Update on myocarditis – what we know so far and where we may be heading

Abstract

Introduction

Myocarditis is defined as an inflammatory infiltration of the myocardium with associated necrosis and/or degeneration, frequently resulting from different infectious or non-infectious triggers (Table 1).^1–4 The exact incidence of myocarditis is difficult to ascertain. Myocarditis continues to be underdiagnosed because of the large number of asymptomatic cases.³ Yet it remains one of the most important causes of dilated cardiomyopathy (DCM) with up to 30% of cases progressing to DCM.⁶ Furthermore, myocarditis is one of the most common causes of sudden cardiac death in young adults.⁷ Most studies of myocarditis report male predominance and a median age of patients with lymphocytic myocarditis of approximately 42 years.^6,8–10 Although the aetiology of myocarditis often remains unidentified, specific and treatable causes that should be investigated include infections, systemic autoimmune diseases and hypersensitivity to certain medications (Table 1).^11–14

Table 1.

Aetiology of myocarditis/inflammatory cardiomyopathy.

1. Infectious myocarditis
Bacterial	Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Corynebacterium diphtheriae, Haemophilus influenzae, Mycobacterium (tuberculosis), Mycoplasma pneumoniae, Brucella
Spirochaetal	Borrelia (Lyme disease), Leptospira (Weil disease)
Fungal	Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucormycoses, Nocardia, Sporothrix
Protozoal^a	Trypanosoma cruzi, Toxoplasma gondii, Entamoeba, Leishmania
Parasitic^a	Trichinella spiralis, Echinococcus granulosus, Taenia solium
Rickettsial	Coxiella burnetii (Q fever), Rickettsia rickettsii (Rocky Mountain spotted fever), R. tsutsugamuschi
Viral	RNA viruses: Coxsackieviruses A and B, echoviruses, polioviruses, influenza A and B viruses, respiratory syncytial virus, mumps virus, measles virus, rubella virus, hepatitis C virus, dengue virus, yellow fever virus, Chikungunya virus, Junin virus, Lassa fever virus, rabies virus, human immunodeficiency virus-1
	DNA viruses: adenoviruses, parvovirus B19, cytomegalovirus, human herpes virus-6, Epstein–Barr virus, varicella-zoster virus, Herpes simplex virus, variola virus, vaccinia virus
2. Immune-mediated myocarditis
Allergens	Tetanus toxoid, vaccines, serum sickness
Allergens	Drugs: penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulphonamides, phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline
Alloantigens	Heart transplant rejection
Autoantigens	Infection-negative lymphocytic, infection-negative giant cell
Autoantigens	Associated with autoimmune or immune-oriented disorders: systemic lupus erythematosus, rheumatoid arthritis, Churg–Strauss syndrome, Kawasaki’s disease, inflammatory bowel disease, scleroderma, polymyositis, myasthenia gravis, insulin-dependent diabetes mellitus, thyrotoxicosis, sarcoidosis, Wegener’s granulomatosis, rheumatic heart disease (rheumatic fever)
3. Exposure to myocardial toxins
Drugs	Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium, catecholamines, haemetine, interleukin-2, trastuzumab, clozapine, immune checkpoint inhibitors (anti-PD I and/or anti-CTLA4) for cancer treatment
Heavy metals	Copper, iron, lead (rare, more commonly cause intramyocyte accumulation)
Miscellaneous	Scorpion sting, snake and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus, arsenic, sodium azide
Hormones	Phaeochromocytoma, Vitamin-B1 deficiency: beri-beri
Physical agents	Radiation, electric shock

Source:¹¹ from Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: 2636–2648, 48a–48d.

Mostly associated with eosinophilic myocarditis.

Clinicopathologic classification of myocarditis

Clinicopathologic classification of myocarditis is mostly clinically oriented, but not widely used.^2,4

Fulminant myocarditis (17%) has very acute onset. It can result in either complete, spontaneous resolution or rapid deterioration and death due to severe cardiac compromise.^13,15 Patients present with abrupt new-onset unexplained class IV heart failure symptoms with normal-sized or dilated left ventricle. Clinical features of acute myocarditis can rapidly change within the first days of illness. Therefore, patients with a new diagnosis of suspected myocarditis and elevated troponin levels or changes on electrocardiogram (ECG) changes should be hospitalized for several days of monitoring. During this time window, some patients will manifest signs of heart failure, early cardiogenic shock or unstable arrhythmias.^16,17 Histologically, there are multiple active foci of inflammatory infiltrate. Data from clinical registries suggest that in acute cardiomyopathy, histological and molecular patterns obtained by endomyocardial biopsy (EMB) may provide prognostic and diagnostic information that will alter outcomes by enabling disease- or pathogen-specific management.^18–20

Acute (non-fulminant) myocarditis (65%) may have a clinically more subtle onset, with moderate cardiovascular compromise and incomplete recovery, sometimes resulting in cardiac dysfunction, heart failure and, less frequently, death. Histologically, there are active or borderline inflammatory infiltrates that resolve completely over time.^2,17,21–26

Chronic active myocarditis (11%) presents similarly to acute myocarditis. However, chronic myocarditis usually progresses to only mild or moderate cardiac dysfunction, occasionally with a restrictive pathology. Histologic examination often shows ongoing fibrosis, suggesting chronic inflammatory changes.^{13,24,26–30}

Chronic persistent myocarditis (7%) presents with subtle onset, with non-resolving active or borderline inflammatory infiltrates seen on histologic examination. Usually, there is no cardiovascular compromise.

