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Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis

In clinical practice myocarditis is increasingly recognized and represents a challenging condition either for diagnostic or therapeutic issues. Nevertheless, there are no specific guidelines issued by international major Cardiology societies to guide management. In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aim of the paper is to improve management and provide stadardised criteria for future registries and clinical research on myocarditis. Selected highlights of the ESC report will be presented.
Myocarditis is a challenging diagnosis. The real incidence is unknown since endomyocardial biopsy (EBM), the diagnostic gold standard is infrequently used in clinical practice. In young adults who died for sudden death, myocarditis has been reported from 2 to 42% of necropsic cases. Biopsy-proven myocarditis is reported in 9 – 16% of adult patients with unexplained non-ischaemic dilated cardiomyopathy (DCM) and in 46% of children with an identified cause of DCM. Myocarditis often resolves spontaneously without specific treatment. However progression to DCM has been reported in up to 30% of biopsy-proven cases. Prognosis in myocarditis patients also varies according to the underlying aetiology.
Myocardial Disease


Definitons :

  • Myocarditis (WHO /ISFC): Inflammatory disease of the myocardium diagnosed by established histological*, immunological and immunohistochemical criteria**.

*N.B. established histological Dallas criteria defined as follows: ‘histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non- ischaemic origin.
**N.B. unspecified immunohistochemical criteria, we propose an abnormal inflammatory infiltrate to be defined as follows: ≥14 leucocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD 3 positive T-lymphocytes ≥7 cells/mm2’.

  • Inflammatory Cardiomyopathy (WHO /ISFC): Myocarditis in association with cardiac dysfunction.

N.B. Inflammatory cardiomyopathy, involved in the pathogenesis of DCM, includes idiopathic, autoimmune and infectious subtypes. Dilated Cardiomyopathy (ESC; WHO /ISFC):
DCM is a clinical diagnosis characterized by dilation and impaired contraction of the left or both ventricles that is not explained by abnormal loading conditions or coronary artery disease.
N.B. DCM includes idiopathic, familial/genetic, viral and/or immune, alcoholic/toxic subtypes.
The histological diagnosis of myocarditis includes different forms, classified according to the type of inflammatory cell infiltrate: lymphocytic, eosinophilic, polymorphic, giant cell myocarditis, and cardiac sarcoidosis.

Aetiology

Although the aetiology of myocarditis often remains undetermined, a large variety of infectious agents, systemic diseases, drugs, and toxins can cause the disease. Viral infections are the most important cause of myocarditis in North America and Europe with genomes of enterovirus, adeno- virus, influenza viruses, human herpes virus-6 (HHV-6), Epstein-Barr-virus, cytomegalovirus, hepatitis C virus, and parvovirus B19 reported in the myocardium of patients with myocarditis and DCM. Lymphocytic and giant cell myocarditis are presumed idiopathic or autoimmune if no viruses are identified in EMB and other known causes are excluded. Similarly, the diagnosis of idiopathic granulomatous myocarditis (cardiac sarcoidosis) requires negative stains for microorganisms. Autoimmune myocarditis may occur with exclusive cardiac involvement or in the context of autoimmune disorders with extra-cardiac manifestations, (especially hypereosinophilic syndrome, scleroderma, and systemic lupus erythematosus).
In human myocarditis, there is evidence for viral and autoimmune mechanisms, acting in individuals with or without a genetic predisposition (familial or sporadic cases, respectively). Genetic factors also play a major role in the progression to DCM.

Clinical Presentation

Myocarditis presents in many different ways, ranging from mild symptoms of chest pain and palpitations associated with transient ECG changes to life-threatening cardiogenic shock and ventricular arrhythmia. Cardiologists may be especially challenged by ACS-like presentations that have been increasingly reported in recent years. The disease may affect individuals of all ages, although it is most frequent in the young. This diversity of clinical scenarios implies that the diagnosis of myocarditis requires a high level of suspicion early in the course of the disease and the use of appropriate investigations to identify its cause. In all cases of suspected myocarditis, it is mandatory to exclude coronary artery disease and other cardiovascular, e.g. hypertension, or extra-cardiac non-inflammatory diseases that could explain the

The gold standard for the diagnosis is EBM. However, in clinicial practice non-invasive imaging techniques such as cardiac magnetic resonance (CMR) imaging can be useful in making the diagnosis of myocarditis and for monitoring disease progression.

Ancillary features which support the clinical suspicion of myocarditis include:

  • Fever ≥38.0°C at presentation or within the preceding 30 days with or without evidence   of a respiratory (chills, headache, muscle aches, general malaise) or gastrointestinal (decreased appetite, nausea, vomiting, diarrhoea) infection
  • Peri-partum period
  • Previous clinically suspected or definite myocarditis
  • Personal and/or family history of allergic asthma, other types of 
allergy, extra-cardiac autoimmune disease, toxic agents
  • Family history of DCM,myocarditis(according to the present criteria).

Proposed diagnostic criteria for clinically suspected myocarditis include:

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.). Suspicion is higher with higher number of fulfilled criteria.
If the patient is asymptomatic ≥2 diagnostic criteria should be met.

Clinical Presentation

I. Acute chest pain, pericarditic, or pseudo-ischaemic

II. New-onset (days up to 3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs

III. 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

IV. Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden cardiac death

V. 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.
According to the Task Force experts a definite diagnosis of myocarditis requires EBM confirmatory findings of the clinically suspected cases.

Comment

The WG report on myocarditis is the first attempt to provide specific diagnostic criteria and management recommendations for myocarditis by an International Cardiology Society.
The report summarizes current knowledge on the aetiology, pathogenesis and diagnosis of myocarditis and may provide standardised definitions to be used in future registries and clinical studies on the topic.
Future research is needed to validate proposed diagnostic criteria. Moreover clinical trials are warranted to assess the efficacy and safety of proposed medical therapies (i.e. antiviral therapies, immunosuppressive therapies) and their real impact on clinical outcomes. This research will better address the need for EBM specifically in clinical practice.

References



1. 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 Sep;34(33):2636-48. doi: 10.1093/eurheartj/eht210. Epub 2013 Jul 3.
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Notes to editor


Presented by: Massimo Imazio, MD, FESC
Department of Cardiology, Maria Vittoria Hospital Torino, Italy

Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Mogensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron P, Elliott PM.
Eur Heart J. 2013 Sep;34(33):2636-48. doi: 10.1093/eurheartj/eht210. Epub 2013 Jul 3.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.