Myocarditis I51.4

Chronic myocarditis was already known as a heart muscle disease in the mid-18th century. Around 1900, the term primary myocardial disease appeared. And it was not until 1957 that the term cardiomyopathy was coined, although by 1980 there were several definitions. It was not until 1995 that the WHO classification "heart muscle diseases that lead to heart dysfunction" was coined, which now also includes arrhythmogenic right ventricular cardiomyopathy (ARVC) and restrictive cardiomyopathy (Ludwig 2008).

Myocarditis is an acute or chronic inflammatory disease of the heart muscle cells, which can also affect the interstitium and coronary vessels (Emminger 2010) and is defined by immunological, histochemical and histological criteria (Herold 2018).

According to the WHO, myocarditis is one of the acquired forms of primary cardiomyopathies (Schumacher 2008).

A differentiation is made between:

• acute myocarditis (onset of the disease < 2 weeks)
• chronic myocarditis (so-called inflammatory cardiomyopathy; this can develop into dilated cardiomyopathy.

According to the findings of the biopsy, myocarditis is subdivided according to the criteria of WHF-

Classification of 1999 (Michels 2010):

Active/acute myocarditis. In the bioptate are found:

• Lymphocytic infiltrate with monoclonal antibodies immunoglobulin and complement fixation.

Persistent myocarditis. In the bioptate are also found:

• an expression of HLA-I and HLA-II antigen
• Adhesion molecules (ICAM)

Healing Myocarditis

• Evidence of a decreasing infiltrate
• Evidence of a decreasing HLA- I- and HLA- II- expression

Borderline myocarditis. In the bioptate are detectable:

• < 14 lymphocytes/ mm²

Chronic myocarditis or inflammatory cardiomyopathy. Detection of:

• > 14 lymphocytes (plus macrophages) / mm², immunoglobulin and complement fixationHistological differentiation according to the 1987 Dallas classification ( Michels 2010):

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For the diagnosis of acute or active myocarditis the following evidence is required:

• inflammatory infiltrate
• Edema
• Myocytolysis

In persistent myocarditis the picture is unchanged:

• inflammatory infiltrate
• Edema
• Myocytolysis

With the healing myocarditis one finds:

• a receding infiltrate
• a reparative fibrosis
• a myocytolysis that is only facultative

Borderline myocarditis is characterized by:

• interspersed lymphocytes < 14 lymphocytes / mm²
• there is no myocytolysis

The chronic or inflammatory cardiomyopathy:

• this is not defined in the Dallas criteria

The number of unreported cases of myocarditis is very high. In sudden deaths of young adults, myocarditis is found in about 10% of autopsies (Herold 2018).

Myocarditis is divided into a:

• infectious
• and
• a non-infectious form.

The infectious form can be caused by almost all pathogens, most frequently by viruses and Trypanosoma cruzi (pathogen of Chagas disease - Kasper 2015).

According to Herold 2018, infective myocarditis can be caused by:

• viruses (applies to about 50% of the diseases):

Enteroviruses (are with approx. 33 % the second most common in Germany [Pinger 2019]) Coxsackie A, Coxsackie B1 - B5, Epstein-Barr virus, human herpes virus 6 (HPV6), adenoviruses (detectable in 8 % [Pinger 2019]), echo viruses, influenza viruses, HIV, hepatitis C viruses, parvovirus B 19 (are the most frequently detectable viruses in Germany with approx. 37 % [Pinger 2019]) and others.

• bacteria:
  • in a septic course, especially bacterial endocarditis caused by enterococci, staphylococci etc.
  • beta-hemolytic streptococci of the serogroup A (e.g. in angina tonsillaris, erysipelas, scarlet fever)
  • Borrelia burgdorferi (Lyme disease)
  • Diphtheria
  • Syphilis (rare)
  • Typhoid fever (less common)
  • Tuberculosis (rare)
• Mycoses (especially with immunosuppression)
• Protozoa (Chagas disease, see above, toxoplasmosis)
• Parasites (echinococcus, trichinae etc.)

Non-infectious myocarditis can be caused by:

• collagenosis
• Rheumatoid Arthritis
• Vasculitides
• n. a radio of the mediastinum
• Hypersensitivity myocarditis (eosinophilic form, caused by drugs such as sulfonamide, penicillin, tetracycline, streptomycin, paraaminosalicylic acid, methyldopa etc.) [Roskamm 1999])
• Giant cell myocarditis (also called idiopathic interstitial fiddler's myocarditis)

Note: Due to cross-antigenicity of viral and myocardial structures, virus-induced myocarditis can lead to immune phenomena.

