Diagnosis, risk stratification and management of myocarditis

Learning objectives

To provide knowledge about the aetiology of myocarditis.

To improve diagnostic and therapeutic skills iof physicians taking care of patients with myocarditis.

To provide knowledge about follow-up care of patients after myocarditis.

Introduction

Myocarditis is defined as an inflammation of the myocardium resulting from various infectious and non-infectious causes, such as viruses, adverse drug reactions or toxins. The condition can present with a subacute, acute, fulminant or chronic course. Inflammation of the myocardium in the context of organ dysfunction is referred to as inflammatory cardiomyopathy.1 Infectious causes are most commonly viruses, while non-infectious causes may result from hypersensitivity to drugs, toxic agents or systemic autoimmune conditions.2

Clinically, the presentation of myocardial inflammation may range from asymptomatic, self-resolving and potentially undiagnosed, acute coronary syndrome (ACS)-like to a fulminant form, requiring urgent mechanical circulatory support (MCS) (table 1).

Heart failure (HF) symptoms, chest pain, troponin elevation and electrocardiographic (ECG) abnormalities after a recent influenza-like illness are red flags for myocarditis. With the development of new modalities of cardiac magnetic resonance (CMR) imaging and more standardised diagnostic guidelines, the value of non-invasive diagnosis of myocarditis continues to increase. Confirmation of myocarditis can be accomplished by histological investigation of an endomyocardial biopsy (EMB) specimen. However, there remains a need for therapy guidelines as consensus recommendations are mostly based on small clinical studies and expert opinion.

Risk stratification of patients with myocarditis is important since it is a common cause of sudden cardiac death (SCD) in young adults.3 Long-term complications of myocarditis most frequently include dilated cardiomyopathy (DCM).4 This article aims to provide an overview of the condition of myocarditis and its management by outlining current expert recommendations.

Epidemiology

In 2019, the estimated prevalence of myocarditis was 712 780 cases globally.5 6 In the 35–39 years age group, this is equal to a prevalence rate of 6.1 cases of myocarditis per 100 000 men and a rate of 4.4 cases of myocarditis per 100 000 women.6 Since subacute myocarditis is often underdiagnosed, the actual number of cases is difficult to determine and is most likely higher. Acute myocarditis (AM) is most often found in relatively young patients.7

In 2019, mortality from myocarditis in adults aged 35–39 years old was 1 in 72 men and 1 in 87 women. These rates were markedly higher in adults aged 80–84 years old, with 1 in every 19 cases of myocarditis in men and 1 in every 15 cases in women resulting in death.6

Aetiology

In North America and Europe, viruses are the most common cause of myocarditis.2 The most frequently detected viruses are enteroviruses (eg, coxsackievirus), parvovirus B19, human herpes virus-6, Epstein-Barr virus and herpes simplex virus.7

Virus-mediated myocarditis is induced through direct viral cytotoxic injury of the myocardium (eg, in coxsackie myocarditis).7 Alternatively, viruses trigger activation of autoimmune mechanisms, which results in immune-mediated myocarditis after viral infection (eg, influenza or coronaviruses).7

Giant cell myocarditis (GCM; figure 1) is considered a rare, yet very rapidly progressive cause of myocarditis,8 which affects young patients with a mean age range between 42 and 56 years.9 In one-fifth of cases, GCM is found to be associated with systemic autoimmune diseases10 and therefore is also assumed to be of autoimmune aetiology.2 Recently, we have demonstrated no relevant involvement of pathogenic viruses in GCM using a sequencing method with sensitivity comparable to PCR with which we screened for all known pathogenic viruses.11 Clinically, GCM most commonly presents with HF, ventricular arrhythmias and atrioventricular (AV) block and can be mistaken for a myocardial infarction.10

Figure 1Figure 1Figure 1

Giant cell myocarditis. Histology of a patient with giant cell myocarditis (H&E staining, magnification 200× and 400×). The yellow arrow points towards a giant cell. Courtesy of Karin Klingel, University Hospital Tübingen, Germany.

