**1. Introduction**

Myocarditis is defined by the ESC as an inflammatory disease of the myocardium diagnosed by established histological, immunological and immunohistochemical criteria. Histological criteria consist of histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of nonischemic origin while immunohistochemical criteria consist of ≥14 leucocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD3 positive T-lymphocytes ≥7 cells/mm2 [1].

The clinical presentation of myocarditis varies significantly. It can range from acute coronary syndrome-like to acute or chronic heart failure forms. Specifically, it may present as acute chest pain frequently associated with recent infections, as newonset heart failure (symptoms within 2 weeks to 3 months), as chronic heart failure (symptoms >3 months) or as a "life-threatening" – fulminant condition (refractory arrhythmias, cardiogenic shock). In general, acute coronary syndrome-like presentation has been associated with a better overall prognosis while heart failure is usually associated with a worse one, resulting in dilated cardiomyopathy or even death.

Diagnosis of acute myocarditis requires a workup consisting of both routine and specialized tests. ECG is usually abnormal in most cases, however, there are no specific signs. The most common findings are sinus tachycardia and repolarization abnormalities (either negative T waves or concave ST-T segment elevation as also seen in acute pericarditis) [1].

Unfortunately, there are no specific biomarkers for the diagnosis of myocarditis. Inflammatory markers are usually raised along with markers of myocardial injury (troponin, creatine kinase and its MB isoenzyme) and brain natriuretic peptides. Viral antibodies in the serum provide no information and may lead to an incorrect diagnosis. In general, only findings in myocardial tissue can be considered reliable with the exception of systemic diseases like hepatitis C, Lyme disease, HIV or rickettsial infections [1].

Echocardiography should always be performed in suspected myocarditis both for ruling out other cardiac diseases and for assessing ventricular function. In acute myocarditis, the findings may include regional wall motion abnormalities (usually beyond the supply area of coronary arteries), global ventricular dysfunction and/or pericardial effusion. Increased wall thickness may be observed most likely as a result of edema. Ventricular dilation is rare in the acute setting. While there are no specific signs seen through echocardiography, newer imaging techniques may provide some additional information since myocardial strain is most commonly affected in the inferolateral wall [2].

The exclusion of coronary artery disease should be performed in all patients suspected of myocarditis. This can be done through either classical or computed tomography coronary angiography.

The most important examination in myocarditis workup is the cardiac magnetic resonance (CMR) which provides information on both ventricular function and tissue characterization. In clinically stable patients, CMR can almost single-highhandedly confirm the diagnosis through the use of the updated Lake Louise criteria. These criteria require finding evidence of both myocardial edema (as seen through T2 mapping or T2-weighted images) and non-ischemic myocardial injury (as seen through T1 imaging, extracellular volume or late gadolinium enhancement) while supportive criteria include the presence of concomitant pericarditis or systolic left ventricular dysfunction [3]. For many years, the most commonly used criterion was the pattern of late gadolinium enhancement (LGE) which represent myocardial necrosis and fibrosis. In myocarditis, LGE is usually seen in the subepicardial and midmyocardial layers [4] and in the inferolateral wall [5]. Its presence in the anteroseptal wall is associated with a worse prognosis [6].

Despite the important role of CMR, diagnosis of myocarditis is confirmed through proposed criteria by a position statement of the European Society of Cardiology. A combination of at least 1 clinical and 1 para-clinical criteria is necessary or at least 2 para-clinical criteria in the case of asymptomatic patients. Clinical

#### *Extracorporeal Membrane Oxygenation for the Support of Adults with Acute Myocarditis DOI: http://dx.doi.org/10.5772/intechopen.109313*

criteria include: (i) acute chest pain; (ii) new-onset or chronic heart failure symptoms; (iii) palpitation, unexplained arrhythmias or syncope and (iv) unexplained cardiogenic shock. Para-clinical criteria include: (i) ECG findings such as repolarization abnormalities, atrio-ventricular block, sinus tachycardia, frequent premature ventricular complexes etc.; (ii) elevated levels of troponin; (iii) functional and structural abnormalities on cardiac imaging and (iv) consistent findings through tissue characterization by CMR [1].