Acute myocarditis: In about 75% of cases passagere antibodies are detectable. These usually disappear again after clinical improvement. Diagnostically they are of no importance. They are the following antibodies:

• Antimyolemmal antibodies of type IgM (AMLA)
• Antisarcolemmal antibodies of the IgM type (ASA)
• IgM antibodies and complement factor C3 can be detected in myocardial biopsy

Chronic myocarditis: In the chronic form the following antibodies may be detectable:

• Auto- antibodies against beta1- adrenergic receptors

The majority of myocarditis is asymptomatic (Emminger 2010). But there are also fulminant courses with lethal outcome. However, these are rare (Herold 2018). In most cases, myocarditis is directly related to a previous infection. The following symptoms can occur in myocarditis:

• Acute thoracic pain in the sense of pericarditis or pseudo-ischemic
• acute dyspnea (not lasting longer than 3 months) or chronic dyspnea (lasting longer than 3 months)
• Fatigue
• Signs of heart failure
• Palpitations
• Arrhythmias
• uncertain syncopations
• cardiogenic shock
• survived cardiac death

Echocardiography: In many cases, echocardiography reveals unremarkable findings. However, regionally, disturbances in kinetics may occur. In the presence of heart failure, the heart may be dilated and show a decreased ejection fraction. If pericarditis is concomitant, pericardial effusion may be detectable (Herold 2018).

Focal regional wall thickening indicative of existing edema is also possible (differential diagnosis may eventually require exclusion of HCM). Similarly, systolic left ventricular dysfunction of varying severity, right ventricular dysfunction, or diastolic dysfunction (differential diagnostic exclusion of RCM) may be detectable (Pinger 2019). However, an unremarkable finding on echocardiography does not exclude myocarditis (Pinger 2019).

Scintigraphy: Indium-labeled anti-myosin antibody testing shows a high negative predictive value of 92%. However, to date, this examination has not gained acceptance (Pinger 2019).

Chest X-ray

The radiograph is usually unremarkable at baseline, but may show cardiac enlargement later in the course due to coexisting heart failure (Herold 2018). Signs of pulmovenous congestion may likewise be present (Reinhardt 2007).

Cardiac MRI

Cardiac MRI is currently the best non-invasive modality for myocarditis and should always be performed when myocarditis is suspected. The changes are evaluated according to the so-called Lake-Louise criteria. Typically, the following findings can be obtained in the case of myocarditis:

Edema: Inflamed areas show hyperintensity (edema) in the fat-saturated T2- weighting; a ratio > 1.9 is considered pathological and represents an indication of myocardial edema (Niebauer 2015).

Early gadolinium enhancement: hyperemia occurs when a capillary leak exists (Pinger 2019). In T1- weighting after contrast administration, the uptake of contrast in the inflamed areas is measured and related to the contrast uptake of skeletal muscle. The normal ratio is < 2.5; early gadolinium enhancement with ratios above 4.0 or an absolute increase of > 45% are indicative of myocarditis (Herold 2018).

Late Gadolinium Enhancement: A 0late gadolinium enhancement indicates irreversible cell damage (Pinger 2019). The inflammatory altered areas of the myocardium take up contrast in delayed enhancement sequences (also called late gadolinium enhancement), which occurs subepicardially in the acute phase of myocarditis, especially in the inferior lateral wall portions of the left ventricle.

In myocardial infarction, however, unlike myocarditis, the accumulation of contrast agent is typically subendocardial and can be assigned to a coronary artery supply area (Puls 2010). Both T1-weighting and T2-weighting have their limitations in the presence of concomitant skeletal muscle inflammation (Niebauer 2015).

Possible signs of inflammation (leukocytosis, BSG acceleration, CRP increase, etc.)