WHO/ISFC definition

Inflammatory disease of the myocardium diagnosed by established histological (established according to the histological Dallas criteria) and immunohistochemical criteria (unspecified immunohistochemical criteria, proposed as an abnormal inflammatory infiltrate to be defined as ≥14 leucocytes/mm² including up to 4 monocytes/mm² with the presence of CD 3 positive T-lymphocytes ≥7 cells/mm².^3,4,13 In contrast to the definition of inflammatory cardiomyopathy, the term DCM is a strict morphological and functional diagnosis characterized by dilation and impairment right and/or left ventricular contraction that is not caused by abnormal loading conditions or coronary artery disease.

Aetiology of myocarditis and its specific treatment

Although the aetiology of myocarditis often remains undetermined, a large variety of infectious agents, systemic diseases, drugs and toxins may be the cause (Table 1). With the development of new molecular techniques such as polymerase chain reaction (PCR) and in situ hybridization, the spectrum of most frequently detected viruses in EMBs shifted from enteroviruses and adenovirus to mainly parvovirus B19 (PVB19) and human herpesvirus 6. Up to 50% of all cases may not have a clear underlying cause of dilated cardiomyopathy (i.e. idiopathic cases).^13,26,31

Infective causes

Viral myocarditis. Cardiotropic viruses such as enteroviruses (specifically Coxsackie group B) may cause direct cardiotoxic injuries, cytokine activation, cytoskeletal damage and autoimmune responses.^11,12 However, data suggest that the incidence of myocarditis after infection is lower than previously estimated. Viral myocarditis is often considered when accompanied by a clinical picture of recent febrile illness, often with prominent myalgias, followed by rapid onset of cardiac symptoms.^27,30 However, direct proof is lacking, and many cases of idiopathic dilated cardiomyopathies have been attributed to antecedent viral myocarditis.^12,32 The prognostic value of a viral genome amplified from heart tissue seems to vary with the virus. Still no antiviral therapy has been shown in a clinical trial (or adequately studied) to modify the risk of death or heart transplantation in acute myocarditis.^12,32–44 Thus, routine viral serology testing is not recommended by current guidelines.¹¹

Human immunodeficiency virus (HIV)-related cardiomyopathy. HIV disease has been recognized as an important cause of DCM, with an estimated incidence of 1.6%. HIV type 1 (HIV-1) virus appears to infect myocardial cells in a patchy distribution, leading to cytokine activation and progressive tissue damage.^45,46 Cardiac autoimmunity, nutritional deficiencies and drug toxicities (i.e. mitochondrial damage from zidovudine and vasculitis or coronary artery disease associated with highly active antiretroviral therapy regimens) are possible contributing causes.^47,48 In addition, other known viral pathogens, including cytomegalovirus, Epstein–Barr virus and Coxsackievirus B, have been isolated from EMB specimens of HIV-positive patients with myocarditis in conjunction with HIV nucleic acid sequences, suggesting that opportunistic viral infections may play an important role in the pathogenesis of this type of cardiomyopathy.^45–49

Giant cell myocarditis

Giant cell myocarditis (GCM) is a rare disorder of unknown aetiology. The hallmark feature is the presence of fused, multinucleated (> 20 nuclei) epithelioid giant cells of histocytic origin within a diffuse, intramyocardial inflammatory infiltrate with lymphocytes.^8,9,50–55

GCM often presents with an aggressive clinical course, with progression over days to weeks. Rapidly progressive heart failure is observed in 75% of affected patients. Sustained ventricular tachyarrhythmia occurs in 29% of patients with GCM and atrioventricular block occurs in 50%.^9,53,55

The prognosis is poor without therapy. Even with standard heart failure therapy the disease is often refractory leading to the requirement for mechanical circulatory support or heart transplantation. Long-term follow-up data on survival are currently not available.^51,52

Small observational series have suggested potential benefits of immunosuppressive therapy, but only one randomized, prospective multicentre study has been performed.⁵³ Consideration for early cardiac transplantation is appropriate (71% five-year survival after successful transplantation). Often, mechanical support may be required as a temporary bridge to recovery or transplantation.^54,56 A 20% to 25% rate of histologic recurrence in surveillance EMBs has been observed after transplantation.^53,55 However, as the retrospective analysis of Maleszewski et al. emphasized, biopsy-proven GCM can be successfully managed in the current era with combined immunosuppression, achieving a better long-term prognosis and even avoiding heart transplantation.^50,52

Hypersensitivity reaction (eosinophilic myocarditis)^13,31,57,58

Eosinophilic endomyocardial disease (i.e. Loeffler endomyocardial fibrosis) occurs as a major complication of idiopathic hypereosinophilic syndrome as a result of direct toxic damage caused by eosinophil granule proteins within the heart. Drug-induced eosinophilic myocarditis is independent of cumulative dose and duration of therapy.

The absence of peripheral eosinophilia does not rule out eosinophilic myocarditis. Although observational series suggest potential clinical benefits of corticosteroid therapy, the best strategy is to remove the causative agent, if it can be identified.

Medications that may cause eosinophilic myocarditis include the following (see Table 1):

a) Antibiotics (e.g. ampicillin, chloramphenicol, tetracycline and sulphisoxazole);

b) Diuretics (e.g. hydrochlorothiazide and spironolactone);

c) Anticonvulsants (e.g. phenytoin and carbamazepine);

d) Other drugs (e.g. lithium, clozapine and indomethacin);

e) Tetanus toxoid.

