Neuromuscular Disease-associated Cardiomyopathy

Neuromuscular disease associated cardiomyopathy is myocardial and conduction system disease that accompanies inherited myopathies and neuropathies, most often Duchenne and Becker muscular dystrophy, myotonic dystrophy type 1, Emery-Dreifuss muscular dystrophy and LMNA disease, limb girdle muscular dystrophies, Friedreich ataxia, Pompe disease and mitochondrial disease.

Cardiac involvement is nearly universal in Duchenne muscular dystrophy by the late teens, and is present in over half of people with myotonic dystrophy type 1 as conduction disease and arrhythmia. Cardiac disease is now a leading cause of death as respiratory care improves.

Pattern differs by disease: dilated cardiomyopathy with inferolateral fibrosis (Duchenne and Becker, sarcoglycanopathies), conduction block with atrial and ventricular arrhythmia (myotonic dystrophy, Emery-Dreifuss, LMNA), hypertrophic cardiomyopathy (Friedreich ataxia, Pompe), and mixed phenotypes in mitochondrial disease.

Cardiac symptoms are often masked by limited mobility, so surveillance is needed rather than symptom driven review.

Pathophysiology.

Absence of dystrophin (Duchenne) destabilises the sarcolemma, causing repeated myocyte injury, calcium overload and replacement fibrosis that starts in the basal inferolateral left ventricular wall.

Myotonic dystrophy involves toxic CTG repeat RNA that disrupts splicing of cardiac ion channel and conduction genes, producing infranodal conduction disease and re-entrant arrhythmia. LMNA and Emery-Dreifuss variants disrupt the nuclear envelope, with atrial standstill, atrioventricular block and malignant ventricular arrhythmia.

Respiratory failure, hypoxia and hypercapnia, and corticosteroid effects add to myocardial stress.

Often asymptomatic until late. Presentation includes dyspnoea, fatigue, palpitations, syncope and heart failure. Skeletal muscle signs depend on the disease: proximal weakness and calf pseudohypertrophy (Duchenne), myotonia, frontal balding and cataracts (myotonic dystrophy), contractures and rigid spine (Emery-Dreifuss), ataxia and scoliosis (Friedreich).

• ECG and ambulatory ECG at diagnosis and at least yearly: tall right precordial R waves and deep Q waves in the lateral leads (Duchenne), PR and QRS prolongation and atrioventricular block (myotonic dystrophy), sinus node dysfunction and atrial standstill (Emery-Dreifuss).
• Echocardiography and cardiac MRI with late gadolinium enhancement: MRI is preferred in Duchenne because windows are often poor, and detects fibrosis before ejection fraction falls.
• NT-proBNP and troponin (troponin can rise from skeletal muscle in some myopathies).
• Genetic testing to confirm the disease and stratify risk.
• Respiratory assessment: forced vital capacity, overnight oximetry or capnography.
• Electrophysiology study in myotonic dystrophy with unexplained syncope.

Differential diagnosis.

• Idiopathic dilated cardiomyopathy and other genetic cardiomyopathy (arrhythmogenic, desmin, filaminopathy).
• Myocarditis and sarcoidosis.
• Respiratory related right heart disease and pulmonary hypertension.
• Corticosteroid or drug related cardiac effects.

Duchenne and Becker muscular dystrophy.