Treatment of myocarditis is consistent with heart failure treatment in hemodynamically stable patients. B-blockers and ACE inhibitors have been the mainstay of therapy for many decades with good results. The addition of mineralocorticoid receptor antagonists (MRAs) can be considered in cases of persistent left ventricular dysfunction. Newer treatments such as angiotensin receptor neprilysin inhibitors (ARNIs) or sodium-glucose co-transporter 2 inhibitors (SGLT2-i) have not been examined in myocarditis patients apart from animal studies [7, 8] but may prove useful in the future. Finally, device treatment such as ICD implantation is important in case of recurrent ventricular arrhythmias, aborted sudden cardiac death (as secondary prevention) or persistent ventricular dysfunction (as primary prevention). However, ICD implantation should be avoided in the acute setting, since arrhythmias may be ameliorated. In the above-mentioned cases of secondary prevention, wearable ICDs may be of use and the decision for permanent ICD implantation can take place during the follow-up [9]. More specialized myocarditis treatment (immunosuppressive treatment and mechanical circulatory support) will be further analyzed below.

This chapter will be mostly focused on fulminant variations since those generally have an indication for extracorporeal life support. Fulminant myocarditis requires urgent management and a quick referral to tertiary expert centers for advanced heart failure therapies. Due to its urgency, the diagnostic work-up should happen simultaneously with management. As a result, the first step usually includes imaging of the coronary arteries to exclude the possibility of the acute coronary syndrome. Management should include support of the respiratory system – usually requiring the use of either non-invasive or invasive ventilation – and circulatory support – requiring the use of inotropes or mechanical circulatory support in later stages [10].

While in less severe forms, diagnosis of myocarditis is often made through CMR, patients presenting with fulminant myocarditis are in a too critical condition to undergo this examination [11]. The "gold standard" for myocarditis diagnosis has long been the endomyocardial biopsy (EMB) which can also provide information on the specific etiology of myocarditis in each patient. From a pathological standpoint, there are three main types of myocarditis: lymphocytic, eosinophilic and giant-cell while, as far as etiology is of concern, it can be viral or non-viral. The differentiation of which type of myocarditis one deals with, is necessary for providing etiology-specific treatment. Specifically, viral forms of myocarditis may benefit from virus-specific treatment [12] (e.g. acyclovir for HHV-6, interferon for enteroviruses, etc.) while non-viral forms may benefit from immunosuppression. Eosinophilic myocarditis benefits from corticosteroid administration while also treating the underlying cause of eosinophilia (parasitic infections, hematologic syndromes, etc.). Finally, giant cell myocarditis is the variation with the worse prognosis requiring combination immunosuppressive treatment and consideration for urgent ventricular assist device implantation or heart transplantation [13–15]. As a result, it comes as no surprise that the performance of EMB in fulminant myocarditis patients is associated with a better

prognosis [16, 17]. It should be noted that EMB may not necessarily reveal the proper etiology due to the absence of pathological findings from the sample site. In high clinical suspicion (especially in the case of giant-cell myocarditis), EMB should be repeated in order to acquire samples from different sites.

In cases where the patient's clinical condition rapidly deteriorates despite hemodynamic support, corticosteroids and even immunosuppression should be administered while awaiting biopsy results. Studies on both animal and human subjects have shown that corticosteroid administration has not been associated with exacerbation in the case of possible viral disease or worse overall prognosis in the case of fulminant myocarditis [18].

In critically ill patients with significantly reduced ejection fraction, inotrope administration may stabilize their clinical condition. However, the treating team should be ready to use mechanical circulatory support devices (intra-aortic balloon pump, percutaneous ventricular assist devices or extracorporeal membrane oxygenation).