Collagen vascular diseases such as Wegener granulomatosis or Churg–Strauss syndrome (i.e. allergic granulomatosis and vasculitis) may also lead to eosinophilic myocarditis.

Other causes include parasitic infection, drug hypersensitivity, and cellular rejection after cardiac transplantation, as well as postvaccinia myocarditis after smallpox vaccination.

Immunological causes

Systemic autoimmune disorders. Although the histologic appearance of myocarditis occurring as part of sarcoidosis, systemic lupus erythematosus or polymyositis is similar to that seen in isolated myocarditis, the natural history is different. Systemic causes of myocarditis often respond poorly to medical therapy and cardiac transplantation, and their prognoses are often unfavourable. However, small retrospective surveys and case series have identified a significant decrease in mortality and improved clinical course among cardiac sarcoid patients treated with corticosteroids and other immunosuppressive strategies.

Immune checkpoint inhibitors. During the last few years the use of immune checkpoint inhibitors (ICIs) in cancer medicine has significantly increased.^59–61 Several side effects, including adverse cardiovascular events, have been recognized.^59–63 In particular, ICI induced myocarditis is a common cardiovascular side effect, with an approximate incidence of 1.9% amongst patients treated and a median time of onset of 34 days after starting ICI.⁶⁰ The disease requires immediate treatment due to a high mortality rate.

Clinical presentation and diagnosis of myocarditis

Myocarditis may present entirely asymptomatically or manifest with chest pain syndrome ranging from mild persistent chest pain of acute myopericarditis (35% of cases) to severe symptoms that mimic acute myocardial infarction.^2,31–34 Chest pain associated coronary artery vasospasm may rarely occur in patients with myocarditis. Alternatively, chest pain may be more typical for pericarditis, thus suggesting pericardial involvement.^{2,21,22,31,64–67}

Approximately 60% of patients may have antecedent arthralgias, malaise, fever, sweats or chills consistent with viral infections (e.g. pharyngitis, tonsillitis and upper respiratory tract infection) 1–2 weeks before onset.^20,21

The hallmark symptoms are those of heart failure (e.g. dyspnoea, fatigue and oedema). In many patients who develop heart failure, fatigue and decreased exercise capacity are the initial manifestations. However, diffuse, severe myocarditis can progress rapidly and result in acute myocardial failure and cardiogenic shock. In some instances, patients may present with arrhythmia in the form of syncope, palpitations due to heart block, ventricular tachyarrhythmia or even sudden cardiac death. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias. Palpitations secondary to premature atrial or ventricular contractions are common.^{13,23,25,26,28,45,65,68–71}

Signs of acute decompensated heart failure may include an S3-gallop (third heart sound), central and peripheral oedema, jugular venous distension, hepatomegaly, rales and wheezes, and tachycardia. An audible pericardial friction rub may accompany concomitant myopericarditis.¹¹

Coronary artery disease should be ruled out in the first instance, preferably through coronary angiography stenosis ≥ 50%). Second, pre-existing cardiovascular disease or other causes that may explain the clinical condition have to be excluded. As proposed in the position statement of Caforio et al. new criteria for the diagnosis of clinically suspected myocarditis were based on the clinical presentation consistent with the diagnosis and the presence of one or more abnormalities of non-invasive testing (Table 2).¹¹ In the scenario of clinically suspected myocarditis non-invasive imaging techniques, for example, cardiac magnetic resonance (CMR) imaging, may help to triage patients. EMB remains the gold standard for the definitive diagnosis of myocarditis. In patients without indication for EMB, CMR is the non-invasive gold standard for the diagnosis of myocarditis.

Table 2.

Diagnostic criteria for clinically suspected myocarditis.

• Clinical presentations: - Acute chest pain, pericarditic, or pseudo-ischaemic - New-onset (days up to three months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs - Subacute/chronic (>3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs - Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden cardiac death - Unexplained cardiogenic shock

• Diagnostic criteria: I. ECG/Holter/stress test features: - Newly abnormal 12 lead ECG and/or Holter and/or stress testing, any of the following: I- to III-degree atrioventricular block, or bundle branch block, ST/T wave change (ST-elevation or non-ST-elevation, T wave inversion), sinus arrest, ventricular tachycardia or fibrillation and asystole, atrial fibrillation, reduced R wave height, intraventricular conduction delay (widened QRS complex), abnormal Q waves, low voltage, frequent premature beats, supraventricular tachycardia II. Myocardiocytolysis markers: elevated TnT/TnI III. Functional and structural abnormalities on cardiac imaging (echo/angio/CMR): - New, otherwise unexplained LV and/or RV structure and function abnormality (including incidental finding in apparently asymptomatic subjects): regional wall motion or global systolic or diastolic function abnormality, with or without ventricular dilatation, with or without increased wall thickness, with or without pericardial effusion, with or without endocavitary thrombi IV. Tissue characterization by CMR: - Oedema and/or LGE of classical myocarditic pattern (see text)

Clinically suspected myocarditis if ≥1 clinical presentation and ≥1 diagnostic criteria from different categories, in the absence of: (1) angiographically detectable coronary artery disease (coronary stenosis ≥ 50%); (2) known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (e.g. valve disease, congenital heart disease, hyperthyroidism, etc.) (see text). Suspicion is higher with higher number of fulfilled criteria. If the patient is asymptomatic ≥2 diagnostic criteria should be met.