• Start an ACE inhibitor or ARB by about age 10 years, or at diagnosis of fibrosis, before ventricular dysfunction. Enalapril: 0.1 mg/kg daily in 1 to 2 doses in children, titrated to a maximum 0.5 mg/kg daily (maximum 20 mg daily).
• Adults: ramipril 2.5 mg daily titrated to 10 mg daily or perindopril 2 to 8 mg daily. Monitor blood pressure, potassium and creatinine at 1 to 2 weeks.
• Add a mineralocorticoid antagonist: eplerenone 25 mg daily, increased to 50 mg daily (maximum 50 mg) after 4 weeks if potassium under 5.0 mmol/L; or spironolactone 12.5 to 50 mg daily.
• Check potassium at 1 week and 4 weeks; avoid if eGFR under 30 mL/min/1.73 m2.
• Add a beta blocker (carvedilol 3.125 mg twice daily titrated to 25 mg twice daily; or bisoprolol 1.25 mg titrated to 10 mg daily) for ventricular dysfunction or resting tachycardia; reduce bisoprolol in eGFR under 20 and severe hepatic impairment.
• Glucocorticoids (deflazacort 0.9 mg/kg daily or prednisolone 0.75 mg/kg daily) delay cardiomyopathy and preserve function; monitor bone health, growth, blood pressure and glucose.
• Heart failure: usual drugs with furosemide 20 to 40 mg daily for congestion; sacubitril/valsartan in adults at 24/26 mg twice daily titrated to 97/103 mg twice daily (maximum).
• Advanced disease: ICD for ejection fraction 35% or under or arrhythmia; ventricular assist device or transplantation in selected patients.
• Avoid depolarising muscle relaxants (suxamethonium) and volatile anaesthetics, which cause rhabdomyolysis, hyperkalaemia and cardiac arrest.

Myotonic dystrophy type 1.

• Annual ECG. Permanent pacing for PR over 240 ms, QRS over 120 ms, or second or third degree atrioventricular block; an ICD-capable device is favoured given the risk of ventricular arrhythmia, especially with ejection fraction under 50%.
• Anticoagulation for atrial fibrillation or flutter regardless of CHA2DS2-VASc score: apixaban 5 mg twice daily (2.5 mg twice daily if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over).
• Avoid class I sodium channel blockers (flecainide, disopyramide, quinidine) and use caution with mexiletine for myotonia (ECG before and after starting, usual dose 150 mg twice daily increased to 200 mg three times daily; avoid with second or third degree block unpaced).
• Anaesthetic and respiratory sedation risk is high.

Emery-Dreifuss and LMNA disease. Early ICD with pacing capability because sudden death occurs despite pacing. Anticoagulate atrial fibrillation or standstill. Treat heart failure with:

• Sacubitril/valsartan 24/26 mg orally twice daily titrated to 97/103 mg twice daily (maximum).
• Spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30).
• Dapagliflozin 10 mg daily (eGFR 25 or over).

Use a beta blocker only in paced patients or those without conduction disease.

Friedreich ataxia and Pompe disease.

• Friedreich ataxia: treat arrhythmia and heart failure with ramipril 2.5 mg daily titrated to 10 mg, bisoprolol 1.25 mg daily titrated to 10 mg and spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30), checking potassium and creatinine at 1 to 2 weeks.
• Friedreich ataxia: avoid drugs that worsen hypertrophic obstruction.
• Pompe disease: alglucosidase alfa 20 mg/kg intravenously every 2 weeks (infantile onset cardiomyopathy responds), with infusion reaction precautions; start early.

Respiratory support. Non-invasive ventilation for nocturnal hypoventilation; correct hypoxia and hypercapnia, since both worsen pulmonary hypertension and arrhythmia.

Monitoring. ECG, echocardiography or MRI, and ambulatory ECG every 6 to 12 months (Duchenne from age 10 or earlier); device checks every 3 to 6 months; forced vital capacity every 6 months.

Referral and escalation. Refer to a neuromuscular multidisciplinary service with cardiac input. Urgent review for syncope or presyncope, PR over 240 ms, QRS over 120 ms or any atrioventricular block (myotonic dystrophy, Emery-Dreifuss, LMNA disease), ventricular tachycardia, atrial flutter in atrial standstill, decompensation, respiratory failure or hypoventilation, and before any anaesthesia or sedation.

Special groups.

• Pregnancy: high risk with reduced ejection fraction or respiratory restriction; stop ACE inhibitors, ARBs, ARNI, spironolactone and eplerenone before conception.
• Female carriers of Duchenne and Becker variants: screen for cardiomyopathy from adulthood.
• Children: paediatric dosing and ACE inhibitor start before dysfunction.