Various drugs, including novel cancer therapies such as immune-checkpoint inhibitors, may rarely lead to myocarditis.7 The clinical presentation of immune-checkpoint inhibitor-induced myocarditis is often severe and frequently presents together with myositis and myasthenia gravis.12 Immune-checkpoint inhibitor-induced myocarditis has been shown to be fatal in up to 67% of cases.12 Life-threatening, glucocorticoid-refractory, immune-checkpoint inhibitor-induced myocarditis has been successfully treated with cytotoxic T lymphocyte antigen 4 modulator (abatacept) and a monoclonal antibody that binds CD52 on peripheral immune cells (alemtuzumab); further evaluation of risks is necessary.13 14

In the context of autoimmunity, systemic autoimmune diseases may cause myocardial inflammation.15 However, manifestation may be limited to the myocardium only, for example, in cardiac sarcoidosis (CS) or hypereosinophilia.2

Notably, the aetiology of myocarditis is often unknown since definitive diagnosis with biopsy is frequently not performed16 and some cases of myocarditis remain subclinical (tables 2 and 3).

Table 2

Causes of myocarditis: infectious and non-infectious

Table 3

Causes of myocarditis: toxic agents

Clinical presentation

The clinical presentation of myocarditis is variable, depending on the different degrees of organ manifestation. Presentation ranges from a subacute form with no symptoms to a fulminant form, which may require MCS.17

There are four main forms of presentation, as suggested by the 2013 statement of the European Society of Cardiology (ESC),2 in which coronary artery disease (CAD) and other known causes of HFare absent:

ACS-like chest pain.

New-onset or worsening HF.

Chronic HF.

Life-threatening (arrhythmic, SCD).

Clinical presentation may include a wide range of cardiac and non-cardiac symptoms. The latter may indicate underlying conditions, for example, focal neuropathy in eosinophilic granulomatosis with polyangiitis. Inflammation of the heart may coexist with other types of cardiomyopathy, such as amyloidosis, and has potential to worsen outcomes.2 18 Clinical presentation has been suggested to be a prognostic predictor of outcome. Patients with AM suffering from HF or ventricular arrhythmias have overall worse outcomes than patients with chest pain.19

Chest pain (ACS-like)

Patients with myocarditis often describe a specific painful gripping sensation around their heart—‘Gripping chest pain syndrome’.20 ACS must be ruled out first due to its similarity in clinical presentation. Novel blood test may aid in differentiating myocarditis from ACS.21 Alternative differential diagnoses may be pulmonary embolism and aortic dissection based on the patient’s history, signs and symptoms.

Heart failure

Inflammation may cause dilation and dysfunction of all four chambers and consequently HF. Within the Myocarditis Treatment Trial, pathologists identified 214 cases of myocarditis out of 2233 patients (10%) who presented with HF due to myocardial inflammation.22 Severity of HF symptoms ranges from exercise intolerance, moderately symptomatic ventricular dysfunction, to cardiogenic shock in fulminant myocarditis.4 Acute fulminant myocarditis characteristically presents with severe ventricular dysfunction and refractory sustained arrhythmias.2 Thus, patients are at a risk of sudden cardiac arrest.23

Right ventricular (RV) failure predominantly presents with jugular venous distension, liver congestion and peripheral oedema, while left ventricular (LV) failure ranges from dyspnoea and orthopnoea to acute pulmonary oedema.

Arrhythmias and SCD

Inflammation of the heart tissue may cause electrical instability, which predisposes to different types of bradycardia and tachyarrhythmias, which may lead to life-threatening events. More frequently, myocarditis leads to sinus tachycardia, atrial fibrillation (AF) and premature ventricular contractions.24 Furthermore, high-grade heart block may lead to syncope. GCM and CS may present with ventricular arrhythmias and conductance disturbances.25 Patients presenting with refractory electrical storms of ventricular tachycardia (VT) or ventricular fibrillation (VF), despite antiarrhythmic therapy, have worse prognosis.23 Severe forms of myocarditis may lead to SCD. One autopsy study reports that 22% of patients under the age of 40 who died suddenly were identified to have died from myocarditis.3

Diagnosis

Initially, all patients with suspected myocarditis should receive clinical assessment (including laboratory screening), echocardiography and ECG.2 As mentioned above, other life-threatening cardiovascular conditions, such as coronary artery disease, should be ruled out first.

