50%, rather than waiting for values below 40%. Early treatment is consistent with the preclinical nature of the injury.

When heart failure with reduced ejection fraction is present, a beta-blocker, mineralocorticoid receptor antagonist and SGLT2 inhibitor are considered according to guidelines, with titration based on blood pressure, heart rate, renal function and potassium. Sacubitril/valsartan may replace conventional renin-angiotensin system blockade in appropriate patients. Direct evidence in Becker muscular dystrophy is limited, so phenotype-guided therapy applies general evidence without pretending that nonexistent disease-specific validation exists.

Fibrosis on CMR with preserved ejection fraction poses a subtler decision. The rationale for early renin-angiotensin system blockade is strong and many specialist pathways intervene, but there are no large randomized trials exclusively in Becker muscular dystrophy defining every threshold. A mineralocorticoid receptor antagonist may be discussed when early signs of injury are present, cautiously extrapolating data from dystrophinopathies. Transparency of evidence distinguishes reasonable practice from experimental certainty.

Diuretics treat congestion and improve symptoms but do not replace anti-remodeling therapy. Digoxin has limited indications and requires attention to renal function and arrhythmias; anticoagulation follows atrial fibrillation, intracardiac thrombus or thromboembolic risk, not the genetic diagnosis alone. Drugs should be reviewed during infections, fasting or dehydration. Volume management avoids both congestion and hypotension that prevents titration.

Corticosteroids may modify skeletal muscle function in some dystrophinopathies, but regimens and evidence are not interchangeable between Duchenne and Becker muscular dystrophy; their specific cardiac impact in Becker does not justify automatic prescription. Molecular therapies developed for particular Duchenne variants should not be transferred without an indication and data. Cardiac care remains necessary even when neuromuscular therapy improves strength or CK.

Devices, advanced heart failure and transplantation

An ICD is indicated for secondary prevention after ventricular fibrillation or hemodynamically significant sustained ventricular tachycardia in the absence of a reversible cause, and is assessed for primary prevention according to function, symptoms and general criteria. Extensive fibrosis, syncope and nonsustained tachycardia increase concern but do not individually constitute a universally validated Becker threshold. The defibrillator decision balances arrhythmic risk, functional outlook, complications and informed preferences.

Cardiac resynchronization is considered with systolic dysfunction, a wide QRS and appropriate morphology according to standard criteria. Lateral scar may reduce response and guide lead placement, while a transvenous system may be complex in patients with difficult venous access. A subcutaneous ICD avoids the circulation but provides neither pacing nor resynchronization. Device selection should anticipate foreseeable evolution without implanting unnecessary functions.

Advanced heart failure requires early referral to an experienced center. Repeated admissions, medication intolerance, worsening renal function, hypotension, arrhythmias and functional decline are more meaningful signals than a single ejection fraction. Assessment includes hemodynamics, nutrition, strength, swallowing, respiratory function, rehabilitation capacity and family support. The advanced-therapy window may close if one waits for shock or multiorgan failure.

Heart transplantation is not contraindicated by the diagnosis of Becker muscular dystrophy. Many candidates have moderate weakness, adequate ventilation and prospects for postoperative recovery; transplant series in muscular dystrophies show selected survival comparable with controls. Immunosuppression, infections and steroids may, however, worsen frailty and require dedicated rehabilitation. Individual selection replaces exclusion based on the disease name.

An LVAD may be used as a bridge to transplantation or, in selected cases, as destination therapy. Right ventricular function, chest dimensions, ability to manage the device, infection risk and upper-limb strength influence outcomes; experience in patients with Becker muscular dystrophy demonstrates feasibility but remains numerically limited. Mechanical support requires a multidisciplinary plan broader than anatomic suitability for implantation.

Heterozygous women, family and reproduction

Women with a pathogenic DMD variant are not simply unaffected carriers. X-chromosome inactivation creates a mosaic of cardiomyocytes expressing the normal or mutant allele; when the distribution is unfavorable, fibrosis, dilation and arrhythmias develop even without weakness. Female dystrophinopathy may be exclusively cardiac and present in adulthood.

ECG, echocardiography and CMR are indicated after genetic identification, with periodic reassessment if baseline is normal and more frequent follow-up when LGE or functional abnormalities are present. Normal CK does not exclude involvement and the absence of muscle symptoms does not reduce the need for screening. In a woman with fibrosis, anti-remodeling treatment is assessed as in men, taking pregnancy and contraception into account. Surveillance of women prevents late diagnosis of apparently idiopathic DCM.

