HSM is a drug-mediated autoimmune reaction toward the cardiac muscle, characterized by signs and symptoms of hypersensitivity (skin rash, fever, eosinophilia, and malaise) and nonspecific ECG findings that may occur not necessarily early in the course of drug use (up to 2 years from initial drug assumption). Burke et al. analyzed postmortem histologic samples of patients with HSM to describe histologic findings, patterns of distribution of cellular infiltrates, drug associations, and clinical-histologic correlation [16]: HSM is defined by the infiltration of eosinophils, lymphocytes, and histiocytes in the absence of fibrosis or granulation tissue. Involvement of myocardium is often focal and may be missed in up to 50 % of EMB. The right ventricle (RV) was involved in the majority of patients. Cardiac arrhythmias or unexplained death occurred in 29 of 69 patients, and even worse prognosis was reported by Fenoglio et al. (20 sudden cardiac deaths in 24 patients) [17]. The differential diagnosis with GCM or necrotizing eosinophilic myocarditis can be made only by EMB, but it is crucial for possible treatment; therefore, accompanying symptoms should be carefully sought. Necrotizing eosinophilic myocarditis associated with the hypereosinophilic syndrome typically evolves over weeks to months, presenting with biventricular failure or arrhythmias, including sudden cardiac deaths (SCD). It has an exceptionally poor prognosis with most cases diagnosed at autopsy.

GCM is a rare form of autoimmune myocarditis, of unknown pathogenesis, characterized by fulminant course, and grave prognosis, despite best medical treatment. It was previously described only in postmortem samples or explanted hearts. More recently, a multicenter international registry described 63 patients who had a transplant-free survival of 5.5 months without immunosuppressive treatment [18]. Cooper et al. enrolled 11 patients with histologically confirmed GCM, reporting that treatment with steroids, cyclosporine, and monoclonal antilymphocyte antibodies improves long-term survival [19]. A relapse of the disease is described after acute discontinuation of treatment, confirming previously reported findings of histologic recurrence, in posttransplant follow-up EMB. It usually presents with acute deterioration in LVEF, ventricular arrhythmias, and heart block.

PP-CMP is rare dilative CMP of unknown etiology affecting women in the last month of pregnancy or within 5 months from delivery, although similar dilative CMP has been described also earlier in pregnancy. It presents with profound cardiogenic shock and major arrhythmias, in young healthy patients, without cardiac or extra-cardiac comorbidities. Although prone to spontaneous recovery, it may present with severe LV dysfunction, mandating prompt mechanical support, and, like acute myocarditis, progresses to dilative CMP, requiring VAD or heart transplantation, despite the best medical treatment. Maternal mortality rate reaches 25–50 %. In literature, several case reports advocate the use of ECMO to allow recovery or to bridge the patients to VAD or transplantation. We report Gavaert et al.’s work describing a 10-year experience with 6 patients affected by PP-CMP, all supported by IABP, 1 by ECMO, 4 implanted with an LVAD, 2 of which were transplanted, and the last being still on list at time of publication. EMB were performed in 2 patients at the time of VAD implant [20].

Pheochromocytoma is a catecholamine-secreting tumor. It originates from the chromaffin cells in the adrenal medulla or in extra-adrenal paragangliomas. It presents with a variety of symptoms, but although catecholamine-induced CMP is a well-known entity, it presents usually with more benign features and more rarely with unexplained or intractable cardiogenic shock due to paroxysmal release of catecholamines. Grinda et al. described the first case report of successful use of VAD to rescue catecholamine-induced CMP. Huang et al. reported a case series of 3 patients, rescued with venoarterial peripherally inserted ECMO, two of which were under CPR [21]. Literature offers several case reports of centrally [22] and peripherally [23, 24] inserted ECMO and VAD [25]. Septostomy was performed in some cases to decompress the LV. Functional recovery usually occurs within the first few days allowing for further diagnosis and surgical treatment of underlying disease. Interestingly, Sheinberg et al. reported a Takotsubo (apical ballooning appearance of LV) in a pheochromocytoma, successfully rescued by venoarterial ECMO and IABP [23].