EMB is required for definitive diagnosis. For patients who do not receive an invasive diagnostic evaluation, the diagnosis of clinically suspected myocarditis can be established based on clinical evaluation and non-invasive imaging. This has been outlined in the 2013 consensus statement of the ESC (figure 2).

Figure 2Figure 2Figure 2

Criteria for diagnosis of clinically suspected myocarditis. Source: Caforio et al.2

Physical examination

Pericardial friction rub may be heard on auscultation in perimyocarditis.

Laboratory

There are no specific biomarkers for myocarditis, although non-specific inflammatory markers like c-reactive protein (CRP) and procalcitonin may be elevated, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), myoglobin26 and troponin may reflect the extent of the disease; generally, troponin is more sensitive in myocarditis than creatine kinase.27 A complete blood count with differential may detect an autoimmune-mediated pathogenesis such as eosinophilia. In this regard, screening for autoimmune diseases should also include antinuclear antibodies and antineutrophil cytoplasmic antibodies.

Electrocardiogram

ECG has low sensitivity in detecting abnormalities in myocarditis (approximately 50%)28 and findings are not pathognomonic, but very similar to ACS. All patients should undergo ECG. Abnormalities in myocarditis may include concave and diffuse ST segment elevations without reciprocal changes in other leads and T-wave inversions (figure 3).2 17 PR-depression may be detected if there is involvement of the pericardium.29

Figure 3Figure 3Figure 3

ECG of a patient with myocarditis. Widespread ST segment elevations/deviations with concave shape and without reciprocal changes in other leads. aVR, augmented vector right; aVL, augmented vector left; aVF, augmented vector foot. Reproduced from Heidecker B, Prasad S, and Eriksson U, Peri-myocarditis. In: Lüscher T, ed, Manual of Cardiovascular Medicine, Oxford, UK (in press) with permission from Oxford University Press.

More severe abnormalities may include atrial or ventricular ectopic beats, AV or bundle branch blocks, and rarely VT or AF or VF. Monitoring of arrhythmias is important since myocarditis is one of the most common causes of SCD in young adults.7

Echocardiography

An echocardiogram is an easily accessible and non-invasive tool for evaluation of myocardial function in patients with suspected myocarditis. Structural changes seen on echocardiography are unspecific and may include wall thickening or dilation, wall motion abnormalities and changes in the shape of the heart with increased sphericity.30 Additionally, echocardiography is an important tool to monitor treatment response.

It has been shown that patients with AM, with a preserved left ventricular ejection fraction (LVEF) at initial presentation, are associated with comparatively low risk of development of inflammatory cardiomyopathy.19 In contrast, in AM measurement of LVEF <50% on the first echocardiography, sustained ventricular arrhythmias and low cardiac output syndrome increase the risk of cardiac events.19

Cardiovascular MRI

The CMR technique provides a non-invasive tool for characterisation of the myocardium with increasing diagnostic value within the last decade. The 2013 position statement on myocardial and pericardial diseases from the ESC suggests the performance of CMR imaging prior to EMB in haemodynamically stable patients.2

However, as EMB is the gold standard for tailored treatment in life-threatening forms of myocarditis,31 CMR imaging should not delay the performance of EMB in critically ill patients.2

CMR imaging (figure 4) is a valuable non-invasive diagnostic alternative when EMB is not indicated and is relevant to evaluate regions that cannot be accessed by EMB, for example, the pericardium and the epicardium.32

Figure 4Figure 4Figure 4

Cardiac MRI of a patient with myocarditis. Left: T2 image, high signal (arrow), indicating oedema in acute inflammation. Right: late gadolinium enhancement (arrow), indicating fibrosis. Reproduced from Heidecker B, Prasad S, and Eriksson U, Peri-myocarditis. In: Lüscher T, ed, Manual of Cardiovascular Medicine Oxford, UK (in press) with permission from Oxford University Press.