ECG: electrocardiogram; TNT: troponin T; TNI: troponin I; CMR: cardiac magnetic resononce; LV: left ventricle; RV: right ventricle; LGE: late gadolinium enhancement

Myocarditis should be suspected in the presence of:¹¹

One or more of the clinical presentations in Table 2 with or without additional features such as: fever over 38°C at presentation or within the preceding 30 days with or without evidence of respiratory of gastrointestinal infection; peri-partum period; personal and/or family history of allergic asthma, other types of allergy, extra-cardiac autoimmune disease, toxic agents; or family history of DCM, myocarditis;

And one or more of the diagnostic criteria from categories I–IV in Table 2;

If the patient is asymptomatic, two or more diagnostic criteria from categories I–IV.

In addition to the general characteristics mentioned above, there are specific findings in certain subtypes of myocarditis:

Sarcoid myocarditis: lymphadenopathy, also with arrhythmias and conduction defects, and sarcoid involvement of other organs (up to 70%);^45,48,72,73

Acute rheumatic fever (usually affects the heart in 50% to 90%): associated signs such as erythema marginatum, polyarthralgia, chorea, and subcutaneous nodules (i.e. Jones Criteria);⁷⁴

Hypersensitivity or eosinophilic myocarditis: pruritic maculopapular rash and history of onset temporarily related to initiation of potential culprit medications;^57,75

GCM: sustained ventricular tachycardia in rapidly progressive heart failure; presentation is aggressive with very high mortality if there is treatment delay.^{9,14,52,55,76,77}

Laboratory evaluation

Inflammatory markers of myocarditis^{21–23,26,34,35,64,66}

Complete blood count. Leucocytosis is common (often lymphocytic), although the presence of eosinophilia may suggest hypersensitivity (eosinophilic) myocarditis.^{1–3,11–15}

Elevated acute phase reactants such as erythrocyte sedimentation rates or ultrasensitive C-reactive protein are good monitors of clinical progression or response to therapy, but they have low specificity for myocarditis.^50,52,57 Novel inflammatory biomarkers under investigation include tumour necrosis factor-α, interleukins, interferon-γ, serum-soluble Fas, and soluble Fas ligand levels. Elevation of these markers portends a worse prognosis.^49–63 Erythrocyte sedimentation rates and C-reactive protein should be assessed in all patients.

Serum viral antibody titres are usually increased fourfold or more acutely and gradually fall during convalescence. However, there was no correlation between virus serology⁷⁸ and EMB findings and measurement of viral antibody titres is not recommended by current guidelines.^3,79–90

Anticardiac antibody titres. Because of their low specificity, measurement of anticardiac antibody titres (against sarcolemma, myosin, laminin, ADP/ATP translocator or β-adrenergic receptors) are currently not considered standard of care in suspected myocarditis (only 62% of myocarditis cases have titres≥ 1:40).⁹¹

Serum cardiac markers and enzymes

Cardiac troponins, creatine kinase and myoglobin levels are elevated in many cases of acute myocarditis; however, cardiac markers and enzymes are not specific for cardiac inflammatory processes. Cardiac troponin should be evaluated in all patients. Creatinine kinase is elevated in only 7.5% of patients with biopsy-proven myocarditis, whereas cardiac troponin I or T is elevated in at least 50% of patients with biopsy-proven myocarditis.^92,93 Concerning myoglobin, one study analysed the degree of myoglobin staining in EMBs of patients with myocarditis using immunohistochemistry and found that myoglobin expression relates to disease severity as well as the duration of acute myocarditis.⁹⁴ Since myocarditis typically presents as a systemic illness that may also affect skeletal muscle, it is plausible that more severe acute myocarditis may be associated with the release of myoglobin from skeletal muscle, which could contribute to higher blood levels of the markers.^95,96 Highly elevated cardiac markers and enzymes may help to rule in acute cases, but absence of them does not exclude myocarditis.⁹⁷ Moreover, a recent study showed that normalization of cardiac markers after three months does not predict convalescence as shown in CMR studies.⁹⁸ However, transcriptomic biomarkers of total and microribonucleic acids have shown promise to improve diagnostic and prognostic assessment of myocarditis in the future.^71,86,99,100

Rheumatologic screening

Screening of antinuclear antibodies and rheumatoid factor is indicated if the following conditions are suspected:^{2,11,22,25,29,82,101}

Systemic lupus erythematosus: anti-dsDNA (reported positive anti-Ro/SSA and anti-La/SSB in lupus carditis in children);

Polymyositis: anti-Jo1;

Wegener granulomatosis: c-ANCA (antineutrophil cytoplasmic antibody);

Scleroderma: anti-Scl70.