An affected man transmits the variant to all daughters and to no sons; a heterozygous woman has a 50% probability of transmitting it in each pregnancy. Cascade testing should target the familial variant and be accompanied by counseling that explains the broad variability, including intermediate and heart-dominant phenotypes. Family segregation identifies people at risk and may clarify variants that were initially uncertain.

Before pregnancy, ventricular function, fibrosis, arrhythmias and treatment are assessed. ACE inhibitors, ARBs, angiotensin receptor-neprilysin inhibitors and mineralocorticoid receptor antagonists require review because of fetal risk; increased blood volume and the postpartum period may destabilize cardiomyopathy. Prenatal and preimplantation diagnosis are options to discuss without coercion. Cardiogenetic planning separates maternal risk from transmission of the variant.

Exercise, respiratory function and anesthesia

Complete inactivity accelerates deconditioning, osteopenia and loss of independence, whereas intense eccentric exercise and overload to exhaustion may increase muscle injury. Submaximal aerobic activity and light strengthening are individualized with the neurologist, physiatrist and cardiologist, avoiding competitive exertion when dysfunction, arrhythmias or extensive fibrosis are present. Exercise prescription seeks participation without turning fragile muscle into a target for aggressive training.

Respiratory function is often better preserved and declines later than in Duchenne muscular dystrophy, but should not be presumed normal. Sitting and supine spirometry, inspiratory strength, cough and nocturnal symptoms identify diaphragmatic weakness or hypoventilation; scoliosis, obesity and obstructive sleep apnea may add to the burden. Ventilatory reserve affects symptoms, beta-blocker safety, candidacy for procedures and recovery after transplantation.

Before anesthesia, ejection fraction, rhythm, devices, volume status, respiratory capacity and mobility difficulties are documented. Succinylcholine should be avoided because of the risk of rhabdomyolysis and hyperkalemia; volatile anesthetics may be associated with anesthesia-induced rhabdomyolysis in dystrophinopathies, and many teams prefer intravenous techniques, especially for major procedures. Anesthetic planning should be individualized and available before the day of surgery.

The anesthetic reaction of dystrophinopathy is not equivalent to classic genetic susceptibility to malignant hyperthermia, an important distinction that avoids imprecise terminology and protocols. Hyperkalemia, muscle injury, myocardial depression, hypoventilation and aspiration nevertheless remain real risks. Analgesia, respiratory physiotherapy and noninvasive ventilation may reduce postoperative complications. Perioperative safety results from coordinated control of heart, muscle and breathing.

Prognosis and organization of care

Cardiomyopathy is one of the leading causes of death in Becker muscular dystrophy and may determine prognosis more than weakness. Age, extent of fibrosis, biventricular function, arrhythmias, treatment tolerance and rate of decline contribute to risk; none alone permits exact prediction. Dynamic prognosis is updated after each structural, electrical or functional change.

Early diagnosis concretely changes the course because it permits treatment before dilation, family screening and planning of advanced therapies. Conversely, waiting for symptoms risks discovering disease when scar, right-sided failure or organ damage limits options. The advantage of surveillance lies in recognizing a treatable trend, not merely producing repeated normal tests.

The referral center coordinates cardiology, neurology, genetics, pulmonology, rehabilitation, anesthesia and transition medicine. Transfer from pediatric to adult care should carry the variant, original images, functional curves, medications and emergency plan, avoiding a new baseline that loses prior history. Longitudinal continuity is particularly important in a disease that may accelerate after years of apparent stability.

Every patient should know the warning signs that require earlier reassessment: syncope, persistent palpitations, new dyspnea, orthopnea, edema, rapid weight gain or unexplained loss of independence. Decisions about ICD, LVAD and transplantation should be shared in time, including personal goals and caregiving burden. Anticipatory care combines scientific rigor and practical planning, preserving autonomy without minimizing cardiac risk.

Research is refining mapping, biomarkers and genotype-phenotype correlations, but does not justify replacing follow-up with a molecular prediction. Any future therapies capable of increasing or correcting dystrophin will also have to demonstrate effective cardiac distribution and benefit on long-term events. Measurement of cardiac benefit requires function, fibrosis, rhythm, hospitalizations and survival, not skeletal muscle response alone.