Sensitivity of CMR imaging in acute myocardial inflammation is highest within less than 2–4 weeks from presentation.32 Later in the course, imaging signal intensities become more diffuse and formerly defined lesions become less identifiable.32 CMR imaging has evolved into a valuable prognostic tool. In this regard, the increase of native T2 times or T2 signal intensity without late gadolinium enhancement (LGE) in acute inflammation has been suggested to be a predictor of improved recovery and outcomes.32 Recently, the Lake Louise criteria (LLC) have been updated by a new consensus statement (table 4), filling diagnostic gaps by using CMR mapping.32 Here, T2 mapping is used for detection of tissue oedema, while native T1 signal intensity increase, increase in extracellular volume and LGE indicate non-ischaemic myocardial injury.32

Table 4

Original and updated CMR criteria for myocardial inflammation: Lake Louise criteria

The MyoRacer Trial revealed that T1 mapping has the highest diagnostic accuracy (81%) in patients with acute symptoms, while the original LLC yielded the lowest diagnostic accuracy in the same patient group (59%).33 However, in patients with chronic symptoms, diagnostic accuracy of T1 mapping was much lower (45%). T2 mapping appeared to be useful in patients with chronic (>14 days) myocardial symptoms (73%).33

Both CMR imaging and EMB do not reach full sensitivity in comparison with autopsy studies, yet combined application overcomes some limitations of CMR imaging and EMB individually.34 There have been efforts to use CMR imaging for patient risk stratification. In this regard, it was shown that patients with clinically suspected myocarditis on CMR imaging with normal LV volumes and LVEF in the absence of LGE had lower mortality risk.35 Currently, the use of CMR imaging is increasingly expanded to follow-up of AM.32

Endomyocardial biopsy

EMB is the gold standard which allows for analysis of the myocardium with histological, immunological and immunohistochemical criteria, but does not achieve 100% diagnostic sensitivity.32 This can be improved by collection of multiple specimens (minimum of three samples, each sized 1–2 mm) from different areas of the myocardium.36 The Dallas criteria, used as a guide for establishing myocardial diagnosis, define myocarditis as the ‘histological evidence of inflammatory infiltrates within the myocardium, associated with myocyte degeneration and necrosis of non-ischemic origin’.2 The 2013 consensus statement by the ESC proposed an abnormal inflammatory infiltrate to be defined as ‘≥14 leukocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD3 positive T lymphocytes ≥7 cells/mm2’. In addition to histological and immunohistochemical analyses of biopsies, tissues and blood samples should also undergo PCR to screen for viruses.2 There has been evidence for immunohistochemical detection of inflammation as a predictor of cardiac death or heart transplantation.37

EMB provides histological proof of underlying cardiac conditions, for example, findings of non-caseating granulomas in sarcoidosis or multinucleated giant cells with a lymphocytic inflammatory infiltrate and myocyte necrosis, indicating GCM. Furthermore, EMB allows for characterisation of the severity of the myocardial manifestation. Importantly, EMB is used to rule out active viral replication when immunosuppression is considered.2

An EMB should particularly be considered when there is suspicion for a specific cardiomyopathy that may benefit from specific therapy based on the results of the histology.2 However, as EMB is an invasive method of diagnosis, there is a small risk of complications. Expert centres have reported generally lower complication rates than centres with lower patient volumes.7

One large two-centre study reported major adverse events to occur at a rate of 0.64% in LV-EMB and 0.82% in RV-EMB. The same study reported minor complications at a rate as high as 2.89% in LV-EMB and 5.10% in RV-EMB.38 Major complications included cardiac tamponade with a need for pericardiocentesis and stroke. Minor complications were transient chest pain, non-sustained VT, transient hypotension, third-degree AV block with temporary need for a pacemaker and small pericardial effusions.38 A 2020 expert consensus statement suggested indications for EMB in different clinical scenarios (box 1).7

Box 1 Indications for endomyocardial biopsy (EMB)

Case-to-case evaluation for indication of EMB is important.