Diagnostic procedures

ECG

ECG is widely used for diagnostic screening. The ECG often reveals sinus tachycardia, although the presence of non-specific ST-segment and T-wave abnormalities may represent focal or global ischaemia. Occasionally, ECG changes may include ST-segment elevation, thus mimicking an acute myocardial infarction. Usually these ST elevations are concave and diffuse.^1,11 Pericarditis can accompany myocarditis and manifest with classic findings on ECG such as diffuse ST-elevations and PR-depression.¹⁶ Also, atrial or ventricular conduction delays as well as supraventricular and ventricular arrhythmias can occur in patients with inflammatory heart disease. In some cases, fascicular block or atrioventricular conduction disturbances and ventricular tachyarrhythmia may be haemodynamically significant. A prolonged QRS duration of ≥ 120 ms was found to be an independent predictor for cardiac death or heart transplantation.³¹ Hence, a 12-lead ECG should be performed in all patients with clinically suspected myocarditis.^11,102–107 The sensitivity of the ECG for myocarditis is low, (approximately 47%).¹

Echocardiogram

A complete echocardiogram is standard procedure for patients with suspected myocarditis in order to exclude alternative causes of heart failure, detect the presence of intracardiac thrombi and associated valvular disease, and quantify the degree of left ventricular (LV) dysfunction to monitor response to therapy. Thus, it does not provide direct evidence of myocarditis. Occasionally, focal wall motion abnormalities and presence of pericardial fluid may prompt further workup or intervention. The assessment of different echocardiographic parameters has also a relevant impact on the outcome of our patients. In a series of patients with biopsy-proven myocarditis, significant reduction in right ventricular function was a powerful predictor of death or the need for cardiac transplantation.^18,28,68,70

In recent years, the speckle-tracking method was increasingly used in the field of echocardiography for the diagnosis of myocarditis. Hsiao et al. demonstrated that LV strain and strain rate could be useful measurements for diagnosis of patients suspected of having myocarditis.^2,108

In summary, all patients with clinically suspected myocarditis should undergo a standard transthoracic echocardiogram at presentation. It should be repeated during hospitalization if there is a worsening of the patient’s haemodynamic status.³

Nuclear imaging

Antimyosin scintigraphy (indium III monoclonal antimyosin antibody) facilitates the identification of myocardial inflammation with high sensitivity of 91% and negative predictive value of 93%; however, low specificity (32%).¹¹ On the other hand, Gallium-67 scanning and, more recently, positron emission tomography using 18 fluorodeoxyglucose identifies severe myocardial cellular infiltration with high sensitivity. It is mostly being used in the acute phase of sarcoidosis and to monitor disease progression.^11,109–113

Coronary angiography

Coronary angiography is often indicated to rule out coronary artery disease as the cause of new-onset heart failure, because the clinical presentation of myocarditis may mimic myocardial infarction (i.e. pseudoinfarct pattern), especially if there are focal wall motion abnormalities and localizing electrocardiographic changes.^2,3,13,22,26 This may be performed through cardiac catheterization or coronary computed tomography in very young patients with low pre-test likelihood for coronary artery disease.

CMR imaging

CMR imaging has evolved as a non-invasive tool to support the diagnosis of myocarditis (Figure 1), as recommended by the American Heart Association scientific statement as Class IIB, level of evidence C.^44,114,115 It is reasonable to perform CMR in clinically stable patients prior to EMB or in scenarios in which EMB is not indicated. CMR imaging should not be performed in life-threatening scenarios where EMB is urgently indicated.^{3,31,77,115–117}

Figure 1.

Cardiac magnetic resonance findings in patients presenting with myocarditis.13

Ideally, CMR is used to identify acute, active myocardial inflammation, as it achieves the highest sensitivity if performed within two weeks of symptom onset. Thus, the T2-weighted oedema imaging is routinely used as a tool for evaluating the presence of ‘acute myocardial inflammation’ (Figure 1(a) and (b)).¹¹⁸ T1-weighted images obtained both before and a few minutes after gadolinium-infusion, also known as ‘early gadolinium enhancement phase’, are prone to possible artefacts that decrease its specificity, while several studies have demonstrated diagnostic value.^87,114,119

T1-weighted segmented inversion-recovery gradient-echo sequence was shown to be superior to others used for contrast-enhancement as it improved the difference in signal intensity between myocardial regions with and without gadolinium accumulation, thus differentiating between the healthy and the diseased myocardial regions. Such kind of method, also known as ‘late gadolinium enhancement (LGE) phase’ defines two common patterns of myocardial damage: either an intramural, rimlike pattern in the septal wall or a subepicardial distribution in the free LV-wall (Figure 1(c) and (d)). However, LGE imaging does not differentiate between acute and chronic inflammation but represents the damaged myocardial region.^11,13,87,119

In summary for CMR tissue characterization, the following applies:

Oedema is best seen in T2 imaging

Hyperaemia and capillary leak is a feature of early gadolinium enhancement (T1)

LGE (inversion recovery-prepared gadolinium-enhanced T1-weighted images) shows necrosis and fibrosis

As of today, current European Society of Cardiology guidelines recommend to base CMR findings on the Lake Louis Criteria using a combination of the three above-mentioned different CMR techniques. CMR findings are consistent with myocardial inflammation if at least two of the criteria below (a-c) are present.^3,114 Further CMR studies are consistent with myocardial injury and/or scar caused by myocardial inflammation if criterion (c) is present:

(a) Myocardial signal intensity increase in T2-weighted oedema images

(b) Increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in T1 images (before and after contrast injection)

(c) At least one focal lesion with non-ischaemic regional distribution in inversion recovery prepared gadolinium-enhanced T1-weighted images (LGE): foci exclude the subendocardial layer and involve the subepicardium.

