Myocardial diseases: myocarditis

01Definition and overview

Myocarditis is an inflammatory disease of the myocardium, diagnosed by histology, immunohistochemistry or cardiac MRI. Clinically it is called:

• suspected (possible), with a typical presentation and supporting tests, but no MRI or biopsy proof;
• confirmed (definite), when cardiac MRI or an endomyocardial biopsy shows it.

It is described by its tempo (acute up to 4 weeks, subacute up to 3 months, chronic beyond that) and by its severity. Acute myocarditis is complicated when it brings an ejection fraction below 50 per cent, sustained ventricular arrhythmias, advanced heart block, heart failure or shock, and uncomplicated otherwise. Fulminant myocarditis, about 3 to 9 per cent of cases, means cardiogenic shock that needs drugs or devices to support the circulation. Chronic myocarditis with a dilated or poorly contracting ventricle is called inflammatory cardiomyopathy.

The biopsy also names the type of inflammation, which guides treatment: lymphocytic (the commonest; viral, after a virus or, in recent series more often, immune-mediated), eosinophilic, giant cell and granulomatous (sarcoidosis).

Myocarditis often affects the pericardium as well. While the diagnosis is being made, the two are grouped as inflammatory myopericardial syndrome; when pericarditis dominates and the ventricle is normal, the condition is called myopericarditis, and it is described with pericardial diseases.

02Etiology and pathophysiology

Causes

How the damage happens

1. 1

   Viral injury

   Cardiotropic viruses enter the myocytes through receptors such as the coxsackie-adenovirus receptor. They damage the cells directly in the first days.
2. 2

   The immune response

   Innate and then T-cell immunity clears the virus but also injures the myocardium. Released heart proteins, such as myosin, and molecular mimicry can start an autoimmune response that continues after the virus has gone.
3. 3

   Resolution or remodelling

   In most patients the inflammation settles and the heart recovers. In some it persists or leaves fibrosis, and the ventricle dilates and weakens: dilated cardiomyopathy.

Not every heart reacts the same way. Disease-causing variants in cardiomyopathy genes, such as those for desmoplakin and titin, are found in about 1 in 5 adults with complicated myocarditis, against about 4 per cent with uncomplicated disease, so a severe or recurrent myocarditis can be the first sign of an inherited cardiomyopathy. Genetic testing is considered when there is a family history, severe ventricular arrhythmias, septal or ring-like scarring on MRI, persisting dysfunction or a recurrence.

Inflammation and scarring in the myocardium create circuits for re-entry and damage the conduction system, which explains the ventricular arrhythmias and heart block, prominent in giant cell myocarditis, sarcoidosis, Lyme disease and Chagas disease.

03Clinical features

Myocarditis is commonest in young adults and in men. A viral illness, with fever, aches, a sore throat or diarrhoea, often precedes it by days to a few weeks, usually 2 to 4. The presentations:

• chest pain mimicking an acute coronary syndrome, with ECG changes and a raised troponin but normal coronary arteries, the commonest presentation in young people; pleuritic pain suggests pericardial involvement;
• new heart failure, over days to weeks, with breathlessness, fatigue and oedema, with a dilated or normal-sized ventricle;
• palpitations, syncope or sudden death from ventricular arrhythmias or heart block;
• cardiogenic shock in fulminant myocarditis.

The examination may be normal, or show tachycardia out of proportion to the fever, quiet heart sounds, a third heart sound, a pericardial rub and the signs of heart failure.

Some forms have their own clues:

• giant cell myocarditis: middle-aged adults with rapidly progressive heart failure, ventricular tachycardia and heart block that do not respond to usual treatment, sometimes with thymoma or autoimmune disease;
• eosinophilic myocarditis: a raised eosinophil count, a rash or a new drug, asthma and sinus disease in eosinophilic granulomatosis with polyangiitis;
• myocarditis from immune checkpoint inhibitors: usually within the first three months of treatment, often with myositis and myasthenia-like weakness;
• vaccine myocarditis: young men, a few days after the second dose of an mRNA vaccine, usually mild;
• Chagas cardiomyopathy: years after infection in Latin America, with right bundle branch block and left anterior fascicular block, an apical aneurysm, heart block, ventricular tachycardia and emboli.