Acute myocarditis with cardiogenic shock (fulminant myocarditis) or acute heart failure.

Acute myocarditis with ventricular arrhythmias or high-degree atrioventricular block.

Acute myocarditis or chronic inflammatory cardiomyopathy in the context of peripheral eosinophilia.

Acute myocarditis or dilated cardiomyopathy suspected for chronic inflammatory cardiomyopathy with continuous/recurrent release of necrosis markers, particularly when autoimmune condition is likely or ventricular arrhythmias or second-degree/third-degree AV block is present.

Immune-checkpoint inhibitor-associated myocarditis.

Risk stratification in acute clinical presentation

Long-term survival of patients with myocarditis is closely related to initial presentation. For example, an LVEF ≤40% and a positive LGE in mid-cardiac wall on CMR imaging were associated with a 10-year event-free survival probability of under 40%, while an LVEF >40% and no LGE in mid-cardiac on CMR imaging were associated with a 10-year event-free survival probability of over 80% in patients with viral myocarditis.39

Recent expert consensus has proposed a risk-based approach in the setting of AM (figure 5)7: high-risk patients present with symptoms of acute HF or cardiogenic shock, LVEF below 40%, and severe arrhythmias such as VT or VF. These should be treated in centres with expertise in heart transplantation and MCS. Additionally, these patients should receive EMB early and CMR imaging before discharge from the hospital. Steroids should be considered in these patients, depending on clinical course and biopsy results.

Figure 5Figure 5Figure 5

Risk stratification in acute myocarditis. Risk-based approach to acute myocarditis proposed by Ammirati et al (2020).7 Left: clinical features that characterise high (red boxes), intermediate (yellow boxes) or low (green boxes) risk are summarised according to the presence of low BP and severity of AHF, initial LVEF on first echocardiogram, and ECG (presence of VT or VF or advanced AVB). Right: how these risk features may influence patient management in terms of referral to expert centres, t-MCS, need for EMB or CMRI, and consideration for steroid treatment. Tag sign indicates recommended actions. No symbol indicates not recommended. *Immunosuppression with intravenous steroids may be considered and often used in patients with fulminant myocarditis; however, clinical studies that demonstrate their efficacy are lacking. Figure with permission from Ammirati E, et al.7 AHF, acute heart failure; AVB, atrioventricular block; BP, blood pressure; CMRI, cardiac MRI; EMB, endomyocardial biopsy; FM, fulminant myocarditis; LVEF, left ventricular ejection fraction; t-MCS, temporary mechanical circulatory support; VF, ventricular fibrillation; VT, ventricular tachycardia.

Intermediate-risk patients present with mild to moderate acute HF symptoms, LVEF between 30% and 49%, and possibly severe arrhythmias. Transfer to a clinic with specific expertise in MCS should be considered, a diagnostic work-up with CMR imaging and possibly EMB should be performed, and steroids may be indicated depending on clinical course and diagnostic results.

Low-risk patients typically have no blood pressure fluctuations or acute HF symptoms and the condition is typically self-limited. Furthermore, LVEF is only mildly reduced (≥50%) and severe arrhythmias do not occur. Patient transfer to especially equipped clinics and MCS is not required. CMR imaging is sufficient and EMB not necessary unless the results are expected to change management, that is, if a specific cardiomyopathy is suspected.