Recently, consensus recommendations have been published to improve diagnostic accuracy of myocardial inflammation by addition of T2-weighted CMR imaging to the preexisting Lake Louise Criteria (LLC) for diagnosis of myocarditis (2018 LLC). When the original LLC were compared with the 2018 LLC, sensitivity was shown to be higher.¹²⁰

If a subtype of myocarditis is suspected that requires specific treatment, EMB is the diagnostic tool of choice.^{1,8,76,77,84,87,115,121–123}

The use of CMR also plays a role in patients with myocardial infarction and non-obstructive coronary artery disease.⁶⁷ As mentioned in a previous pilot study, using CMR led to a more than six-fold increase in the detection rate of myocarditis. Based on these findings, a novel diagnostic algorithm proposed by Patriki et al. led to an average 4.9-fold increase in the rate of myocarditis detection over two subsequent years.^67,124–131

Endomyocardial biopsy

The gold standard in the diagnosis of myocarditis is EMB, which identifies the underlying aetiology and the type of inflammation (e.g. giant cell, eosinophilic myocarditis, sarcoidosis). Results frequently impact therapy of the patient.^{8,11,23,29,48,77,84,111,121,122,132,133}

EMB should be considered in patients with rapid deterioration of cardiac function of unknown aetiology who do not respond to standard medical therapy.¹⁵ Incidence of biopsy-proven myocarditis in recent-onset, unexplained heart failure can be as low as 8% to 10%.¹²¹ Concerns have emerged that this is caused by low sensitivity of the Dallas criteria, and several recent trials evaluating immunosuppressive therapy have utilized supplemental pathologic criteria to assess myocarditis, including upregulation of human leukocyte antigen, replication of virus, and anticardiac antibodies.^{15,121,134,135}

False-negative rates are high (50% even with four or five biopsies) because of the small number of lymphocytes and difficulties in distinguishing cell types, with wide interobserver variability. To optimize diagnostic accuracy and reduce sampling error in focal myocarditis, EMB should be performed early in the course of the disease and multiple specimens should be taken. Tissue obtained from EMB should be analysed using histology, immunohistochemistry and viral PCR. At least three myocardial samples, each 1–2 mm in size, should be taken (from the right or from the left ventricle) and immediately fixed in 10% buffered formalin at room temperature for light microscopy; additional samples should be taken, snap frozen in liquid nitrogen and stored at –80°C, or stored in RNAlater tubes at room temperature, for viral PCR.^{3,6,77,116,136–138}

In addition, immunohistochemistry is gaining further acceptance in the diagnosis of myocarditis. To increase its diagnostic sensitivity, use of a large panel of monoclonal and polyclonal antibodies (including anti-CD3, T-lymphocytes, anti-CD68, macrophages; and anti HLA-DR) is required for the identification and characterization of the inflammatory infiltrate and for the detection of HLA-DR upregulation on EMB tissue sections as marker of infectious-negative autoimmune myocarditis where immunosuppression can be considered.^3,138

All patients with clinically suspected myocarditis should be considered for selective coronary angiography and EMB if a subtype is suspected that would require specific therapy based on histology (Table 2). EMB may be considered in patients with the following conditions in which a diagnostic biopsy may provide information on prognosis and/or therapeutic options:

(a) Rapidly progressive heart failure symptoms despite conventional therapy or new-onset frequent ventricular tachyarrhythmia or conduction disturbances;

(b) Suspected specific causes of myocarditis (e.g. GCM, eosinophilic myocarditis, cardiac sarcoidosis and vaccinia myocarditis).

Currently, EMB provides relatively high diagnostic and prognostic value in suspected myocarditis patients with low complication rates of < 1%.³

Treatment and management of myocarditis

Outcome and prognosis of myocarditis depends solely on aetiology, its clinical presentation and disease stage. Even though treatment of myocarditis should be focused on its causal pathophysiology, the effect of a specific causative therapy has been confirmed in only a few studies of inflammatory heart disease such as sarcoidosis and GCM. Because of the high incidence of LV dysfunction, additional standard heart failure therapy is generally recommended in those patients. Still there is a lack of clinical trials of heart failure therapy in patients with myocarditis.^{21,23–25,32,45,68,71,85,137,139–145}

Figure 2.

A proposed diagnostic approach for patients with suspected myocarditis according to characteristics shown in Table 2.

Heart failure management

Patients who present with myocarditis with acute dilated cardiomyopathy should be treated according to the current guidelines of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Standard heart failure therapy consists of diuretics, angiotensin-converting enzyme inhibitors, β-blockers and aldosterone antagonists. Calcium-channel blockers, are generally not recommended in the management of acute heart failure. Studies have not investigated when and how to discontinue standard heart failure therapy in patients who recover LV function⁵ There are no definitive recommendations yet and the decision should be made on an individual basis.

Because of its proarrhythmic properties in animal models, digoxin should be avoided. It has been shown that high doses of digitoxin increased myocardial production of pro-inflammatory cytokines and worsened myocardial injury.^139,144,147

Anticoagulation to prevent thromboembolic events is usually recommended in patients with apical aneurysm with thrombus (e.g. Chagas disease, atrial fibrillation and prior embolic episodes).^148,149

In cardiogenic shock due to acute myocarditis, particularly in fulminant myocarditis, where the haemodynamic status of the patient is severely compromised, inotropic therapy with milrinone levosimendane, dobutamine or mechanical circulatory support, including extracorporeal membrane oxygenation (ECMO) or mechanical assist devices (LV assist devices) for haemodynamic support and afterload reduction may provide a bridge to transplant or recovery. Nowadays according to some case reports the usage of Impella-based strategies with or without combination of extracorporeal life support (ECMO plus Impella), in combination with right ventricular Impella RP, or as a prolonged use of the LV-Impella can decrease both inflammation and afterload to promote myocardial recovery/remission in patients with chronic fulminant myocarditis. Clinical trials will be required to provide sufficient evidence for general guidelines and recommendations.^{13,17,21,54,56,65,150–158}