04Diagnosis and management

Tests

• ECG: ST elevation or depression, T wave inversion, low voltage, Q waves, bundle branch block, atrioventricular block, ectopic beats or ventricular tachycardia. A normal ECG does not exclude myocarditis.
• Blood tests: a raised troponin in most acute cases (it is usually normal in chronic myocarditis), CRP, natriuretic peptides, the eosinophil count, and tests for a suspected cause such as autoimmune disease or Lyme disease. Routine viral serology does not help, except for hepatitis C, HIV and Lyme disease.
• Echocardiography: normal or reduced ventricular function, regional wall motion abnormalities, a thickened, oedematous wall in fulminant cases, and a pericardial effusion.
• Coronary angiography, invasive or CT, to exclude a coronary cause in a patient with chest pain, ECG changes and a raised troponin.
• Cardiac MRI, the key test for confirming the diagnosis: myocardial oedema on T2-based images with at least one T1-based marker of injury (a raised T1 or extracellular volume, or late gadolinium enhancement). The enhancement is patchy, subepicardial or mid-wall, often inferolateral, and does not follow a coronary territory. It is most accurate early, ideally within the first 2 weeks.
• Endomyocardial biopsy, the reference standard, with histology, immunohistochemistry and PCR for viral genomes. It is done in high-risk patients: fulminant myocarditis, heart failure with a poor ventricle that does not improve, sustained ventricular arrhythmias or high-grade heart block, and suspected giant cell, eosinophilic or sarcoid myocarditis. Complications (perforation and tamponade, arrhythmias, valve damage, rarely death) occur in about 0.6 to 5 per cent, and in up to a quarter of patients with fulminant myocarditis on mechanical support. In fulminant myocarditis an early biopsy is linked to a better outcome, because it finds the forms that need immunosuppression.
• FDG PET/CT when sarcoidosis is suspected.

Treatment

Patients with suspected acute myocarditis and a raised troponin are admitted and monitored for arrhythmias, at least until the risk is clear.

• Heart failure is treated with the usual heart failure drugs: ACE inhibitors or sacubitril–valsartan, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors and diuretics. They are continued for at least 6 months after the ventricle recovers. A beta-blocker is also considered for at least 6 months in acute myocarditis without heart failure, especially with a raised troponin.
• Fulminant myocarditis is treated as cardiogenic shock, with inotropes and vasopressors and, if these are not enough, early mechanical circulatory support, most often extracorporeal membrane oxygenation. Corticosteroids are considered in fulminant myocarditis once infection is excluded. Many hearts recover; the others need a ventricular assist device or transplantation.
• Arrhythmias: temporary pacing for heart block with haemodynamic compromise and permanent pacing if it persists, but not in Lyme carditis before antibiotics, because the block usually resolves within 1 to 2 weeks of intravenous ceftriaxone; antiarrhythmic drugs for ventricular arrhythmias. The decision on an implantable defibrillator is usually made 3 to 6 months after the acute illness, once recovery is clear, with a wearable defibrillator in the meantime for some; it comes earlier in giant cell myocarditis and sarcoidosis.
• Chest pain in uncomplicated myopericarditis is treated with aspirin or an NSAID, and colchicine prevents recurrences of the pericardial component.

Immunosuppression is given when the biopsy or the setting shows a cause that responds to it:

Immunosuppression is not used in ordinary acute viral myocarditis, and when the biopsy shows active viral replication it is avoided. Antiviral treatment has little evidence. Chagas disease is treated with benznidazole or nifurtimox in the acute phase and in younger patients, with amiodarone, pacing and defibrillators for the arrhythmias.

Strenuous exercise and competitive sport are stopped until remission is confirmed, by the symptoms, normal troponin and CRP, the ECG, rhythm monitoring and imaging, because exertion during active inflammation can trigger fatal arrhythmias. Remission takes at least a month; athletes have traditionally waited 3 to 6 months, and the decision is now individual. Patients are followed at 1, 3 to 6 and 12 months, with cardiac MRI repeated within 6 months.

05Epidemiology

The true incidence is unknown, because mild cases are never diagnosed. Registries record about 6 to 9 diagnosed cases per 100,000 people a year, mostly in young men, and the true figure is higher. Myocarditis is commonest between 20 and 40 years of age and about twice as common in men. It is found in a few per cent, and in some series over 10 per cent, of autopsies after sudden death in the young. Myocarditis after mRNA COVID-19 vaccines is rare and mostly affects young men. Immune checkpoint inhibitor myocarditis affects under 1 per cent of treated patients, more with combined treatment. Chagas disease infects several million people in Latin America, about a quarter of whom develop heart disease.

06Prognosis

Uncomplicated acute myocarditis, with normal ventricular function, which is about three quarters of cases, usually resolves without lasting damage. In biopsy-proven myocarditis, which selects sicker patients, up to half recover, up to a quarter keep a stable dysfunction, and 10 to 25 per cent progress to dilated cardiomyopathy, transplantation or death. About 1 in 10 patients has a recurrence.

The ventricular function at 6 months predicts the outcome, as do heart failure at presentation and extensive late gadolinium enhancement on MRI. Many patients with fulminant myocarditis recover their ventricular function after mechanical support, but fulminant disease carries more deaths and transplants than non-fulminant myocarditis, both in the first weeks and over the following years. Giant cell myocarditis is the most dangerous form: untreated, most patients die or need a transplant within months, and immunosuppression extends survival. Immune checkpoint inhibitor myocarditis carries a high mortality, and Chagas cardiomyopathy has a worse outlook than other dilated cardiomyopathies.