Giant Cell Myocarditis

Giant cell myocarditis (GCM) is a rare, rapidly progressive, usually T-cell-mediated autoimmune myocarditis with a diffuse or multifocal inflammatory infiltrate that contains multinucleated giant cells, lymphocytes, eosinophils and macrophages, with myocyte necrosis and without well formed granulomas.

It affects young and middle aged adults (median age about 40 years) with no sex difference. About 20% have an associated autoimmune disease, such as inflammatory bowel disease, myasthenia gravis, thyroiditis or thymoma, and some cases follow drug hypersensitivity. Untreated, survival is measured in months.

With combination immunosuppression, about half of patients are alive without transplantation at several years in registry data. The disease can recur in the transplanted heart in about one in four patients, so immunosuppression continues after transplantation.

Pathophysiology

A T-cell-driven immune attack on the myocardium, possibly triggered by an infection or drug, causes necrosis and replacement fibrosis. It involves the conduction system and the ventricular myocardium extensively, so ventricular arrhythmia and heart block are frequent.

It progresses over days to weeks, and relapse follows if immunosuppression is reduced too early.

• Heart failure of rapid onset (about 75%), cardiogenic shock, or both.
• Ventricular tachycardia or fibrillation (about 30% to 40%), high grade atrioventricular block (about 5% to 15%), syncope, and sudden cardiac death.
• Chest pain, palpitations, fever and malaise.
• Examination: signs of low output and heart failure, and a third heart sound.
• Features of associated disease: myasthenia (ptosis, diplopia, weakness), inflammatory bowel disease, thyroid disease.

Red flags.

• New heart failure with ventricular tachycardia or high grade atrioventricular block
• Progressive worsening over days to weeks despite usual heart failure therapy
• Cardiogenic shock or recurrent arrhythmia
• Rising troponin and wide QRS
• Associated thymoma, myasthenia gravis or inflammatory bowel disease
• Recurrence of symptoms when immunosuppression is reduced

• Endomyocardial biopsy. Essential and urgent in any acute unexplained heart failure with arrhythmia or conduction block. Take at least 5 samples, from the right ventricular septum and, when possible, the left ventricle. Sensitivity is about 80 to 85%, so repeat the biopsy when negative and suspicion persists. Findings: multinucleated giant cells, lymphocytes and eosinophils, myocyte necrosis, no granulomas. Add viral PCR and immunohistochemistry.

• ECG and rhythm monitoring. Atrioventricular block, bundle branch block, ventricular tachycardia.

• Echocardiography. Reduced ejection fraction, thickened walls early from oedema, and right ventricular involvement.

• Cardiac MRI. Patchy mid-wall or subepicardial late gadolinium enhancement. PET shows active inflammation, and both help choose biopsy sites and assess response.

• Laboratory. Troponin, natriuretic peptide, CRP, full blood count with eosinophils, thyroid function, autoimmune screen, HIV, and acetylcholine receptor antibodies if myasthenia is suspected. CT of the chest for thymoma.

Manage in a centre with mechanical circulatory support and transplantation. Start immunosuppression as soon as the diagnosis is made, without waiting for a full workup in a rapidly deteriorating patient.

• Pulse corticosteroid. Methylprednisolone 500 to 1,000 mg intravenously once daily for 3 days, then prednisolone 1 mg/kg orally once daily (maximum 80 mg), tapered by 5 to 10 mg every 2 weeks to 20 mg daily, then slowly to 5 to 10 mg daily, and kept for at least 12 months with the second agent. Reduction is slow, because relapse follows early taper.
• Calcineurin inhibitor. Ciclosporin 2 mg/kg orally twice daily at the start, adjusted to a trough of 150 to 250 ng/mL. Check creatinine, potassium, magnesium, blood pressure and liver enzymes. Interacts with CYP3A4 inhibitors and inducers, amiodarone and statins. Reduce the dose with a creatinine rise over 30% from baseline.
• Antimetabolite. Azathioprine 1 mg/kg orally once daily, increased to a maximum of 2 mg/kg daily (check TPMT or NUDT15 first; full blood count weekly for 4 weeks, then monthly; reduce to a quarter of the dose with allopurinol), or mycophenolate mofetil 1 g orally twice daily (maximum 3 g daily; contraindicated in pregnancy; full blood count monthly).
• Fulminant or refractory disease: rabbit antithymocyte globulin 1.5 mg/kg intravenously once daily for 3 to 5 days, with premedication (methylprednisolone, an antihistamine and paracetamol) and CD3 count monitoring, in a specialist unit.
• Prophylaxis during immunosuppression. Co-trimoxazole 960 mg orally three times weekly (or 480 mg once daily; halve at creatinine clearance 15 to 30 mL/min and avoid under 15 mL/min), calcium and vitamin D, a proton pump inhibitor, and glucose and blood pressure checks. Screen for hepatitis B and tuberculosis before starting.
• Heart failure. Usual drug therapy as tolerated once stable, with diuretics (furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed, higher doses in renal impairment under specialist care). Avoid beta blockers in shock. Avoid non-steroidal anti-inflammatory drugs.
• Arrhythmia.
  • Defibrillate unstable ventricular tachycardia or fibrillation.
  • Amiodarone 150 mg intravenously over 10 minutes, repeated for recurrence, then 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours, maximum 2.2 g in 24 hours. Contraindicated in severe sinus node disease and high grade atrioventricular block without pacing. It raises ciclosporin levels, so check levels.
  • Temporary then permanent pacing for persistent high grade block.
  • Implantable cardioverter defibrillator early because the risk is high even after treatment (a wearable defibrillator is a bridge).
• Mechanical circulatory support. Early venoarterial extracorporeal membrane oxygenation, percutaneous left ventricular support or biventricular assist for shock, as a bridge to recovery or transplantation. Transplantation for refractory disease.
• Associated disease: manage myasthenia, thymoma and inflammatory bowel disease with the relevant specialists.

Special groups. Pregnancy carries very high risk. Ciclosporin, azathioprine and prednisolone are compatible, and mycophenolate and cyclophosphamide are contraindicated.

Monitoring. Continuous ECG until stable. Troponin, natriuretic peptide and ciclosporin level every 1 to 3 days at the start, then weekly. Echocardiography at 1, 4 and 12 weeks. Repeat biopsy at 3 to 6 months and with any relapse, since symptoms are an unreliable marker. Cardiac MRI or PET at 3 to 6 months. Full blood count weekly for 4 weeks and then monthly on azathioprine or mycophenolate, creatinine, potassium, magnesium and blood pressure with each ciclosporin level, and glucose on steroids.

Referral and escalation. Transfer immediately to a transplant and mechanical support centre. Emergency for shock, ventricular arrhythmia or high grade block.