On the other hand, early consideration for cardiac transplantation should be given especially to patients with progressive, biopsy-proven GCM or other types of fulminant myocarditis. Patients with myocarditis have increased rates of rejection and reduced survival after heart transplantation compared with those without myocarditis, and recurrent disease may affect the allograft.^{6,21,51,53–55,139}

Non-steroidal anti-inflammatory drugs and colchicine

Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine have been have been established as first-line therapy in pericarditis. Aggressive therapy is necessary to prevent severe complications such as constrictive pericarditis. However, the clinical data on the effect of NSAIDs in myopericarditis are limited. In the first case–control study performed by Berg et al. it was shown that high-dose ibuprofen and aspirin appear to be safe in the setting of acute myopericarditis with normal LV ejection fraction.^157–166 In the same study, it was observed that there was a trend for decreasing LGE in patients under NSAID therapy. In the future, this treatment approach should be tested prospectively in a large clinical trial.^{3,13,26,29,159–168}

Exercise restriction

In the event of increased physical activity during the acute phase of myocarditis, there may be a risk of worsening myocardial inflammation and necrosis, cardiac remodelling and death, as had been shown in animal models. Myocarditis is a common cause of sudden death in young athletes and young adults.⁷ Thus, patients are usually advised to abstain from vigorous exercise for up to six months or longer after the onset of symptoms. The length of activity restriction can be based of recovery of LV function. However, the duration of abstinence from competitive sports after recovery from acute myocarditis is still a matter of debate.^{13,141,169–171}

Arrhythmia management

First line therapy consists of β-blockers, amiodarone and sotalol. Permanent pacemakers are used for heart block or bradyarrhythmia.^23,45,49,68

The insertion of implantable cardioverter-defibrillators (ICDs) is indicated for patients in the chronic phase with persistently low ejection fraction and for those with malignant arrhythmias that are refractory to medical therapy. Cardiac resynchronization therapy with defibrillator function is indicated for patients with impaired LV function (ejection fraction ≤ 35%) and left bundle branch block in New York Heart Association (NYHA) functional class II–IV.^70,73 However, a premature implantation of an ICD or a cardiac resynchronization therapy/ICD system should be avoided in patients with inflammatory cardiomyopathy as LV function may improve significantly with guideline-based heart failure therapy.^139,155

Immunomodulatory therapy

Because a mechanism-based therapy of myocarditis is not proven, different approaches have been investigated in clinical trials in recent years.¹¹

High dose intravenous immunoglobulin treatment

In a number of systematic autoimmune diseases such as sarcoidosis or systemic lupus erythematosus, it has been shown that high dose intravenous immunoglobulin (IVIG) modulates the immune and inflammatory response by a variety of mechanisms. On the other hand, in recent onset myocarditis and DCM, there was no difference in LV function in patients receiving intravenous immunoglobulin versus patients given placebo. However, in the absence of randomized clinical trials in biopsy-proven myocarditis/DCM of viral or autoimmune origin, the usage of IVIG is currently not recommended by the European Society of Cardiology.^172–175

Immunoadsorption

The main concept of immunoadsorption is the elimination of serum cardiac autoantibodies against various cardiac cell proteins, which have been identified in patients with DCM and myocarditis.⁹¹ In addition, immunoadsorption decreased myocardial inflammation and in patients with inflammatory cardiomyopathy it has been shown that LV systolic function was improved after protein A immunoadsorption. Similar to IVIG treatment, the usage of immunoadsorption is not recommended by the European Society of Cardiology.^176–182

Antiviral therapy

The rationale to use antiviral therapy results from the fact that most common cases of myocarditis are considered to be induced by viral infections. In patients with herpes virus infection, although their clinical efficacy in myocarditis is unproven, a treatment with acyclovir, ganciclovir and valacyclovir may be considered in treatment refractory cases. Several studies on interferon treatment suggest that it eliminates enteroviral and adenoviral genomes in patients with LV dysfunction, it shows an improvement in NYHA functional class and in patients with enteroviral infection is associated with a better 10-year prognosis.^3,183–186 Similar to immunoadsorption and IVIG, interferon therapy has currently not been established as recommended standard therapy in myocarditis.

Immunosuppressive therapy

Clinical trials with immunosuppressive agents such as cyclosporine, prednisolone, azathioprine and steroids in acute myocarditis provided controversial results. Routine immunosuppressive therapy is not recommended because of the neutral findings from multiple trials, including the Myocarditis Treatment Trial and the Intervention in Myocarditis and Acute Cardiomyopathy study. There is no Food and Drug Administration-approved regimen for the treatment of acute and chronic myocarditis.^{2,23,29,30,32,34,36,37,41,42,78,85,89,136,147,177,187–195}

Still, consideration is reserved for patients with new-onset, rapidly deteriorating, advanced heart failure with suspicion of the following conditions:

GCM is treated with combination therapy of prednisolone and cyclosporine with or without muromonab-CD3 – favourable outcome in retrospective and prospective studies at one year;^9,50–53,55

Eosinophilic or sarcoid myocarditis is treated with high-dose steroids;

Specific therapy for underlying collagen vascular diseases, if present;

In therapy refractory cases with high inflammatory component and no signs of viral replication in histology and PCR, immunosuppression may be considered.