Andes virus, Bayou virus, Black Creek Canal virus, Choclo virus, Juquitiba virus, Laguna Negra virus, and Sin Nombre virus, first isolated in the Four Corners region of southwestern, USA, are the etiologic agents of an acute cardiac and respiratory failure called Hantavirus cardiopulmonary syndrome (HCPS), causing deaths (43–76 % of patients) mostly due to multiorgan failure, secondary to intractable cardiogenic shock. Currently, no etiologic treatment is available, and therapy is primarily supportive. Wernly et al. report a two thirds survival and complete recovery of 51 HCPS patients with a predicted mortality of 100 % [26], rescued by venoarterial percutaneous femoral ECMO. Dietl et al reported 38 patients with severe HCPS with similar technique. ECMO had a mean duration of 132 h. Several reports are available in literature [27].

The extreme variability of histologic patterns (i.e., focality of infiltration vs. diffuse biventricular injury) together with innate immune response could significantly affect the presentation and course of the disease, accounting for a multiplicity of clinical patterns. The majority of patients present with a nonspecific prodrome, mostly confined to respiratory and/or gastrointestinal systems, subsequently progressing in overt although still aspecific cardiac involvement. Clinical features of myocarditis are summarized in Table 12.2. Myocarditis is a major cause of DCM, presenting with classical symptoms of heart failure (HF), with atrial and ventricular arrhythmias, usually manageable with standard of treatment. Conduction delay is more common with infiltrative and GCM than with lymphocytic. Myocarditis represents a cause of SCD without structural abnormalities in up to 20 % of cases [28, 29], in young subjects with little or no prodrome and regardless activity or rest. Only a minority of patients were reported to have SCD during physical or emotional stress [28]. Important to mention, even asymptomatic patients are at risk for SCD. Fulminant myocarditis is well characterized by viral prodrome, acute onset, severe cardiovascular compromise, and ventricular dysfunction that either resolves spontaneously or rapidly evolves to a fatal course. Acute myocarditis develops ventricular dysfunction that usually progresses toward DCM. Failure of standard of treatment for congestive HF, refractory arrhythmias, and cardiac arrest is therefore the major indication to LV mechanical support, to bridge the patient to full recovery, or to further support (heart transplantation or long-term support devices) in selected cases with otherwise extremely high mortality over the course of a few days.

As previously discussed, diagnostic process in myocarditis is complex and articulated. It is based on standard screening routine but also on specific biomarkers and invasive tests. The primary goals in approaching this disease are to select patients who will candidate for further testing; to reach a definitive diagnosis, but also to anticipate, compatibly with the clinical scenario which patients may require LV mechanical support; and possibly to estimate the best option and the likelihood of progression to intermediate-term assist devices and/or transplantation. A thorough discussion of available diagnostic tests and their role in myocarditis is beyond the aim of this chapter. Nonetheless, we will report the most relevant features, and we grouped diagnostic tests for each specific category, in the purpose to offer an extremely practical approach in more emergent situations (Table 12.1). Myocarditis requires a high index of suspicion and should be considered whenever a patient (primarily young males, with gastrointestinal and respiratory prodrome) presents with new onset of unexplained cardiovascular abnormalities. Valvular, congenital, ischemic, toxic (especially ethanol and cocaine related), and pulmonary heart disease should be carefully sought and excluded, before establishing a diagnosis of myocarditis. Concomitant symptoms, such as exanthematous disease, specific pathogen-related symptoms, co-existent pericarditis, or a triad of eosinophilia, rash, and exposure to either a new drug or vaccine, may reveal useful to further restrict differential diagnosis. Therefore, careful and thorough history and physical examination are essential and may help in selecting more focused testing. Some features of routine test may be helpful in suggesting myocarditis (Table 12.3), but they are usually non-conclusive.