Genetic associations

There has been increasing data suggesting that some genetic variants lead to more severe manifestations of inflammatory cardiomyopathy. For instance, genetic variants of titin may predispose patients with myocarditis to more severe LV dysfunction in the acute phase.40 It has been shown that human leukocyte antigen (HLA)-DQ1B serotype is associated with lymphocytic myocarditis (figure 6).41 Furthermore, reportedly arrhythmogenic RV cardiomyopathy, which is an autosomal-dominant inherited condition associated with variants of genes coding for desmosomes and desmosome-related proteins, can present as familial recurrent myocarditis.42 Therefore, we recommend genetic testing for pathogenic variants associated with cardiomyopathy in those patients with ventricular myocarditis, particularly if associated with ventricular arrhythmias, and those patients who have first-degree relatives with myocarditis.

Figure 6Figure 6Figure 6

Lymphocytic myocarditis. Histology of a patient with lymphocytic myocarditis (H&E staining, magnification 200× and 400×). The yellow arrow points towards lymphocytes. Courtesy of Karin Klingel, University Hospital Tübingen, Germany.

Treatment

Treatment options can be divided into universal treatment of symptoms, for example, HF symptoms and arrhythmias, and specific treatment of the underlying condition causing myocarditis, for example, immunosuppressive treatment (table 5).

Table 5

Categories of therapy

Universal managementHF therapy

Fast transfer of patients with fulminant myocarditis is essential. Early treatment at medical centres with expertise in MCS and heart transplantation increases the chance of survival.43

HF management in myocarditis aims to support LVEF. In most cases, this is achieved by standard HF medication with ACE inhibitors, beta-blockers (especially bisoprolol, metoprolol and carvedilol), mineralocorticoid receptor antagonists, or angiotensin receptor blocker or an angiotensin receptor-neprilysin inhibitor.44 Calcium channel blockers are generally not recommended in the management of heart failure with reduced ejection fraction (HFrEF) 45 due to their negative inotropic effect.

There has been controversy on the use of cardiac glycosides in myocarditis. While they are indicated for symptomatic systolic HF in New York Heart Association (NYHA) classes II–IV,46 there has been evidence of worsening of virus-associated myocarditis in mice.16 Additionally, due to their negative inotropic effect, glycosides may limit the use of beta-blockers,16 which counteract remodelling of the heart and are thus preferred. Therefore, experts have recommended to defer cardiac glycoside in the management of myocarditis-associated HF.16

MCS (eg, extracorporeal membrane oxygenation or ventricular assist devices) may be indicated for patients presenting with fulminant and haemodynamically unstable myocarditis.47 One study has shown that the 11-year survival without heart transplantation of patients with fulminant myocarditis is twice as high when compared with patients with AM.48 These findings suggest that patients with a fulminant course of myocarditis, when sufficiently treated with haemodynamic support, are associated with a better long-term outcome than patients with more mild forms of myocarditis. Other studies have shown that heart transplantation can improve survival of patients with DCM resulting in end-stage HF.49 50 Given some controversy in the literature with regard to risk prediction in patients with fulminant myocarditis, identification of patients who may benefit from early transplantation remains challenging. Therefore, patients with fulminant myocarditis should be evaluated early by a specialist for advanced HF to decide if transplantation should be recommended.

Antiarrhythmic therapy

Since inflamed tissue has a high chance of recovery, treatment for arrhythmias in myocarditis is primarily supportive.44 Generally, current guidelines from the American Heart Association (AHA) and ESC should be used to determine strategies in the treatment of arrhythmias in myocarditis.23 44 For prevention and treatment of ventricular arrhythmias and SCD, antiarrhythmic drugs such as amiodarone are often used.23 A wearable cardioverter defibrillator should be considered for patients at risk of life-threatening arrhythmias with a foreseeable clinical improvement after recovery of AM.23 Frequently, patients with fulminant myocarditis will be provided a wearable cardioverter defibrillator.23 Implantable cardioverter defibrillators should be avoided in the acute phase of myocarditis,23 although may be considered in patients with malignant ventricular arrhythmias or heart block in the context of GCM or sarcoidosis.23 These patients are at high risk of arrhythmic death or requirement for transplantation.23 Temporary pacemakers should be considered before permanent pacemakers for patients with bradycardia or ventricular arrhythmia-inducing heart block.23

Restrictions

Sustained, high-intensity exercise should be avoided in the acute phase of myocarditis. Current expert consensus recommends abstinence from competitive athletic activity for 3–6 months, regardless of severity of clinical presentation.2 51 Activities of daily living are safe and should be encouraged to avoid deconditioning. Patients should be examined before resuming sports and in follow-up visits.