Increase of CK / CK- MB (the positive predictive value is low, however, as an increase is only found in about 10% of the affected patients [Pinger 2019])

Troponin T/I may be elevated (the positive predictive value is also low [Pinger 2019])

virological or bacteriological examination including stool testing for enteroviruses

BNP can increase with the onset of heart failure, but also during inflammation of the heart muscle

the detection of auto-antibodies is rather unspecific and plays hardly any role

According to the findings of the biopsy, myocarditis is classified according to the criteria of the WHF classification of 1999 (Michels 2010). In case of persistent myocarditis the bioptate:

1. an expression of HLA- I- and HLA- II- antigen
2. Adhesion molecules (ICAM)

Indications of a healing myocarditis are:

• Evidence of a receding infiltrate
• Evidence of a decreasing HLA- I- and HLA- II- expression

In borderline myocarditis the following are detectable: < 14 lymphocytes/ mm²

The diagnosis of myocarditis is still a challenge today. The gold standard is still myocardial biopsy (Kandolf 2011). However, the myocardium usually shows heterogeneous involvement and thus provides false negative results. Therefore, to standardize the examination methods and to compare the myocardial changes, the so-called Lake- Louise criteria (see below for cardio- MRI) were established for the first time in 2009. These show a sensitivity of 67% and a specificity of 91% (Schuler 2017).

In December 2018, a revision of these criteria took place. Thereby, late gadolinium enhancement was left as a single factor (see also w. u. [Maintz 2019]).

According to the 2013 ESC diagnostic criteria, the diagnosis of "myocarditis" can be made if 1 pathologic finding is true in symptomatic patients, and at least 2 pathologic findings are true in asymptomatic patients of:

• abnormalities in the ECG
• elevation of troponin T/I
• corresponding pathological imaging
• tissue characterization in MRI

Kasper (2015) speaks of a confirmed diagnosis of acute myocarditis only when inflammation can be demonstrated in the endomyocardial biopsy either histologically or immunohistochemically. He does not consider other clinical or laboratory criteria to be mandatory. Other diseases that could explain the findings raised must have been previously excluded (Pinger 2019).

Auscultation: Auscultation is rather nonspecific. Volatile systolic murmurs may be present, a pericardial rub may be auscultated in perimyocarditis, and a 3rd heart sound may be present if heart failure is present (Herold 2018).

Laboratory: see there

Imaging (see there).

Molecular and immunohistological differences of inflammatory myocardial diseases:

• immunohistologically, there is active inflammation in virus-positive myocarditis and an active immunologic process in myocarditis triggered by an autoimmune reaction
• molecular biology reveals viral persistence in viral myocarditis and virus-positive myocarditis. No evidence of viral persistence is found in postmyocarditic myocardial disease.

(Long-term) ECG: There are often changes in the ECG, but usually these are only passively detectable.

• Sinus tachycardia
• Arrhythmias
• Conduction disorders (e.g. AV block) occur frequently in diphtheria and Lyme carditis.
• Signs of inner layer damage with
  • ST depression
  • Flattening of the T wave
  • T- negation
• monophasic elevation of the ST segment in the sense of an external damage with simultaneous existing pericarditis (so-called myopericarditis)
• a low voltage can exist

In case of inconspicuous findings in cardio- MRI and clinical suspicion of myocarditis or only one positive MRI- criterion, control of an MRI after 1- 2 weeks is recommended (Pinger 2019).

Endomyocardial biopsy: Because endomyocardial biopsy shows very limited sensitivity (when 10 biopsies were taken, only 37% were positive in those with disease), the indication for biopsy should be based solely on potential therapeutic consequences (Pinger 2019).

Herold (2018) recommends biopsy in the following cases:

• Acute myocarditis (onset of disease < 2 weeks).
• in cases of severe progression to identify rare etiologies, provided that this results in therapeutic consequences (e.g., giant cell myocarditis; if suspected, in this case the start of therapy should be before the pathology result is obtained).

Schwimmbeck (2015), referring to the American Heart Association (AHA) guidelines, considers myocardial biopsy to be indicated in the presence of acute myocarditis:

• heart failure with dilated or normal-sized ventricle and hemodynamic compromise that has been present for less than 2 weeks and has occurred for the first time (recommendation class I, evidence level B)
• First-ever heart failure of more than 2 weeks but not more than 3 months with new-onset arrhythmias, second- or third-degree AV block, or failure to respond to symptomatic treatment within 1 to 2 weeks and dilated left ventricle (recommendation class I, evidence level B)
• Existing dilated heart failure in which an allergic reaction or hypereosinophilia is suspected (recommendation class IIa, evidence level C).

Evaluation of a myocardial biopsy should be performed exclusively in specially equipped and experienced centers (Schwimmbeck 2015).

Histology: The gold standard is still a typical histological finding. However, this typical finding - despite targeted biopsy from the late enhancement areas localized on cardiac MRI and processing of the biopsies both histologically and immunohistochemically and by PCR - can only be detected in 37% to max. 63% of patients (Pinger 2019).