The most recent Heart Failure Society of America guidelines do not recommend routine use of immunosuppressive therapy in patients with myocarditis. More data are needed to identify patient cohorts who will benefit from tailored antiviral and immunosuppressive therapy.

Follow-up

The large majority of patients with myocarditis will recover entirely. Despite recovery of ventricular function, patients frequently complain about a ‘Gripping Chest Pain Syndrome’ as we suggest to call it – a phenomenon in which patients continue to have episodes of sudden, sharp chest pain that feels as if their heart is being squeezed from all sides. The patients typically describe these episodes as a hand holding their heart and squeezing it from outside. The episodes typically last seconds and resolve spontaneously. Symptoms typically subside after a year. Many patients report it, but the pathological relevance of it is not know as of today. Few cases relapse after several years.

In clinical practice, the current myocarditis guidelines recommend to discharge patients when cardiac markers have normalized. High-risk patients may be observed slightly longer and followed as outpatients in shorter intervals, as we have recently shown that disease activity may continue despite normalization of cardiac marker.⁹⁸ Currently, one- to three-month clinical follow-up examinations are recommended after diagnosis to adjust standard heart failure medication or immunosuppression. Serial echocardiographic assessment of ventricular structure and function is often performed, although there are no definitive guidelines regarding the required intervals of echocardiographic assessments after myocarditis.^2,11,13,22 If during follow-up a worsening of the clinical status of a patient is noticed based on history, physical exam, cardiac echocardiography and blood testing (elevated cardiac markers), the patient should be readmitted to undergo EMB or CMR imaging, depending on the degree of illness.³

Prognosis and outcome

The prognosis of patients with myocarditis depends on a series of factors such as clinical presentation, clinical parameters and EMB findings. Patients with acute myocarditis and preserved LV function have a good prognosis with a high rate of spontaneous improvement. Based on population studies, the clinical presentation varies from minor symptoms to cardiogenic shock. Some adults may present with heart failure years after the initial index event of myocarditis.¹⁴ Therefore, at least yearly visits to a cardiologist after an episode of myocarditis are advisable.

Many patients with fulminant myocarditis may have full spontaneous clinical recovery, even after weeks of mechanical support (e.g. intra-aortic balloon counterpulsation and mechanical assist devices). Case series report an 11-year survival rate of 93% for patients with fulminant myocarditis and 45% for non-fulminant myocarditis. On the other hand, in patients with cardiac sarcoidosis or GCM, prognosis depends on an early initiation of treatment (immunosuppressive therapy or transplantation).

Concerning predictors of morbidity and mortality, unfavourable factors for survival include extremes of age (i.e. very old or very young), electrocardiographic abnormalities (e.g. QRS alternations, atrial fibrillation and low voltage), syncope and specific diagnoses (e.g. peripartum cardiomyopathy and GCM). However, favourable factors for survival include normal ventricular function, and shorter clinical history before presentation.^16,19,77,196

Further studies to investigate the utility of novel tools for the analysis of EMB and improvement of diagnostic and prognostic assessment of myocarditis by means of transcriptomic, proteomic or genetic analysis have shown promising results.^{71,86,99,100,187}

Conclusions

Myocarditis is an underdiagnosed cardiac disease resulting from a broad range of infectious, immunologic and toxic causes. Affected patients may recover, develop DCM or even deteriorate to advanced heart failure and death. Although remarkable advances in diagnosis, understanding of pathophysiological mechanisms and treatment of myocarditis have been made during the last decade, standard treatment strategies remain limited to guideline-based heart failure therapy in most cases. New treatment strategies such as immunomodulating and immunosuppressive therapy have been effective only in specific cases of virus-negative inflammatory cardiomyopathy. On the other hand, immunosuppressive therapy is beneficial for GCM and sarcoidosis, as well as patients with acute myocarditis associated with systemic autoimmune diseases, such as systemic lupus erythematosus.

There is some evidence that antiviral treatment and antimicrobial agents may have beneficial effects; however, large randomized-controlled studies are needed to determine their role in treatment of myocarditis. Collaborative networks will be necessary to gather sufficient evidence for guidelines.

Footnotes

Conflict of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Update on myocarditis – what we know so far and where we may be heading

Abstract

Introduction

Clinicopathologic classification of myocarditis

WHO/ISFC definition

Aetiology of myocarditis and its specific treatment

Infective causes

Giant cell myocarditis

Hypersensitivity reaction (eosinophilic myocarditis)13,31,57,58

Immunological causes

Clinical presentation and diagnosis of myocarditis

Laboratory evaluation

Inflammatory markers of myocarditis21–23,26,34,35,64,66

Serum cardiac markers and enzymes

Rheumatologic screening

Diagnostic procedures

ECG

Echocardiogram

Nuclear imaging

Coronary angiography

CMR imaging

Endomyocardial biopsy

Treatment and management of myocarditis

Heart failure management

Non-steroidal anti-inflammatory drugs and colchicine

Exercise restriction

Arrhythmia management

Immunomodulatory therapy

High dose intravenous immunoglobulin treatment

Immunoadsorption

Antiviral therapy

Immunosuppressive therapy

Follow-up

Prognosis and outcome

Conclusions

Footnotes

Conflict of interest

Funding

References

Hypersensitivity reaction (eosinophilic myocarditis)^13,31,57,58

Inflammatory markers of myocarditis^{21–23,26,34,35,64,66}