It is currently recommended to avoid non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of myocarditis since NSAIDS were associated with increased mortality in mouse experiments.16 However, recent data in a small prospective clinical trial suggested safety in myopericarditis.19

Toxin consumption, such as ethanol in excess of one alcoholic beverage per day, should be assessed and patients should be instructed to avoid intake, especially during the acute phase of myocardial inflammation.

Condition-specific managementImmunosuppressive therapy

For safe use of immunosuppressive therapy (IMT), EMB is used to confirm the absence of active viral replication in the myocardium by PCR.2 The AHA does not recommend immunosuppression for routine use. The 2013 ESC consensus statement recommends consideration of immunosuppression in biopsy-proven virus-negative lymphocytic myocarditis and in autoimmune myocarditis, including GCM and myocarditis associated with systemic autoimmune diseases.2 8 52 A recent meta-analysis suggested that prednisolone in combination with azathioprine therapy had positive effect on LVEF and adverse event rate in virus-negative lymphocytic myocarditis.52 Patients with virus-negative GCM may benefit from combined ciclosporin-based immunosuppression.8 52

The ESC recommends the use of steroids in CS presenting with ventricular dysfunction and/or arrhythmia.2 Eosinophilic myocarditis (figure 7) frequently responds to high-dose corticosteroids. It is important to evaluate the causes of eosinophilia, for example, medications or parasites. Additionally, for patients with AM who are unresponsive to standard therapy, the ESC recommends an individualised evaluation for IMT.2

Figure 7Figure 7Figure 7

Eosinophilic myocarditis. Histology of a patient with eosinophilic myocarditis (H&E staining, magnification 200× and 400×). The yellow arrow points towards eosinophils. Courtesy of Leslie T Cooper Jr, Mayo Clinic Jacksonville, USA.

Another point of discussion for experts is the optimal time for initiation of immunosuppression. About half of biopsy-proven myocarditis cases spontaneously resolve within 2–4 weeks after symptom onset; thus, immunosuppression should be started after allowing sufficient time for spontaneous resolution.52 However, for some patient groups with myocarditis, early treatment with immunosuppressive regimens prolongs transplant-free survival, for example, patients with GCM who were treated with prednisolone and ciclosporin.8

Antiviral therapy

There are no sufficient clinical data to support the routine use of antiviral medications in myocarditis. Evaluation of the efficacy of interferon treatment for chronic viral myocarditis with a biopsy-proven myocardial infection with adenovirus, enterovirus or parvovirus B19 showed a viral load elimination or reduction and positive effects on NYHA functional class for patients.53

For enterovirus-associated cardiomyopathy, an improved 10-year prognosis was found with interferon treatment.54

IL-1 beta antibodies

In murine models infected with enterovirus, chronic viral myocarditis treatment with an interleukin-1 (IL-1) beta antibody reduced inflammation, interstitial fibrosis and adverse cardiac remodelling, preventing progression to chronic viral myocarditis.55 56 An ongoing clinical trial is evaluating the efficacy and safety of IL-1 beta blockage in AM (anakinra versus placebo for the treatment of acute myocarditis (ARAMIS), NCT03018834). Recently, a phase III study was able to present positive outcomes in patients with recurrent pericarditis treated with IL-1 blocking agent rilonacept.57

Intravenous immunoglobulin therapy and immunoadsorption

Removal of autoantibodies is an increasingly applied treatment approach in various autoimmune conditions.56 58

Immunoadsorption and subsequent intravenous immunoglobulin therapy have been suggested as an alternative treatment strategy in patients with inflammatory cardiomyopathy and showed an improved cardiovascular function in DCM.56 59

Due to limited evidence on the efficacy of intravenous immunoglobulin therapy (IVIG) in myocarditis, there are no recommendations by the international societies of cardiology as of today. Currently, there is an ongoing multicentre study of immunoadsorption in DCM (NCT00558584).