The Dallas- criteria, established in 1987, were revised in 1998 in the WHO / ISFC- classification. Two ISFC- expert groups defined the immunohistological criteria of an inflammation of the myocardium as given if the following changes are present (Maisch 1998):

• > 14 lymphocytes mm³ resp.
• > 14 macrophages / mm³ required

Coronary angiography: Coronary angiography should only be performed if the previous aforementioned examinations do not allow the differential diagnosis of coronary artery disease to be excluded (Herold 2018).

• restrictive cardiomyopathy (RCM)
• Hypertrophic cardiomyopathy (HCM)
• Dilated cardiomyopathy (DCM)
• Coronary heart disease (CHD)
• Myocardial infarction

The differential diagnostic exclusion of myocarditis is not possible with certainty even at the current state of the art. According to the recommendations of the ESC 2013, all patients with urgent myocarditis, which could not be detected or excluded by previous diagnosis, should undergo coronary angiography as well as endomyocardial biopsy (Pinger 2019).

Causal therapy

Causal treatment options include

• Penicillin in e.g. Lyme carditis, diphtheria, rheumatic myocarditis, Chagas disease etc. (Herold 2018).
• Antiviral therapy: Up to now there is no evidence for an improvement of the prognosis by the administration of antiviral drugs, even in the case of viral DNA / RNA detected by myocardial biopsy. Therefore, antiviral treatment cannot be recommended at present (Herold 2018).
• Immunosuppressive therapy: The administration of immunosuppressive drugs should be decided on a case-by-case basis only, as studies have not yet been able to demonstrate a positive benefit in terms of prognosis. However, there is an indication, for example, for virus-negative (detection by PCR from a myocardial biopsy is required) chronic lymphocytic myocarditis, giant cell myocarditis, autoimmune myocarditis (auto AK detection is required), eosinophilic myocarditis. It is advisable to contact centres that have treatment protocols (Herold 2018).

The treatment of any existing heart failure should be standard. If haemodynamic instability occurs, implantation of an ECMO (extracorporeal membrane oxygenation) may be recommended (Pinger 2019).

Standardized therapy should also be used when arrhythmias occur. An ICD implantation (implantable cardioverter, also called defibrillator) for prophylaxis is not recommended less than 3 months after manifestation of the disease (Pinger 2019).

In 2015, the European Society of Cardiology (ESC) issued a IIa recommendation for wearing an ICD vest for bridging until the myocardium has recovered. Also for patients with severe left ventricular dysfunction and/or with ventricular instability or with inflammatory heart disease such bridging until ICD implantation is recommended (Pinger 2019).

Symptomatic therapy. Symptomatic measures include:

- physical rest as long as there are signs of heart failure (AU- certificate Herold 2018). Pinger (2019) recommends rest for at least 6 months or until ventricular function has recovered. However, he also points out that the duration of physical rest is still completely unclear.

- According to Herold (2018), anticoagulants for thrombosis prophylaxis are necessary as soon as signs of dilated cardiomyopathy become apparent

- The administration of NSAIDs is associated with increased mortality (although controlled studies are lacking). Nevertheless, treatment with NSAIDs is not recommended (Pinger 2019).

Heart Transplantation

If the success of the therapy is insufficient, heart transplantation is the only way to improve the course of the disease. In this case an early listing should be made (Herold 2018).

The vast majority (> 80 %) of viral myocarditis heals completely.

However, harmless rhythm disturbances can persist in > 80 %.

Acute complications, such as severe dysrhythmia, conduction disorders, heart failure can - relatively rarely - lead to a lethal course. High complication rates are mainly found in Coxsackie-B infection (especially infants are at risk), diphtheria and Chagas disease (Herold 2018).

A chronic course is found in about 15% of the patients. These patients develop a dilated cardiomyopathy with signs of heart failure. Granulomatous necrotizing myocarditis has a particularly bad prognosis with a predominantly lethal course (Herold 2018).

A particularly severe course is shown by fulminant lymphocytic myocarditis, which requires intensive care. Here, the lethality rate in the first 4 weeks is over 40% (Kühl 2012).

A poor prognosis is also found for giant cell myocarditis. The average survival time without treatment is about 3 months (Kohl 2000). In about 70 % of patients a heart transplantation is necessary within one year (Magerkurth 2008). Recurrences in transplantation are also not uncommon (Kohl 2000). They occur in 20% - 25% of cases (Cooper 2012).

Even non-valent active myocarditis shows a lethality rate of 25% to 56% within 3 to 10 years due to progressive heart failure and also sudden cardiac death (Cooper 2012).

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