Follow-up and prognosis

Myocarditis can result in full or partial recovery. Chronic subclinical inflammation may lead to DCM.7 Therefore, patients should undergo regular follow-up examinations at least every 6 months over the course of 1 year depending on individual risk factors.2 However, intervals of clinical follow-up should be determined individually depending on severity of clinical presentation. These follow-up visits should be based on clinical assessment, ECG and echocardiography.2

The recurrence rate of AM is approximately 10.3% within 4.5 years of follow-up60 and depends on the subtype. In patients with GCM the combined rate of death, transplantation, ventricular assist device implantation and recurrence was reported to be as high as 47% within 1 year of follow-up.61

As HF has been identified to be of important prognostic value for recovery of patients with myocarditis, HF therapy should be optimised. Beta-blockers especially have gained popularity in having a positive effect on clinical outcome in myocarditis62 and therefore are a cornerstone of HF therapy in myocarditis.

Some patients may require follow-up EMB, for example, re-evaluation for adjustment of IMT.

Future directions

In recent years, identifying genetic variants predisposing patients to cardiac dysfunction with external triggers has become an active area of research. Information from genomic analysis may be helpful for risk assessment of affected family members of the patient and allow for an individualised diagnostic and therapeutic approach. We recommend screening patients with severe myocarditis for genetic variants since this allows for early recognition of conditions such as arrhythmogenic cardiomyopathy.

Another area of interest is to identify triggers for transition of AM to chronic myocarditis as this may affect individualised treatment.25

Further research is needed to understand the role of individual viruses and immune cells in cardiac injury and how this might be contrasting in different kinds of viruses.25

As true for many fields of medicine, investigating sex-specific differences is critical for individualised therapy.63

With use of CMR mapping and standardisation of diagnostic criteria, the quality of diagnosis of myocardial inflammation has improved. This is particularly true for the diagnosis of AM. However, diagnostic accuracy for chronic myocardial inflammation is still low.32 We expect additional optimisation of CMR-technology in the field of myocarditis in the coming years.

The SARS-CoV-2 outbreak has been associated with many organ manifestations, including myocarditis. While the incidence of myocarditis among patients with SARS-CoV-2 appears to be rare overall,64 65 the pathophysiology of SARS-CoV-2-associated myocarditis and observing the long-term outcomes of cardiac involvement are a current task for cardiological experts across the world.25

Key messages

Myocarditis is defined as inflammation of the myocardium and should be diagnosed with histological (Dallas criteria), immunological and immunohistochemical criteria.

Future improvement of diagnostic tools, such as cardiac MRI, and standardisation of diagnostic criteria will allow for increased diagnostic accuracy and stratification of patient groups for more effective and individualised treatment.

Supportive therapy should continuously be re-evaluated and modified for optimisation.

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Education in Heart articles are accredited for CME by various providers. To answer the accompanying multiple choice questions (MCQs) and obtain your credits, click on the ‘Take the Test’ link on the online version of the article. The MCQs are hosted on BMJ Learning. All users must complete a one-time registration on BMJ Learning and subsequently log in on every visit using their username and password to access modules and their CME record. Accreditation is only valid for 2 years from the date of publication. Printable CME certificates are available to users that achieve the minimum pass mark.

Ethics statementsPatient consent for publicationAcknowledgments

We thank Prof. Dr. med. Karin Klinglel, Head Cardiopathology and Infection Pathology at the Institute for Pathology and Neuropathology, University Hospital Tuebingen, for providing histological images of giant cell and lymphocytic myocarditis.

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